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How to useful site cite kamagra wholesale this article:Singh OP. The National Commission for Allied and Healthcare Professions Act, 2020 and its implication for mental health. Indian J Psychiatry 2021;63:119-20The National Commission for Allied and Healthcare Professions Act, 2020 has kamagra wholesale been notified on March 28, 2021, by the Gazette of India published by the Ministry of Law and Justice. This bill aims to “provide for regulation and maintenance of standards of education and services by allied and healthcare professionals, assessment of institutions, maintenance of a Central Register and State Register and creation of a system to improve access, research and development and adoption of latest scientific advancement and for matters connected therewith or incidental thereto.”[1]This act has created a category of Health Care Professionals which is defined as. €œhealthcare professional” includes a scientist, therapist, or other professional who studies, advises, researches, supervises or provides preventive, curative, rehabilitative, therapeutic or promotional health services and who has obtained any qualification of degree under this Act, the duration of which shall not be <3600 h spread over a period of 3 years to 6 years divided into specific semesters.[1]According to the act, “Allied health professional” includes an associate, technician, or technologist who is trained to perform any technical and practical task to support diagnosis and treatment of illness, disease, injury or impairment, and to support implementation of any healthcare treatment and referral plan recommended by a medical, nursing, or any other healthcare professional, and who has obtained any qualification of diploma or degree under this Act, the duration of which shall not be less than 2000 h spread over a period of 2 years to 4 years divided into specific semesters.”[1]It is noticeable that while the term “Health Care Professionals” does not include doctors who are registered under National Medical Council, Mental Health Care Act (MHCA), 2017 includes psychiatrists under the ambit of Mental Health Care Professionals.[2] This discrepancy needs to be corrected - psychiasts, being another group of medical specialists, kamagra wholesale should be kept out of the broad umbrella of “Mental Healthcare Professionals.”The category of Behavioural Health Sciences Professional has been included and defined as “a person who undertakes scientific study of the emotions, behaviours and biology relating to a person's mental well-being, their ability to function in everyday life and their concept of self.

€œBehavioural health” is the preferred term to “mental health” and includes professionals such as counselors, analysts, psychologists, educators and support workers, who provide counseling, therapy, and mediation services to individuals, families, groups, and communities in response to social and personal difficulties.”[1]This is a welcome step to the extent that it creates a diverse category of trained workforce in the field of Mental Health (Behavioural Health Science Professionals) and tries to regulate their training although it mainly aims to promote mental wellbeing. However there is kamagra wholesale a huge lacuna in the term of “Mental Illness” as defined by MHCA, 2017. Only severe disorders are included as per definition and there is no clarity regarding inclusion of other psychiatric disorders, namely “common mental disorders” such as anxiety and depression. This leaves a strong possibility of concept of “psychiatric illnesses” being limited to only “severe psychiatric disorders” (major psychoses) thus perpetuating the stigma and alienation associated with psychiatric kamagra wholesale patients for centuries. Psychiatrists being restricted to treating severe mental disorders as per MHCA, 2017, there is a strong possibility that the care of common mental disorders may gradually pass on under the care of “behavioural health professionals” as per the new act!.

There is need to look into this aspect by the leadership in psychiatry, both organizational and academic psychiatry, and kamagra wholesale reduce the contradictions between the MHCA, 2017 and this nascent act. All disorders classified in ICD 10 and DSM 5 should be classified as “Psychiatric Disorders” or “Mental Illness.” This will not only help in fighting the stigma associated with psychiatric illnesses but also promote the integration of psychiatry with other specialties. References 1.The National Commission kamagra wholesale for Allied and Healthcare Professions Act, 2021. The Gazette of India. Published by kamagra wholesale Ministry of Law and Justice.

28 March, 2021. 2.The Mental Healthcare Act, kamagra wholesale 2017. The Gazette of India. Published by Ministry of Law and Justice kamagra wholesale. April 7, 2017.

Correspondence Address:Om Prakash SinghAA 304, Ashabari Apartments, O/31, Baishnabghata, Patuli kamagra wholesale Township, Kolkata - 700 094, West Bengal IndiaSource of Support. None, Conflict of Interest. NoneDOI. 10.4103/indianjpsychiatry.indianjpsychiatry_268_21Abstract Thiamine kamagra wholesale is essential for the activity of several enzymes associated with energy metabolism in humans. Chronic alcohol use is associated with deficiency of thiamine along with other vitamins through several mechanisms.

Several neuropsychiatric kamagra wholesale syndromes have been associated with thiamine deficiency in the context of alcohol use disorder including Wernicke–Korsakoff syndrome, alcoholic cerebellar syndrome, alcoholic peripheral neuropathy, and possibly, Marchiafava–Bignami syndrome. High-dose thiamine replacement is suggested for these neuropsychiatric syndromes.Keywords. Alcohol use disorder, alcoholic kamagra wholesale cerebellar syndrome, alcoholic peripheral neuropathy, Marchiafava–Bignami syndrome, thiamine, Wernicke–Korsakoff syndromeHow to cite this article:Praharaj SK, Munoli RN, Shenoy S, Udupa ST, Thomas LS. High-dose thiamine strategy in Wernicke–Korsakoff syndrome and related thiamine deficiency conditions associated with alcohol use disorder. Indian J Psychiatry 2021;63:121-6How to cite kamagra wholesale this URL:Praharaj SK, Munoli RN, Shenoy S, Udupa ST, Thomas LS.

High-dose thiamine strategy in Wernicke–Korsakoff syndrome and related thiamine deficiency conditions associated with alcohol use disorder. Indian J Psychiatry [serial online] 2021 [cited 2021 May 19];63:121-6 kamagra wholesale. Available from. Https://www.indianjpsychiatry.org/text.asp?. 2021/63/2/121/313716 Introduction Thiamine is a water-soluble vitamin (B1) that plays a key role in the activity of several enzymes associated with energy metabolism.

Thiamine pyrophosphate (or diphosphate) is the active form that acts as a cofactor for enzymes. The daily dietary requirement of thiamine in adults is 1–2 mg and is dependent on carbohydrate intake.[1],[2] The requirement increases if basal metabolic rate is higher, for example, during alcohol withdrawal state. Dietary sources include pork (being the major source), meat, legume, vegetables, and enriched foods. The body can store between 30 and 50 mg of thiamine and is likely to get depleted within 4–6 weeks if the diet is deficient.[2] In those with alcohol-related liver damage, the ability to store thiamine is gradually reduced.[1],[2]Lower thiamine levels are found in 30%–80% of chronic alcohol users.[3] Thiamine deficiency occurs due to poor intake of vitamin-rich foods, impaired intestinal absorption, decreased storage capacity of liver, damage to the renal epithelial cells due to alcohol, leading to increased loss from the kidneys, and excessive loss associated with medical conditions.[2],[3] Furthermore, alcohol decreases the absorption of colonic bacterial thiamine, reduces the enzymatic activity of thiamine pyrophosphokinase, and thereby, reducing the amount of available thiamine pyrophosphate.[4] Since facilitated diffusion of thiamine into cells is dependent on a concentration gradient, reduced thiamine pyrophosphokinase activity further reduces thiamine uptake into cells.[4] Impaired utilization of thiamine is seen in certain conditions (e.g., hypomagnesemia) which are common in alcohol use disorder.[2],[3],[4] This narrative review discusses the neuropsychiatric syndromes associated with thiamine deficiency in the context of alcohol use disorder, and the treatment regimens advocated for these conditions. A PubMed search supplemented with manual search was used to identify neuropsychiatric syndromes related to thiamine deficiency in alcohol use disorder patients.

Neuropsychiatric Syndromes Associated With Thiamine Deficiency Wernicke–Korsakoff syndromeWernicke encephalopathy is associated with chronic alcohol use, and if not identified and treated early, could lead to permanent brain damage characterized by an amnestic syndrome known as Korsakoff syndrome. Inappropriate treatment of Wernicke encephalopathy with lower doses of thiamine can lead to high mortality rates (~20%) and Korsakoff syndrome in ~ 80% of patients (ranges from 56% to 84%).[5],[6] The classic triad of Wernicke includes oculomotor abnormalities, cerebellar dysfunction, and confusion. Wernicke lesions are found in 12.5% of brain samples of patients with alcohol dependence.[7] However, only 20%–30% of them had a clinical diagnosis of Wernicke encephalopathy antemortem. It has been found that many patients develop Wernicke–Korsakoff syndrome (WKS) following repeated subclinical episodes of thiamine deficiency.[7] In an autopsy report of 97 chronic alcohol users, only16% had all the three “classical signs,” 29% had two signs, 37% presented with one sign, and 19% had none.[8] Mental status changes are the most prevalent sign (seen in 82% of the cases), followed by eye signs (in 29%) and ataxia (23%).[8] WKS should be suspected in persons with a history of alcohol use and presenting with signs of ophthalmoplegia, ataxia, acute confusion, memory disturbance, unexplained hypotension, hypothermia, coma, or unconsciousness.[9] Operational criteria for the diagnosis of Wernicke encephalopathy have been proposed by Caine et al.[10] that requires two out of four features, i.e., (a) dietary deficiency (signs such as cheilitis, glossitis, and bleeding gums), (b) oculomotor abnormalities (nystagmus, opthalmoplegia, and diplopia), (c) cerebellar dysfunction (gait ataxia, nystagmus), and (d) either altered mental state (confusion) or mild memory impairment.As it is very difficult to clinically distinguish Wernicke encephalopathy from other associated conditions such as delirium tremens, hepatic encephalopathy, or head injury, it is prudent to have a lower threshold to diagnose this if any of the clinical signs is seen. Magnetic resonance imaging (MRI) brain scan during Wernicke encephalopathy shows mammillary body atrophy and enlarged third ventricle, lesions in the medial portions of thalami and mid brain and can be used to aid diagnosis.[11],[12] However, most clinical situations warrant treatment without waiting for neuroimaging report.

The treatment suggestions in the guidelines vary widely. Furthermore, hardly any evidence-based recommendations exist on a more general use of thiamine as a preventative intervention in individuals with alcohol use disorder.[13] There are very few studies that have evaluated the dose and duration of thiamine for WKS, but higher doses may result in a greater response.[6],[14] With thiamine administration rapid improvement is seen in eye movement abnormalities (improve within days or weeks) and ataxia (may take months to recover), but the effects on memory, in particular, are unclear.[4],[14] Severe memory impairment is the core feature of Korsakoff syndrome. Initial stages of the disease can present with confabulation, executive dysfunction, flattened affect, apathy, and poor insight.[15] Both the episodic and semantic memory are affected, whereas, procedural memory remains intact.[15]Thomson et al.[6] suggested the following should be treated with thiamine as they are at high risk for developing WKS. (1) all patients with any evidence of chronic alcohol misuse and any of the following. Acute confusion, decreased conscious level, ataxia, ophthalmoplegia, memory disturbance, and hypothermia with hypotension.

(2) patients with delirium tremens may often also have Wernicke encephalopathy, therefore, all of these patients should be presumed to have Wernicke encephalopathy and treated, preferably as inpatients. And (3) all hypoglycemic patients (who are treated with intravenous glucose) with evidence of chronic alcohol ingestion must be given intravenous thiamine immediately because of the risk of acutely precipitating Wernicke encephalopathy.Alcoholic cerebellar syndromeChronic alcohol use is associated with the degeneration of anterior superior vermis, leading to a clinical syndrome characterized by the subacute or chronic onset of gait ataxia and incoordination in legs, with relative sparing of upper limbs, speech, and oculomotor movements.[16] In severe cases, truncal ataxia, mild dysarthria, and incoordination of the upper limb is also found along with gait ataxia. Thiamine deficiency is considered to be the etiological factor,[17],[18] although direct toxic effects of alcohol may also contribute to this syndrome. One-third of patients with chronic use of alcohol have evidence of alcoholic cerebellar degeneration. However, population-based studies estimate prevalence to be 14.6%.[19] The effect of alcohol on the cerebellum is graded with the most severe deficits occurring in alcohol users with the longest duration and highest severity of use.

The diagnosis of cerebellar degeneration is largely clinical. MRI can be used to evaluate for vermian atrophy but is unnecessary.[20] Anterior portions of vermis are affected early, with involvement of posterior vermis and adjacent lateral hemispheres occurring late in the course could be used to differentiate alcoholic cerebellar degeneration from other conditions that cause more diffuse involvement.[21] The severity of cerebellar syndrome is more in the presence of WKS, thus could be related to thiamine deficiency.[22],[23] Therefore, this has been considered as a cerebellar presentation of WKS and should be treated in a similar way.[16] There are anecdotal evidence to suggest improvement in cerebellar syndrome with high-dose thiamine.[24]Alcoholic peripheral neuropathyPeripheral neuropathy is common in alcohol use disorder and is seen in 44% of the users.[25] It has been associated predominantly with thiamine deficiency. However, deficiency of other B vitamins (pyridoxine and cobalamin) and direct toxic effect of alcohol is also implicated.[26] Clinically, onset of symptoms is gradual with the involvement of both sensory and motor fibers and occasionally autonomic fibers. Neuropathy can affect both small and large peripheral nerve fibers, leading to different clinical manifestations. Thiamine deficiency-related neuropathy affects larger fiber types, which results in motor deficits and sensory ataxia.

On examination, large fiber involvement is manifested by distal limb muscle weakness and loss of proprioception and vibratory sensation. Together, these can contribute to the gait unsteadiness seen in chronic alcohol users by creating a superimposed steppage gait and reduced proprioceptive input back to the movement control loops in the central nervous system. The most common presentations include painful sensations in both lower limbs, sometimes with burning sensation or numbness, which are early symptoms. Typically, there is a loss of vibration sensation in distal lower limbs. Later symptoms include loss of proprioception, gait disturbance, and loss of reflexes.

Most advanced findings include weakness and muscle atrophy.[20] Progression is very gradual over months and involvement of upper limbs may occur late in the course. Diagnosis begins with laboratory evaluation to exclude other causes of distal, sensorimotor neuropathy including hemoglobin A1c, liver function tests, and complete blood count to evaluate for red blood cell macrocytosis. Cerebrospinal fluid studies may show increased protein levels but should otherwise be normal in cases of alcohol neuropathy and are not recommended in routine evaluation. Electromyography and nerve conduction studies can be used to distinguish whether the neuropathy is axonal or demyelinating and whether it is motor, sensory, or mixed type. Alcoholic neuropathy shows reduced distal, sensory amplitudes, and to a lesser extent, reduced motor amplitudes on nerve conduction studies.[20] Abstinence and vitamin supplementation including thiamine are the treatments advocated for this condition.[25] In mild-to-moderate cases, near-complete improvement can be achieved.[20] Randomized controlled trials have showed a significant improvement in alcoholic polyneuropathy with thiamine treatment.[27],[28]Marchiafava–Bignami syndromeThis is a rare but fatal condition seen in chronic alcohol users that is characterized by progressive demyelination and necrosis of the corpus callosum.

The association of this syndrome with thiamine deficiency is not very clear, and direct toxic effects of alcohol are also suggested.[29] The clinical syndrome is variable and presentation can be acute, subacute, or chronic. In acute forms, it is predominantly characterized by the altered mental state such as delirium, stupor, or coma.[30] Other clinical features in neuroimaging confirmed Marchiafava–Bignami syndrome (MBS) cases include impaired gait, dysarthria, mutism, signs of split-brain syndrome, pyramidal tract signs, primitive reflexes, rigidity, incontinence, gaze palsy, diplopia, and sensory symptoms.[30] Neuropsychiatric manifestations are common and include psychotic symptoms, depression, apathy, aggressive behavior, and sometimes dementia.[29] MRI scan shows lesions of the corpus callosum, particularly splenium. Treatment for this condition is mostly supportive and use of nutritional supplements and steroids. However, there are several reports of improvement of this syndrome with thiamine at variable doses including reports of beneficial effects with high-dose strategy.[29],[30],[31] Early initiation of thiamine, preferably within 2 weeks of the onset of symptoms is associated with a better outcome. Therefore, high-dose thiamine should be administered to all suspected cases of MBS.

Laboratory Diagnosis of Thiamine Deficiency Estimation of thiamine and thiamine pyrophosphate levels may confirm the diagnosis of deficiency. Levels of thiamine in the blood are not reliable indicators of thiamine status. Low erythrocyte transketolase activity is also helpful.[32],[33] Transketolase concentrations of <120 nmol/L have also been used to indicate deficiency, while concentrations of 120–150 nmol/L suggest marginal thiamine status.[1] However, these tests are not routinely performed as it is time consuming, expensive, and may not be readily available.[34] The ETKA assay is a functional test rather than a direct measurement of thiamin status and therefore may be influenced by factors other than thiamine deficiency such as diabetes mellitus and polyneuritis.[1] Hence, treatment should be initiated in the absence of laboratory confirmation of thiamine deficiency. Furthermore, treatment should not be delayed if tests are ordered, but the results are awaited. Electroencephalographic abnormalities in thiamine deficiency states range from diffuse mild-to-moderate slow waves and are not a good diagnostic option, as the prevalence of abnormalities among patients is inconsistent.[35]Surrogate markers, which reflect chronic alcohol use and nutritional deficiency other than thiamine, may be helpful in identifying at-risk patients.

This includes gamma glutamate transferase, aspartate aminotransferase. Alanine transaminase ratio >2:1, and increased mean corpuscular volume.[36] They are useful when a reliable history of alcohol use is not readily available, specifically in emergency departments when treatment needs to be started immediately to avoid long-term consequences. Thiamine Replacement Therapy Oral versus parenteral thiamineIntestinal absorption of thiamine depends on active transport through thiamine transporter 1 and 2, which follow saturation kinetics.[1] Therefore, the rate and amount of absorption of thiamine in healthy individuals is limited. In healthy volunteers, a 10 mg dose results in maximal absorption of thiamine, and any doses higher than this do not increase thiamine levels. Therefore, the maximum amount of thiamine absorbed from 10 mg or higher dose is between 4.3 and 5.6 mg.[37] However, it has been suggested that, although thiamine transport occurs through the energy-requiring, sodium-dependent active process at physiologic concentrations, at higher supraphysiologic concentrations thiamine uptake is mostly a passive process.[38] Smithline et al.

Have demonstrated that it is possible to achieve higher serum thiamine levels with oral doses up to 1500 mg.[39]In chronic alcohol users, intestinal absorption is impaired. Hence, absorption rates are expected to be much lower. It is approximately 30% of that seen in healthy individuals, i.e., 1.5 mg of thiamine is absorbed from 10 mg oral thiamine.[3] In those consuming alcohol and have poor nutrition, not more than 0.8 mg of thiamine is absorbed.[2],[3],[6] The daily thiamine requirement is 1–1.6 mg/day, which may be more in alcohol-dependent patients at risk for Wernicke encephalopathy.[1] It is highly likely that oral supplementation with thiamine will be inadequate in alcohol-dependent individuals who continue to drink. Therefore, parenteral thiamine is preferred for supplementation in deficiency states associated with chronic alcohol use. Therapy involving parenteral thiamine is considered safe except for occasional circumstances of allergic reactions involving pruritus and local irritation.There is a small, but definite risk of anaphylaxis with parenteral thiamine, specifically with intravenous administration (1/250,000 intravenous injections).[40] Diluting thiamine in 50–100 mg normal saline for infusion may reduce the risk.

However, parenteral thiamine should always be administered under observation with the necessary facilities for resuscitation.A further important issue involves the timing of administration of thiamine relative to the course of alcohol abuse or dependence. Administration of thiamine treatment to patients experiencing alcohol withdrawal may also be influenced by other factors such as magnesium depletion, N-methyl-D-aspartate (NMDA) receptor upregulation, or liver impairment, all of which may alter thiamine metabolism and utilization.[6],[14]Thiamine or other preparations (e.g., benfotiamine)The thiamine transporters limit the rate of absorption of orally administered thiamine. Allithiamines (e.g., benfotiamine) are the lipid-soluble thiamine derivatives that are absorbed better, result in higher thiamine levels, and are retained longer in the body.[41] The thiamine levels with orally administered benfotiamine are much higher than oral thiamine and almost equals to intravenous thiamine given at the same dosage.[42]Benfotiamine has other beneficial effects including inhibition of production of advanced glycation end products, thus protecting against diabetic vascular complications.[41] It also modulates nuclear transcription factor κB (NK-κB), vascular endothelial growth factor receptor 2, glycogen synthase kinase 3 β, etc., that play a role in cell repair and survival.[41] Benfotiamine has been found to be effective for the treatment of alcoholic peripheral neuropathy.[27]Dosing of thiamineAs the prevalence of thiamine deficiency is very common in chronic alcohol users, the requirement of thiamine increases in active drinkers and it is difficult to rapidly determine thiamine levels using laboratory tests, it is prudent that all patients irrespective of nutritional status should be administered parenteral thiamine. The dose should be 100 mg thiamine daily for 3–5 days during inpatient treatment. Commonly, multivitamin injections are added to intravenous infusions.

Patients at risk for thiamine deficiency should receive 250 mg of thiamine daily intramuscularly for 3–5 days, followed by oral thiamine 100 mg daily.[6]Thiamine plasma levels reduce to 20% of peak value after approximately 2 h of parenteral administration, thus reducing the effective “window period” for passive diffusion to the central nervous system.[6] Therefore, in thiamine deficient individuals with features of Wernicke encephalopathy should receive thiamine thrice daily.High-dose parenteral thiamine administered thrice daily has been advocated in patients at risk for Wernicke encephalopathy.[43] The Royal College of Physicians guideline recommends that patients with suspected Wernicke encephalopathy should receive 500 mg thiamine diluted in 50–100 ml of normal saline infusion over 30 min three times daily for 2–3 days and sometimes for longer periods.[13] If there are persistent symptoms such as confusion, cerebellar symptoms, or memory impairment, this regimen can be continued until the symptoms improve. If symptoms improve, oral thiamine 100 mg thrice daily can be continued for prolonged periods.[6],[40] A similar treatment regimen is advocated for alcoholic cerebellar degeneration as well. Doses more than 500 mg intramuscular or intravenous three times a day for 3–5 days, followed by 250 mg once daily for a further 3–5 days is also recommended by some guidelines (e.g., British Association for Psychopharmacology).[44]Other effects of thiamineThere are some data to suggest that thiamine deficiency can modulate alcohol consumption and may result in pathological drinking. Benfotiamine 600 mg/day as compared to placebo for 6 months was well tolerated and found to decrease psychiatric distress in males and reduce alcohol consumption in females with severe alcohol dependence.[45],[46] Other Factors During Thiamine Therapy Correction of hypomagnesemiaMagnesium is a cofactor for many thiamine-dependent enzymes in carbohydrate metabolism. Patients may fail to respond to thiamine supplementation in the presence of hypomagnesemia.[47] Magnesium deficiency is common in chronic alcohol users and is seen in 30% of individuals.[48],[49] It can occur because of increased renal excretion of magnesium, poor intake, decreased absorption because of Vitamin D deficiency, the formation of undissociated magnesium soaps with free fatty acids.[48],[49]The usual adult dose is 35–50 mmol of magnesium sulfate added to 1 L isotonic (saline) given over 12–24 h.[6] The dose has to be titrated against plasma magnesium levels.

It is recommended to reduce the dose in renal failure. Contraindications include patients with documented hypersensitivity and those with heart block, Addison's disease, myocardial damage, severe hepatitis, or hypophosphatemia. Do not administer intravenous magnesium unless hypomagnesemia is confirmed.[6]Other B-complex vitaminsMost patients with deficiency of thiamine will also have reduced levels of other B vitamins including niacin, pyridoxine, and cobalamin that require replenishment. For patients admitted to the intensive care unit with symptoms that may mimic or mask Wernicke encephalopathy, based on the published literature, routine supplementation during the 1st day of admission includes 200–500 mg intravenous thiamine every 8 h, 64 mg/kg magnesium sulfate (≈4–5 g for most adult patients), and 400–1000 μg intravenous folate.[50] If alcoholic ketoacidosis is suspected, dextrose-containing fluids are recommended over normal saline.[50] Precautions to be Taken When Administering Parenteral Thiamine It is recommended to monitor for anaphylaxis and has appropriate facilities for resuscitation and for treating anaphylaxis readily available including adrenaline and corticosteroids. Anaphylaxis has been reported at the rate of approximately 4/1 million pairs of ampoules of Pabrinex (a pair of high potency vitamins available in the UK containing 500 mg of thiamine (1:250,000 I/V administrations).[40] Intramuscular thiamine is reported to have a lower incidence of anaphylactic reactions than intravenous administration.[40] The reaction has been attributed to nonspecific histamine release.[51] Administer intravenous thiamine slowly, preferably by slow infusion in 100 ml normal saline over 15–30 min.

Conclusions Risk factors for thiamine deficiency should be assessed in chronic alcohol users. A high index of suspicion and a lower threshold to diagnose thiamine deficiency states including Wernicke encephalopathy is needed. Several other presentations such as cerebellar syndrome, MBS, polyneuropathy, and delirium tremens could be related to thiamine deficiency and should be treated with protocols similar to Wernicke encephalopathy. High-dose thiamine is recommended for the treatment of suspected Wernicke encephalopathy and related conditions [Figure 1]. However, evidence in terms of randomized controlled trials is lacking, and the recommendations are based on small studies and anecdotal reports.

Nevertheless, as all these conditions respond to thiamine supplementation, it is possible that these have overlapping pathophysiology and are better considered as Wernicke encephalopathy spectrum disorders.Figure 1. Thiamine recommendations for patients with alcohol use disorder. AHistory of alcohol use, but no clinical features of WE. BNo clinical features of WE, but with risk factors such as complicated withdrawal (delirium, seizures). CClinical features of WE (ataxia, opthalmoplegia, global confusion)Click here to viewFinancial support and sponsorshipNil.Conflicts of interestThere are no conflicts of interest.

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Clin Sci 1972;43:153-63. 38.Hoyumpa AM Jr., Strickland R, Sheehan JJ, Yarborough G, Nichols S. Dual system of intestinal thiamine transport in humans. J Lab Clin Med 1982;99:701-8. 39.Smithline HA, Donnino M, Greenblatt DJ.

Pharmacokinetics of high-dose oral thiamine hydrochloride in healthy subjects. BMC Clin Pharmacol 2012;12:4. 40.Latt N, Dore G. Thiamine in the treatment of Wernicke encephalopathy in patients with alcohol use disorders. Intern Med J 2014;44:911-5.

41.Raj V, Ojha S, Howarth FC, Belur PD, Subramanya SB. Therapeutic potential of benfotiamine and its molecular targets. Eur Rev Med Pharmacol Sci 2018;22:3261-73. 42.Xie F, Cheng Z, Li S, Liu X, Guo X, Yu P, et al. Pharmacokinetic study of benfotiamine and the bioavailability assessment compared to thiamine hydrochloride.

J Clin Pharmacol 2014;54:688-95. 43.Cook CC, Hallwood PM, Thomson AD. B Vitamin deficiency and neuropsychiatric syndromes in alcohol misuse. Alcohol Alcohol 1998;33:317-36. 44.Lingford-Hughes AR, Welch S, Peters L, Nutt DJ, British Association for Psychopharmacology, Expert Reviewers Group.

BAP updated guidelines. Evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity. Recommendations from BAP. J Psychopharmacol 2012;26:899-952. 45.Manzardo AM, He J, Poje A, Penick EC, Campbell J, Butler MG.

Double-blind, randomized placebo-controlled clinical trial of benfotiamine for severe alcohol dependence. Drug Alcohol Depend 2013;133:562-70. 46.Manzardo AM, Pendleton T, Poje A, Penick EC, Butler MG. Change in psychiatric symptomatology after benfotiamine treatment in males is related to lifetime alcoholism severity. Drug Alcohol Depend 2015;152:257-63.

47.Dingwall KM, Delima JF, Gent D, Batey RG. Hypomagnesaemia and its potential impact on thiamine utilisation in patients with alcohol misuse at the Alice Springs Hospital. Drug Alcohol Rev 2015;34:323-8. 48.Flink EB. Magnesium deficiency in alcoholism.

Alcohol Clin Exp Res 1986;10:590-4. 49.Grochowski C, Blicharska E, Baj J, Mierzwińska A, Brzozowska K, Forma A, et al. Serum iron, magnesium, copper, and manganese levels in alcoholism. A systematic review. Molecules 2019;24:E1361.

50.Flannery AH, Adkins DA, Cook AM. Unpeeling the evidence for the banana bag. Evidence-based recommendations for the management of alcohol-associated vitamin and electrolyte deficiencies in the ICU. Crit Care Med 2016;44:1545-52. 51.Lagunoff D, Martin TW, Read G.

Agents that release histamine from mast cells. Annu Rev Pharmacol Toxicol 1983;23:331-51. Correspondence Address:Samir Kumar PraharajDepartment of Psychiatry, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka IndiaSource of Support. None, Conflict of Interest. NoneDOI.

10.4103/psychiatry.IndianJPsychiatry_440_20 Figures [Figure 1].

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AbstractBrazil is currently home to the kamagra oral jelly how to use video largest Japanese population http://www.ec-neuwiller-saverne.ac-strasbourg.fr/informations-ecole/reglement-interieur/ outside of Japan. In Brazil today, Japanese-Brazilians are considered to be successful members of Brazilian society. This was not always the case, however, kamagra oral jelly how to use video and Japanese immigrants to Brazil endured much hardship to attain their current level of prestige. This essay explores this community’s trajectory towards the formation of the Japanese-Brazilian identity and the issues of mental health that arise in this immigrant community. Through the analysis of Japanese-Brazilian novels, TV shows, film and public health studies, I seek to disentangle the themes of gender and modernisation, and how these themes concurrently grapple with Japanese-Brazilian mental health issues.

These fictional narratives provide a lens into the experience of the Japanese-Brazilian community that is unavailable in traditional medical studies about their mental health.filmliterature and medicinemental health caregender studiesmedical humanitiesData availability statementData are available in a public, open access repository.Introduction and philosophical backgroundWork in the medical humanities has noted the importance of the ‘medical gaze’ and how it may ‘see’ kamagra oral jelly how to use video the patient in ways which are specific, while possessing broad significance, in relation to developing medical knowledge. To diagnosis. And to the social position of the medical profession.1 Some authors have emphasised that vision is a distinctive modality of perception which merits its own kamagra oral jelly how to use video consideration, and which may have a particular role to play in medical education and understanding.2 3 The clothing we wear has a strong impact on how we are perceived. For example, commentary in this journal on the ‘white coat’ observes that while it may rob the medical doctor of individuality, it nonetheless grants an elevated status4. In contrast, the patient hospital gown may rob patients of individuality in a way that stigmatises them,5 reducing their status in the ward, and ultimately dehumanises them, in conflict with the humanistic approaches seen as central to the best practice in the care of older patients, and particularly those living with dementia.6The broad context of our concern is the visibility of patients and their needs.

We draw on observations made during an ethnographic study of the everyday care of people living with dementia within acute hospital wards, to consider how patients’ clothing may impact on the way they were perceived by themselves kamagra oral jelly how to use video and by others. Hence, we draw on this ethnography to contribute to discussion of the ‘medical gaze’ in a specific and informative context.The acute setting illustrates a situation in which there are great many biomedical, technical, recording, and timetabled routine task-oriented demands, organised and delivered by different staff members, together with demands for care and attention to particular individuals and an awareness of their needs. Within this ward setting, we focus on patients who are living with dementia, since this group may be particularly vulnerable to a dehumanising gaze.6 We frame our discussion within the broader context of the general philosophical question of how we acquire knowledge of different types, and the moral consequences of this, particularly knowledge through visual perception.Debates throughout the history of philosophy raise questions about the nature and sources of our knowledge. Contrasts are often drawn between kamagra oral jelly how to use video more reliable or less reliable knowledge. And between knowledge that is more technical or ‘objective’, and knowledge that is more emotionally based or more ‘subjective’.

A frequent point of kamagra oral jelly how to use video discussion is the reliability and characteristics of perception as a source of knowledge. This epistemological discussion is mostly focused on vision, indicating its particular importance as a mode of perception to humans.7Likewise, in ethics, there is discussion of the origin of our moral knowledge and the particular role of perception.8 There is frequent recognition that the observer has some significant role in acquiring moral knowledge. Attention to qualities of the moral observer is not in itself a denial of moral reality. Indeed, it is the kamagra oral jelly how to use video very essence of an ethical response to the world to recognise the deep reality of others as separate persons. The nature of ethical attention to the world and to those around us is debated and has been articulated in various ways.

The quality of ethical attention may vary and achieving a high level of ethical attention may require certain conditions, certain virtues, and the time and mental space to attend to the situation and claims of the other.9Consideration has already been given to how different modes of attention to the world might be of relevance to the practice of medicine. Work that examines different ways of processing information, and of interacting with and being in the world, can be found in Iain McGilchrist’s The Master and His Emissary,10 where he draws on neurological discoveries and applies kamagra oral jelly how to use video his ideas to the development of human culture. McGilchrist has recently expanded on the relevance of understanding two different approaches to knowledge for the practice of medicine.11 He argues that task-oriented perception, and a wider, more emotionally attuned awareness of the environment are necessary partners, but may in some circumstances compete, with the competitive edge often being given to the narrower, task-based attention.There has been critique of McGilchrist’s arguments as well as much support. We find his work a useful framework for understanding important debates in the ethics of medicine and of nursing about relationships of kamagra oral jelly how to use video staff to patients. In particular, it helps to illuminate the consequences of patients’ dress and personal appearance for how they are seen and treated.Dementia and personal appearanceOur work focuses on patients living with dementia admitted to acute hospital wards.

Here, they are a large group, present alongside older patients unaffected by dementia, as well as younger patients. This mixed population provides a useful setting to consider the impact of personal appearance on different patient groups.The role of appearance in the presentation of kamagra oral jelly how to use video the self has been explored extensively by Tseëlon,12 13 drawing on Goffman’s work on stigma5 and the presentation of the self14 using interactionist approaches. Drawing on the experiences on women in the UK, Tseëlon argues Goffman’s interactionist approach best supports how we understand the relationship appearance plays in self presentation, and its relationships with other signs and interactions surrounding it. Tseëlon suggests that understandings in this area, in the role appearance and clothing have in the presentation of the self, have been restricted by the perceived trivialities of the topic and limited to the field of fashion studies.15The personal appearance of older patients, and patients living with dementia in particular, has, more recently, been shown to be worthy of attention and of particular significance. Older people are often assumed to be left out of fashion, yet a concern with appearance remains.16 17 Lack of attention to kamagra oral jelly how to use video clothing and to personal care may be one sign of the varied symptoms associated with cognitive impairment or dementia, and so conversely, attention to appearance is one way of combatting the stigma associated with dementia.

Families and carers may also feel the importance of personal appearance. The significant body of work by Twigg and Buse in kamagra oral jelly how to use video this field in particular draws attention to the role clothing has on preserving the identity and dignity or people living with dementia, while also constraining and enabling elements of care within long-term community settings.16–19 Within this paper, we examine the ways in which these phenomena can be even more acutely felt within the impersonal setting of the acute hospital.Work has also shown how people living with dementia strongly retain a felt, bodily appreciation for the importance of personal appearance. The comfort and sensuous feel of familiar clothing may remain, even after cognitive capacities such as the ability to recognise oneself in a mirror, or verbal fluency, are lost.18 More strongly still, Kontos,20–22 drawing on the work of Merleau-Ponty and of Bourdieu, has convincingly argued that this attention to clothing and personal appearance is an important aspect of the maintenance of a bodily sense of self, which is also socially mediated, in part via such attention to appearance. Our observations lend support to Kontos’ hypothesis.Much of this previous work has considered clothing in the everyday life of people living with dementia in the context of community or long-term residential care.18 Here, we look at the visual impact of clothing and appearance in the different setting of the hospital ward and consider the consequent implications for patient care. This setting enables us to consider how the short-term and unfamiliar environments of the acute ward, together with the contrast between personal and institutional attire, impact on the perception of the patient by self and by others.There is a body of literature that examines the work of restoring the appearance of residents within long-term community care settings, for instance Ward et al’s work that demonstrates the importance of hair and grooming as a key component of care.23 24 The work of Iltanen-Tähkävuori25 examines the usage of garments designed for long-term care kamagra oral jelly how to use video settings, exploring the conflict between clothing used to prevent undressing or facilitate the delivery of care, and the distress such clothing can cause, being powerfully symbolic of lower social status and associated with reduced autonomy.26 27Within this literature, there has also been a significant focus on the role of clothing, appearance and the tasks of personal care surrounding it, on the older female body.

A corpus of feminist literature has examined the ageing process and the use of clothing to conceal ageing, the presentation of a younger self, or a ‘certain’ age28 It argues that once the ability to conceal the ageing process through clothing and grooming has been lost, the aged person must instead conceal themselves, dressing to hide themselves and becoming invisible in the process.29 This paper will explore how institutional clothing within hospital wards affects both the male and female body, the presentation of the ageing body and its role in reinforcing the invisibility of older people, at a time when they are paradoxically most visible, unclothed and undressed, or wearing institutional clothing within the hospital ward.Institutional clothing is designed and used to fulfil a practical function. Its use may therefore perhaps incline us towards a ‘task-based’ mode of attention, which as McGilchrist argues,10 while having a vital place in our understanding of the world, may on occasion interfere with the forms of attention that may be needed to deliver good person-oriented care responsive to individual needs.MethodsEthnography involves the in-depth study of people’s actions and accounts within their natural everyday setting, collecting relatively unstructured data from a range of sources.30 Importantly, it can take into account the perspectives of patients, carers and hospital staff.31 Our approach to ethnography is informed by the symbolic interactionist research tradition, which aims to provide an interpretive understanding of the social world, with an emphasis on interaction, focusing on understanding how action and meaning are constructed within a setting.32 The value of this approach is the depth of understanding and theory generation it can provide.33The goal of ethnography is to identify social processes within the data. There are multiple complex and nuanced interactions within these clinical settings that are capable of ‘communicating many messages at once, even of subverting on one level what it appears to be “saying” on another’.34 kamagra oral jelly how to use video Thus, it is important to observe interaction and performance. How everyday care work is organised and delivered. By obtaining observational data from within each institution on the everyday work of hospital wards, their family carers and the nursing and healthcare assistants (HCAs) who carry out this work, we can explore the ways in which hospital organisation, procedures kamagra oral jelly how to use video and everyday care impact on care during a hospital admission.

It remedies a common weakness in many qualitative studies, that what people say in interviews may differ from what they do or their private justifications to others.35Data collection (observations and interviews) and analysis were informed by the analytic tradition of grounded theory.36 There was no prior hypothesis testing and we used the constant comparative method and theoretical sampling whereby data collection (observation and interview data) and analysis are inter-related,36 37 and are carried out concurrently.38 39 The flexible nature of this approach is important, because it can allow us to increase the ‘analytic incisiveness’35 of the study. Preliminary analysis of data collected from individual sites informed the focus of later stages of sampling, data collection and analysis in other sites.Thus, sampling requires a flexible, pragmatic approach and purposive and maximum variation sampling (theoretical sampling) was used. This included five hospitals selected kamagra oral jelly how to use video to represent a range of hospitals types, geographies and socioeconomic catchments. Five hospitals were purposefully selected to represent a range of hospitals types. Two large university teaching hospitals, two medium-sized general hospitals and one smaller general hospital.

This included one urban, two inner city and two kamagra oral jelly how to use video hospitals covering a mix of rural and suburban catchment areas, all situated within England and Wales.These sites represented a range of expertise and interventions in caring for people with dementia, from no formal expertise to the deployment of specialist dementia workers. Fractures, nutritional disorders, urinary tract and pneumonia40 41 are among the principal causes of admission to acute hospital settings among people with dementia. Thus, we focused observation within kamagra oral jelly how to use video trauma and orthopaedic wards (80 days) and medical assessment units (MAU. 75 days).Across these sites, 155 days of observational fieldwork were carried out. At each of the five sites, a minimum of 30 days observation took place, split between the two ward types.

Observations were carried out by two researchers, each working in clusters kamagra oral jelly how to use video of 2–4 days over a 6-week period at each site. A single day of observation could last a minimum of 2 hours and a maximum of 12 hours. A total of 684 hours of observation were conducted for this study. This produced approximately 600 000 words of observational fieldnotes that were transcribed, cleaned kamagra oral jelly how to use video and anonymised (by KF and AN). We also carried out ethnographic (during observation) interviews with trauma and orthopaedic ward (192 ethnographic interviews and 22 group interviews) and MAU (222 ethnographic interviews) staff (including nurses, HCAs, auxiliary and support staff and medical teams) as they cared for this patient group.

This allowed us to question what they are doing and why, and what are the caring practices of ward staff when interacting with people living with dementia.Patients within these settings with a diagnosis of kamagra oral jelly how to use video dementia were identified through ward nursing handover notes, patient records and board data with the assistance of ward staff. Following the provision of written and verbal information about the study, and the expression of willingness to take part, written consent was taken from patients, staff and visitors directly observed or spoken to as part of the study.To optimise the generalisability of our findings,42 our approach emphasises the importance of comparisons across sites,43 with theoretical saturation achieved following the search for negative cases, and on exploring a diverse and wide range of data. When no additional empirical data were found, we concluded that the analytical categories were saturated.36 44Grounded theory and ethnography are complementary traditions, with grounded theory strengthening the ethnographic aims of achieving a theoretical interpretation of the data, while the ethnographic approach prevents a rigid application of grounded theory.35 Using an ethnographic approach can mean that everything within a setting is treated as data, which can lead to large volumes of unconnected data and a descriptive analysis.45 This approach provides a middle ground in which the ethnographer, often seen as a passive observer of the social world, uses grounded theory to provide a systematic approach to data collection and analysis that can be used to develop theory to address the interpretive realities of participants within this setting.35Patient and public involvementThe data presented in this paper are drawn from a wider ethnographic study supported by an advisory group of people living with dementia and their family carers. It was this advisory group that informed us of the need of a better understanding of the kamagra oral jelly how to use video impacts of the everyday care received by people living with dementia in acute hospital settings. The authors met with this group on a regular basis throughout the study, and received guidance on both the design of the study and the format of written materials used to recruit participants to the study.

The external oversight group for this study included, and was chaired, by carers of people living with dementia. Once data analysis was complete, the advisory group commented on our initial kamagra oral jelly how to use video findings and recommendations. During and on completion of the analysis, a series of public consultation events were held with people living with dementia and family carers to ensure their involvement in discussing, informing and refining our analysis.FindingsWithin this paper, we focus on exploring the medical gaze through the embedded institutional cultures of patient clothing, and the implications this have for patients living with dementia within acute hospital wards. These findings emerged from our wider analysis of our ethnographic kamagra oral jelly how to use video study examining ward cultures of care and the experiences of people living with dementia. Here, we examine the ways in which the cultures of clothing within wards impact on the visibility of patients within it, what clothing and identity mean within the ward and the ways in which clothing can be a source of distress.

We will look at how personal grooming and appearance can affect status within the ward, and finally explore the removal of clothing, and the impacts of its absence.Ward clothing culturesAcross our sites, there was variation in the cultures of patient clothing and dress. Within many wards, it kamagra oral jelly how to use video was typical for all older patients to be dressed in hospital-issued institutional gowns and pyjamas (typically in pastel blue, pink, green or peach), paired with hospital supplied socks (usually bright red, although there was some small variation) with non-slip grip soles, while in other wards, it was standard practice for people to be supported to dress in their own clothes. Across all these wards, we observed that younger patients (middle aged/working age) were more likely to be able to wear their own clothes while admitted to a ward, than older patients and those with a dementia diagnosis.Among key signifiers of social status and individuality are the material things around the person, which in these hospital wards included the accoutrements around the bedside. Significantly, it was observed that people living with dementia were more likely to be wearing an institutional hospital gown or institutional pyjamas, and to have little to individuate the person at the bedside, on either their cabinet or the mobile tray table at their bedside. The wearing of institutional clothing was typically connected to fewer personal items on display or within reach of the patient, with any items kamagra oral jelly how to use video tidied away out of sight.

In contrast, younger working age patients often had many personal belongings, cards, gadgets, books, media players, with young adults also often having a range of ‘get well soon’ gifts, balloons and so on from the hospital gift shop) on display. This both afforded some elements of familiarity, but also marked the person out as someone with individuality and a certain social standing and place.Visibility of patients on a wardThe significance of the kamagra oral jelly how to use video obscurity or invisibility of the patient in artworks depicting doctors has been commented on.4 Likewise, we observed that some patients within these wards were much more ‘visible’ to staff than others. It was often apparent how the wearing of personal clothing could make the patient and their needs more readily visible to others as a person. This may be especially so given the contrast in appearance clothing may produce in this particular setting. On occasion, this may be remarked on by staff, and the resulting attention received kamagra oral jelly how to use video favourably by the patient.A member of the bay team returned to a patient and found her freshly dressed in a white tee shirt, navy slacks and black velvet slippers and exclaimed aloud and appreciatively, ‘Wow, look at you!.

€™ The patient looked pleased as she sat and combed her hair [site 3 day 1].Such a simple act of recognition as someone with a socially approved appearance takes on a special significance in the context of an acute hospital ward, and for patients living with dementia whose personhood may be overlooked in various ways.46This question of visibility of patients may also be particularly important when people living with dementia may be less able to make their needs and presence known. In this example, a whole bay of patients was seemingly ‘invisible’. Here, the ethnographer is observing a four-bed bay occupied by male patients living with dementia.The man in bed 17 is sitting in his bedside kamagra oral jelly how to use video chair. He is dressed in green hospital issue pyjamas and yellow grip socks. At 10 a.m., the physiotherapy kamagra oral jelly how to use video team come and see him.

The physiotherapist crouches down in front of him and asks him how he is. He says he is unhappy, and the physiotherapist explains that she’ll be back later to see him again. The nurse checks on him, asks him if he wants a pillow, and puts it behind his head explaining kamagra oral jelly how to use video to him, ‘You need to sit in the chair for a bit’. She pulls his bedside trolley near to him. With the help of a Healthcare Assistant they make the bed.

The Healthcare Assistant kamagra oral jelly how to use video chats to him, puts cake out for him, and puts a blanket over his legs. He is shaking slightly and I wonder if he is cold.The nurse explains to me, ‘The problem is this is a really unstimulating environment’, then says to the patient, ‘All done, let’s have a bit of a tidy up,’ before wheeling the equipment out.The neighbouring patient in bed 18, is now sitting in his bedside chair, wearing (his own) striped pyjamas. His eyes are open, and he kamagra oral jelly how to use video is looking around. After a while, he closes his eyes and dozes. The team chat to patient 19 behind the curtains.

He says he doesn’t want to sit, and they say that is fine unless the doctors tell them otherwise.The nurse puts music on an old radio with a CD player which is at the kamagra oral jelly how to use video doorway near the ward entrance. It sounds like music from a musical and the ward it is quite noisy suddenly. She turns down the volume a bit, but it is very jaunty and upbeat. The man kamagra oral jelly how to use video in bed 19 quietly sings along to the songs. €˜I am going to see my baby when I go home on victory day…’At ten thirty, the nurse goes off on her break.

The rest of the team are spread around the other bays and side kamagra oral jelly how to use video rooms. There are long distances between bays within this ward. After all the earlier activity it is now very calm and peaceful in the bay. Patient 20 is sitting kamagra oral jelly how to use video in the chair tapping his feet to the music. He has taken out a large hessian shopping bag out of his cabinet and is sorting through the contents.

There is a lot of paperwork in kamagra oral jelly how to use video it which he is reading through closely and sorting.Opposite, patient 17 looks very uncomfortable. He is sitting with two pillows behind his back but has slipped down the chair. His head is in his hands and he suddenly looks in pain. He hasn’t kamagra oral jelly how to use video touched his tea, and is talking to himself. The junior medic was aware that 17 was not comfortable, and it had looked like she was going to get some advice, but she hasn’t come back.

18 drinks his tea and looks at a wool twiddle mitt sleeve, puts it down, and dozes. 19 has finished all his coffee and manages to put the cup down on the trolley.Everyone is tapping their feet or wiggling their toes to the music, or singing quietly kamagra oral jelly how to use video to it, when a student nurse, who is working at the computer station in the corridor outside the room, comes in. She has a strong purposeful stride and looks irritated as she switches the music off. It feels like a jolt to the kamagra oral jelly how to use video room. She turns and looks at me and says, ‘Sorry were you listening to it?.

€™ I tell her that I think these gentlemen were listening to it.She suddenly looks very startled and surprised and looks at the men in the room for the first time. They have all stopped tapping their toes and kamagra oral jelly how to use video stopped singing along. She turns it back on but asks me if she can turn it down. She leaves and goes back to her paperwork outside. Once it is turned back on everyone starts tapping their kamagra oral jelly how to use video toes again.

The music plays on. €˜There’ll be bluebirds over the white cliffs of Dover, just you wait and see…’[Site 3 day 3]The music was played by staff to help combat the drab and unstimulating environment of this hospital ward for the patients, the very kamagra oral jelly how to use video people the ward is meant to serve. Yet for this member of ward staff the music was perceived as a nuisance, the men for whom the music was playing seemingly did not register to her awareness. Only an individual of ‘higher’ status, the researcher, sitting at the end of this room was visible to her. This example illustrates the general question of the visibility or otherwise of patients kamagra oral jelly how to use video.

Focusing on our immediate topic, there may be complex pathways through which clothing may impact on how patients living with dementia are perceived, and on their self-perception.Clothing and identityOn these wards, we also observed how important familiar aspects of appearance were to relatives. Family members may be distressed if they find the person they knew so well, looking markedly different. In the example below, a mother and two adult daughters visit the father of the family, who is not visible to them as the person they were so familiar kamagra oral jelly how to use video with. His is not wearing his glasses, which are missing, and his daughters find this very difficult. Even though he looks very different following his admission—he has lost a large amount of weight and has sunken cheekbones, and his skin has taken on a darker hue—it is his glasses which are a key concern for the family in their recognition of their father:As I enter the corridor to go back to the ward, I meet the wife and daughter of the patient in kamagra oral jelly how to use video bed 2 in the hall and walk with them back to the ward.

Their father looks very frail, his head is back, and his face is immobile, his eyes are closed, and his mouth is open. His skin looks darker than before, and his cheekbones and eye sockets are extremely prominent from weight loss. €˜I am like a bird I want to fly away…’ plays softly in the radio in kamagra oral jelly how to use video the bay. I sit with them for a bit and we chat—his wife holds his hand as we talk. His wife has to take two busses to get to the hospital and we talk about the potential care home they expect her husband will be discharged to.

They hope it will kamagra oral jelly how to use video be close because she does not drive. He isn’t wearing his glasses and his daughter tells me that they can’t find them. We look in the kamagra oral jelly how to use video bedside cabinet. She has never seen her dad without his glasses. €˜He doesn’t look like my dad without his glasses’ [Site 2 day 15].It was often these small aspects of personal clothing and grooming that prompted powerful responses from visiting family members.

Missing glasses kamagra oral jelly how to use video and missing teeth were notable in this regard (and with the follow-up visits from the relatives of discharged patients trying to retrieve these now lost objects). The location of these possessions, which could have a medical purpose in the case of glasses, dental prosthetics, hearing aids or accessories which contained personal and important aspects of a patient’s identity, such as wallets or keys, and particularly, for female patients, handbags, could be a prominent source of distress for individuals. These accessories to personal clothing were notable on these wards by their everyday absence, hidden away in bedside cupboards or simply not brought in with the patient at admission, and by the frequency with which patients requested and called out for them or tried to look for them, often in repetitive cycles that indicated their underlying anxiety about these belongings, but which would become invisible to staff, becoming an everyday background intrusion to the work of the wards.When considering the visibility and recognition of individual persons, missing glasses, especially glasses for distance vision, have a particular significance, for without them, a person may be less able to recognise and interact visually with others. Their presence facilitates the kamagra oral jelly how to use video subject of the gaze, in gazing back, and hence helps to ground meaningful and reciprocal relationships of recognition. This may be one factor behind the distress of relatives in finding their loved ones’ glasses to be absent.Clothing as a source of distressAcross all sites, we observed patients living with dementia who exhibited obvious distress at aspects of their institutional apparel and at the absence of their own personal clothing.

Some older patients were clearly able to verbalise their understandings of the impacts kamagra oral jelly how to use video of wearing institutional clothing. One patient remarked to a nurse of her hospital blue tracksuit. €˜I look like an Olympian or Wentworth prison in this outfit!. The latter I expect…’ The staff laughed as they walked her out of the bay (site 3 day 1).Institutional clothing may be kamagra oral jelly how to use video a source of distress to patients, although they may be unable to express this verbally. Kontos has shown how people living with dementia may retain an awareness at a bodily level of the demands of etiquette.20 Likewise, in our study, a man living with dementia, wearing a very large institutional pyjama top, which had no collar and a very low V neck, continually tried to pull it up to cover his chest.

The neckline was particularly low, because the pyjamas were far too large for him. He continued to fiddle with his kamagra oral jelly how to use video very low-necked top even when his lunch tray was placed in front of him. He clearly felt very uncomfortable with such clothing. He continued using his hands to try to pull it up to cover his exposed chest, during and after the meal was finished (site 3 day 5).For some patients, kamagra oral jelly how to use video the communication of this distress in relation to clothing may be liable to misinterpretation and may have further impacts on how they are viewed within the ward. Here, a patient living with dementia recently admitted to this ward became tearful and upset after having a shower.

She had no fresh clothes, and so the team had provided her with a pink hospital gown to wear.‘I want my trousers, where is my bra, I’ve got no bra on.’ It is clear she doesn’t feel right without her own clothes on. The one-to-one healthcare assistant assigned to this patient tells her, ‘Your bra is dirty, do you want kamagra oral jelly how to use video to wear that?. €™ She replies, ‘No I want a clean one. Where are my trousers?. I want them, I’ve lost kamagra oral jelly how to use video them.’ The healthcare assistant repeats the explaination that her clothes are dirty, and asks her, ‘Do you want your dirty ones?.

€™ She is very teary ‘No, I want my clean ones.’ The carer again explains that they are dirty.The cleaner who always works in the ward arrives to clean the floor and sweeps around the patient as she sits in her chair, and as he does this, he says ‘Hello’ to her. She is kamagra oral jelly how to use video very teary and explains that she has lost her clothes. The cleaner listens sympathetically as she continues ‘I am all confused. I have lost my clothes. I am kamagra oral jelly how to use video all confused.

How am I going to go to the shops with no clothes on!. €™ (site 5 day 5).This person experienced significant distress because of her absent clothes, but this would often be simply attributed to confusion, seen as a feature of her dementia. This then may solidify staff perceptions of her kamagra oral jelly how to use video condition. However, we need to consider that rather than her condition (her diagnosis of dementia) causing distress about clothing, the direction of causation may be the reverse. The absence of her own familiar clothing kamagra oral jelly how to use video contributes significantly to her distress and disorientation.

Others have argued that people with limited verbal capacity and limited cognitive comprehension will have a direct appreciation of the grounding familiarity of wearing their own clothes, which give a bodily felt notion of comfort and familiarity.18 47 Familiar clothing may then be an essential prop to anchor the wearer within a recognisable social and meaningful space. To simply see clothing from a task-oriented point of view, as fulfilling a simply mechanical function, and that all clothing, whether personal or institutional have the same value and role, might be to interpret the desire to wear familiar clothing as an ‘optional extra’. However, for those patients most at risk of disorientation and distress within an unfamiliar environment, it could be a valuable necessity.Personal grooming and social statusIncluding in our consideration of clothing, we observed other aspects kamagra oral jelly how to use video of the role of personal grooming. Personal grooming was notable by its absence beyond the necessary cleaning required for reasons of immediate hygiene and clinical need (such as the prevention of pressure ulcers). Older patients, and particular those living with dementia who were unable to carry out ‘self-care’ independently and were not able to request support with personal grooming, could, over their admission, become visibly unkempt and scruffy, hair could be left unwashed, uncombed and unstyled, while men could become hirsute through a lack of shaving.

The simple act of a visitor dressing and grooming a patient as they prepared for discharge could transform their appearance and leave that patient looking more alert, appear to having increased capacity, than when sitting ungroomed in their bed or bedside chair.It is important to consider the impact of appearance and of personal care in kamagra oral jelly how to use video the context of an acute ward. Kontos’ work examining life in a care home, referred to earlier, noted that people living with dementia may be acutely aware of transgressions in grooming and appearance, and noted many acts of self-care with personal appearance, such as stopping to apply lipstick, and conformity with high standards of table manners. Clothing, etiquette and personal grooming are important indicators kamagra oral jelly how to use video of social class and hence an aspect of belonging and identity, and of how an individual relates to a wider group. In Kontos’ findings, these rituals and standards of appearance were also observed in negative reactions, such as expressions of disgust, towards those residents who breached these standards. Hence, even in cases where an individual may be assessed as having considerable cognitive impairment, the importance of personal appearance must not be overlooked.For some patients within these wards, routine practices of everyday care at the bedside can increase the potential to influence whether they feel and appear socially acceptable.

The delivery of routine timetabled kamagra oral jelly how to use video care at the bedside can impact on people’s appearance in ways that may mark them out as failing to achieve accepted standards of embodied personhood. The task-oriented timetabling of mealtimes may have significance. It was a typical observed feature of this routine, when a mealtime has ended, that people living with dementia were left with visible signs and features of the mealtime through spillages on faces, clothes, bed sheets and bedsides, that leave them at risk of being assessed as less socially acceptable and marked as having reduced independence. For example, kamagra oral jelly how to use video a volunteer attempts to ‘feed’ a person living with dementia, when she gives up and leave the bedside (this woman living with dementia has resisted her attempts and explicitly says ‘no’), remnants of the food is left spread around her mouth (site E). In a different ward, the mealtime has ended, yet a large white plastic bib to prevent food spillages remains attached around the neck of a person living with dementia who is unable to remove it (site X).Of note, an adult would not normally wear a white plastic bib at home or in a restaurant.

It signifies a task-based apparel that is demeaning to an individual’s kamagra oral jelly how to use video social status. This example also contrasts poignantly with examples from Kontos’ work,20 such as that of a female who had little or no ability to verbalise, but who nonetheless would routinely take her pearl necklace out from under her bib at mealtimes, showing she retained an acute awareness of her own appearance and the ‘right’ way to display this symbol of individuality, femininity and status. Likewise, Kontos gives the example of a resident who at mealtimes ‘placed her hand on her chest, to prevent her blouse from touching the food as she leaned over her plate’.20Patients who are less robust, who have cognitive impairments, who may be liable to disorientation and whose agency and personhood are most vulnerable are thus those for whom appropriate and familiar clothing may be most advantageous. However, we kamagra oral jelly how to use video found the ‘Matthew effect’ to be frequently in operation. To those who have the least, even that which they have will be taken away.48 Although there may be institutional and organisational rationales for putting a plastic cover over a patient, leaving it on for an extended period following a meal may act as a marker of dehumanising loss of social status.

By being able to maintain familiar clothing and adornment to visually display social standing and identity, a person living with dementia may maintain a continuity of selfhood.However, it is also possible that dressing and grooming an older person may itself be a task-oriented institutional activity in certain contexts, as discussed by Lee-Treweek49 in the context of a nursing home preparing residents for ‘lounge view’ where visitors would see them, using residents to ‘create a visual product for others’ sometimes to the detriment of residents’ needs. Our observations regarding the importance of patient appearance must therefore be considered as part of the care of the whole person and a significant feature of the institutional culture.Patient status and appearanceWithin these wards, a kamagra oral jelly how to use video new grouping of class could become imposed on patients. We understand class not simply as socioeconomic class but as an indicator of the strata of local social organisation to which an individual belongs. Those in the lowest classes may have limited kamagra oral jelly how to use video opportunities to participate in society, and we observed the ways in which this applied to the people living with dementia within these acute wards. The differential impact of clothing as signifiers of social status has also been observed in a comparison of the white coat and the patient gown.4 It has been argued that while these both may help to mask individuality, they have quite different effects on social status on a ward.

One might say that the white coat increases visibility as a person of standing and the attribution of agency, the patient gown diminishes both of these. (Within these kamagra oral jelly how to use video wards, although white coats were not to be found, the dress code of medical staff did make them stand out. For male doctors, for example, the uniform rarely strayed beyond chinos paired with a blue oxford button down shirt, sleeves rolled up, while women wore a wider range of smart casual office wear.) Likewise, we observed that the same arrangement of attire could be attributed to entirely different meanings for older patients with or without dementia.Removal of clothes and exposureWithin these wards, we observed high levels of behaviour perceived by ward staff as people living with dementia displaying ‘resistance’ to care.50 This included ‘resistance’ towards institutional clothing. This could include pulling up or removing hospital gowns, removing institutional pyjama trousers or pulling up gowns, and standing with gowns untied and exposed at the back (although this last example is an unavoidable design feature of the clothing itself). Importantly, the removal of clothing was limited to institutional kamagra oral jelly how to use video gowns and pyjamas and we did not see any patients removing their own clothing.

This also included the removal of institutional bedding, with instances of patients pulling or kicking sheets from their bed. These acts could and was often interpreted by ward kamagra oral jelly how to use video staff as a patient’s ‘resistance’ to care. There was some variation in this interpretation. However, when an individual patient response to their institutional clothing and bedding was repeated during a shift, it was more likely to be conceived by the ward team as a form of resistance to their care, and responded to by the replacement and reinforcement of the clothing and bedding to recover the person.The removal of gowns, pyjamas and bedsheets often resulted in a patient exposing their genitalia or continence products (continence pads could be visible as a large diaper or nappy or a pad visibly held in place by transparent net pants), and as such, was disruptive to the norms and highly visible to staff and other visitor to these wards. Notably, unlike other behaviours considered by staff to be disruptive or inappropriate within these wards such as shouting or crying out, the removal of bedsheets kamagra oral jelly how to use video and the subsequent bodily exposure would always be immediately corrected, the sheet replaced and the patient covered by either the nurse or HCA.

The act of removal was typically interpreted by ward staff as representing a feature of the person’s dementia and staff responses were framed as an issue of patient dignity, or the dignity and embarrassment of other patients and visitors to the ward. However, such responses to removal could lead to further cycles of removal and replacement, leading to kamagra oral jelly how to use video an escalation of distress in the person. This was important, because the recording of ‘refusal of care’, or presumed ‘confusion’ associated with this, could have significant impacts on the care and discharge pathways available and prescribed for the individual patient.Consider the case of a woman living with dementia who is 90 years old (patient 1), in the example below. Despite having no immediate medical needs, she has been admitted to the MAU from a care home (following her husband’s stroke, he could no longer care for her). Across the kamagra oral jelly how to use video previous evening and morning shift, she was shouting, refusing all food and care and has received assistance from the specialist dementia care worker.

However, during this shift, she has become calmer following a visit from her husband earlier in the day, has since eaten and requested drinks. Her care home would not readmit her, which meant she was not able to be discharged from the unit (an overflow unit due to a high number of admissions to the emergency department during a patch of exceptionally hot weather) until alternative arrangements could be made by social services.During our observations, she remains calm for the first 2 hours. When she does talk, she is very loud kamagra oral jelly how to use video and high pitched, but this is normal for her and not a sign of distress. For staff working on this bay, their attention is elsewhere, because of the other six patients on the unit, one is ‘on suicide watch’ and another is ‘refusing their medication’ (but does not have a diagnosis of dementia). At 15:10 patient 1 begins to remove kamagra oral jelly how to use video her sheets:15:10.

The unit seems chaotic today. Patient 1 has begun to loudly drum her fingers on the tray table. She still has not been brought more kamagra oral jelly how to use video milk, which she requested from the HCA an hour earlier. The bay that patient 1 is admitted to is a temporary overflow unit and as a result staff do not know where things are. 1 has moved her sheets off her legs, her bare knees peeking out over the top of piled sheets.15:15.

The nurse in charge says, ‘Hello,’ when kamagra oral jelly how to use video she walks past 1’s bed. 1 looks across and smiles back at her. The nurse in charge explains to her that she needs to shuffle up the kamagra oral jelly how to use video bed. 1 asks the nurse about her husband. The nurse reminds 1 that her husband was there this morning and that he is coming back tomorrow.

1 says that he hasn’t been and she does kamagra oral jelly how to use video not believe the nurse.15:25. I overhear the nurse in charge question, under her breath to herself, ‘Why 1 has been left on the unit?. €™ 1 has started asking for somebody to come and see her. The nurse in charge tells 1 that she needs to do some jobs first and kamagra oral jelly how to use video then will come and talk to her.15:30. 1 has once again kicked her sheets off of her legs.

A social worker comes onto the unit kamagra oral jelly how to use video. 1 shouts, ‘Excuse me’ to her. The social worker replies, ‘Sorry I’m not staff, I don’t work here’ and leaves the bay.15:40. 1 keeps kicking sheets off her kamagra oral jelly how to use video bed, otherwise the unit is quiet. She now whimpers whenever anyone passes her bed, which is whenever anyone comes through the unit’s door.

1 is the only elderly patient on the unit. Again, the nurse in charge is heard sympathizing that this is kamagra oral jelly how to use video not the right place for her.16:30. A doctor approaches 1, tells her that she is on her list of people to say hello to, she is quite friendly. 1 tells her that she has been here kamagra oral jelly how to use video for 3 days, (the rest is inaudible because of pitch). The doctor tries to cover 1 up, raising her bed sheet back over the bed, but 1 loudly refuses this.

The doctor responds by ending the interaction, ‘See you later’, and leaves the unit.16:40. 1 attempts to talk to the new nurse assigned to the unit kamagra oral jelly how to use video. She goes over to 1 and says, ‘What’s up my darling?. €™ It’s hard to follow 1 now as she sounds very upset. The RN’s first instinct, like with the doctor and the nurse kamagra oral jelly how to use video in charge, is to cover up 1 s legs with her bed sheet.

When 1 reacts to this she talks to her and they agree to cover up her knees. 1 is talking kamagra oral jelly how to use video about how her husband won’t come and visit her, and still sounds really upset about this. [Site 3, Day 13]Of note is that between days 6 and 15 at this site, observed over a particularly warm summer, this unit was uncomfortably hot and stuffy. The need to be uncovered could be viewed as a reasonable response, and in fact was considered acceptable for patients without a classification of dementia, provided they were otherwise clothed, such as the hospital gown patient 1 was wearing. This is an example of an aspect of care where the choice and autonomy granted to patients assessed as having (or assumed to have) cognitive capacity is not available to people who are considered to have impaired cognitive capacity (a diagnosis of dementia) and kamagra oral jelly how to use video carries the additional moral judgements of the appropriateness of behaviour and bodily exposure.

In the example given above, the actions were linked to the patient’s resistance to their admission to the hospital, driven by her desire to return home and to be with her husband. Throughout observations over this 10-day period, patients perceived by staff as rational agents were allowed to strip down their bedding for comfort, whereas patients living with dementia who responded in this way were often viewed by staff as ‘undressing’, which would be interpreted as a feature of their condition, to be challenged and corrected by staff.Note how the same visual data triggered opposing interpretations of personal autonomy. Just as in the example above where distress over loss of familiar clothing may be interpreted as an aspect of confusion, yet lead to, or exacerbate, distress and kamagra oral jelly how to use video disorientation. So ‘deviant’ bedding may be interpreted, for some patients only, in ways that solidify notions of lack of agency and confusion, is another example of the Matthew effect48 at work through the organisational expectations of the clothed appearance of patients.Within wards, it is not unusual to see patients, especially those with a diagnosis of dementia or http://www.em-petits-matelots-offendorf.ac-strasbourg.fr/wp/?p=371 cognitive impairment, walking in the corridor inadvertently in some state of undress, typically exposed from behind by their hospital gowns. This exposure in itself is of course, an intrinsic functional kamagra oral jelly how to use video feature of the design of the flimsy back-opening institutional clothing the patient has been placed in.

This task-based clothing does not even fulfil this basic function very adequately. However, this inadvertent exposure could often be interpreted as an overt act of resistance to the ward and towards staff, especially when it led to exposed genitalia or continence products (pads or nappies).We speculate that the interpretation of resistance may be triggered by the visual prompt of disarrayed clothing and the meanings assumed to follow, where lack of decorum in attire is interpreted as indicating more general behavioural incompetence, cognitive impairment and/or standing outside the social order.DiscussionPrevious studies examining the significance of the visual, particularly Twigg and Buse’s work16–19 exploring the materialities of appearance, emphasise its key role in self-presentation, visibility, dignity and autonomy for older people and especially those living with dementia in care home settings. Similarly, care home studies have demonstrated that institutional clothing, designed to facilitate task-based care, can be potentially dehumanising or and distressing.25 26 Our findings resonate with this work, but find that for people living with dementia within a key site of care, the acute ward, the impact of institutional clothing on the individual patient living with dementia, is poorly recognised, but is significant kamagra oral jelly how to use video for the quality and humanity of their care.Our ethnographic approach enabled the researchers to observe the organisation and delivery of task-oriented fast-paced nature of the work of the ward and bedside care. Nonetheless, it should also be emphasised the instances in which staff such as HCAs and specialist dementia staff within these wards took time to take note of personal appearance and physical caring for patients and how important this can be for overall well-being. None of our observations should be read as critical of any individual staff, but reflects longstanding institutional cultures.Our previous work has examined how readily a person living with dementia within a hospital wards is vulnerable to dehumanisation,51 and to their behaviour within these wards being interpreted as a feature of their condition, rather than a response to the ways in which timetabled care is delivered at their bedside.50 We have also examined the ways in which visual stimuli within these wards in the form of signs and symbols indicating a diagnosis of dementia may inadvertently focus attention away from the individual patient and may incline towards simplified and inaccurate categorisation of both needs and the diagnostic category of dementia.52Our work supports the analysis of the two forms of attention arising from McGilchrist’s work.10 The institutional culture of the wards produces an organisational task-based technical attention, which we found appeared to compete with and reduce the opportunity for ward staff to seek a finer emotional attunement to the person they are caring for and their needs.

Focus on efficiency, pace and kamagra oral jelly how to use video record keeping that measures individual task completion within a timetable of care may worsen all these effects. Indeed, other work has shown that in some contexts, attention to visual appearance may itself be little more than a ‘task’ to achieve.49 McGilchrist makes clear, and we agree, that both forms of attention are vital, but more needs to be done to enable staff to find a balance.Previous work has shown how important appearance is to older people, and to people living with dementia in particular, both in terms of how they are perceived by others, but also how for this group, people living with dementia, clothing and personal grooming may act as a particularly important anchor into a familiar social world. These twin aspects of clothing and appearance—self-perception and perception by others—may be especially important in the fast-paced context of an acute ward environment, where patients living with dementia may be struggling with the impacts of an additional acute kamagra oral jelly how to use video medical condition within in a highly timetabled and regimented and unfamiliar environment of the ward, and where staff perceptions of them may feed into clinical assessments of their condition and subsequent treatment and discharge pathways. We have seen above, for instance, how behaviour in relation to appearance may be seen as ‘resisting care’ in one group of patients, but as the natural expression of personal preference in patients viewed as being without cognitive impairments. Likewise, personal grooming might impact favourably on a patient’s alertness, visibility and status within the ward.Prior work has demonstrated the importance of the medical gaze for the perceptions of the patient.

Other work has also shown how older people, and in particular people living with dementia, may be thought to be beyond concern for appearance, yet this does not kamagra oral jelly how to use video accurately reflect the importance of appearance we found for this patient group. Indeed, we argue that our work, along with the work of others such as Kontos,20 21 shows that if anything, visual appearance is especially important for people living with dementia particularly within clinical settings. In considering the task of washing the patient, Pols53 considered ‘dignitas’ in terms of aesthetic values, in comparison to humanitas conceived as citizen values of equality between persons. Attention to kamagra oral jelly how to use video dignitas in the form of appearance may be a way of facilitating the treatment by others of a person with humanitas, and helping to realise dignity of patients.Data availability statementNo data are available. Data are unavailable to protect anonymity.Ethics statementsPatient consent for publicationNot required.Ethics approvalEthics committee approval for the study was granted by the NHS Research Ethics Service (15/WA/0191).AcknowledgmentsThe authors acknowledge funding support from the NIHR.Notes1.

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AbstractBrazil is my sources currently home to the largest Japanese population outside of Japan kamagra wholesale. In Brazil today, Japanese-Brazilians are considered to be successful members of Brazilian society. This was kamagra wholesale not always the case, however, and Japanese immigrants to Brazil endured much hardship to attain their current level of prestige. This essay explores this community’s trajectory towards the formation of the Japanese-Brazilian identity and the issues of mental health that arise in this immigrant community.

Through the analysis of Japanese-Brazilian novels, TV shows, film and public health studies, I seek to disentangle the themes of gender and modernisation, and how these themes concurrently grapple with Japanese-Brazilian mental health issues. These fictional narratives provide a lens into the experience of the Japanese-Brazilian community that is unavailable in kamagra wholesale traditional medical studies about their mental health.filmliterature and medicinemental health caregender studiesmedical humanitiesData availability statementData are available in a public, open access repository.Introduction and philosophical backgroundWork in the medical humanities has noted the importance of the ‘medical gaze’ and how it may ‘see’ the patient in ways which are specific, while possessing broad significance, in relation to developing medical knowledge. To diagnosis. And to the social position of the medical profession.1 Some authors have emphasised that vision is a distinctive modality of perception which merits kamagra wholesale its own consideration, and which may have a particular role to play in medical education and understanding.2 3 The clothing we wear has a strong impact on how we are perceived.

For example, commentary in this journal on the ‘white coat’ observes that while it may rob the medical doctor of individuality, it nonetheless grants an elevated status4. In contrast, the patient hospital gown may rob patients of individuality in a way that stigmatises them,5 reducing their status in the ward, and ultimately dehumanises them, in conflict with the humanistic approaches seen as central to the best practice in the care of older patients, and particularly those living with dementia.6The broad context of our concern is the visibility of patients and their needs. We draw on observations made during an ethnographic study of the everyday care of kamagra wholesale people living with dementia within acute hospital wards, to consider how patients’ clothing may impact on the way they were perceived by themselves and by others. Hence, we draw on this ethnography to contribute to discussion of the ‘medical gaze’ in a specific and informative context.The acute setting illustrates a situation in which there are great many biomedical, technical, recording, and timetabled routine task-oriented demands, organised and delivered by different staff members, together with demands for care and attention to particular individuals and an awareness of their needs.

Within this ward setting, we focus on patients who are living with dementia, since this group may be particularly vulnerable to a dehumanising gaze.6 We frame our discussion within the broader context of the general philosophical question of how we acquire knowledge of different types, and the moral consequences of this, particularly knowledge through visual perception.Debates throughout the history of philosophy raise questions about the nature and sources of our knowledge. Contrasts are often drawn between more reliable kamagra wholesale or less reliable knowledge. And between knowledge that is more technical or ‘objective’, and knowledge that is more emotionally based or more ‘subjective’. A frequent point of discussion is the kamagra wholesale reliability and characteristics of perception as a source of knowledge.

This epistemological discussion is mostly focused on vision, indicating its particular importance as a mode of perception to humans.7Likewise, in ethics, there is discussion of the origin of our moral knowledge and the particular role of perception.8 There is frequent recognition that the observer has some significant role in acquiring moral knowledge. Attention to qualities of the moral observer is not in itself a denial of moral reality. Indeed, it is the very essence of an ethical response to the world to recognise the deep kamagra wholesale reality of others as separate persons. The nature of ethical attention to the world and to those around us is debated and has been articulated in various ways.

The quality of ethical attention may vary and achieving a high level of ethical attention may require certain conditions, certain virtues, and the time and mental space to attend to the situation and claims of the other.9Consideration has already been given to how different modes of attention to the world might be of relevance to the practice of medicine. Work that examines different ways of processing information, and of interacting with and being in the world, can be found in Iain McGilchrist’s The Master kamagra wholesale and His Emissary,10 where he draws on neurological discoveries and applies his ideas to the development of human culture. McGilchrist has recently expanded on the relevance of understanding two different approaches to knowledge for the practice of medicine.11 He argues that task-oriented perception, and a wider, more emotionally attuned awareness of the environment are necessary partners, but may in some circumstances compete, with the competitive edge often being given to the narrower, task-based attention.There has been critique of McGilchrist’s arguments as well as much support. We find his work a useful framework for understanding important debates in the ethics of medicine kamagra wholesale and of nursing about relationships of staff to patients.

In particular, it helps to illuminate the consequences of patients’ dress and personal appearance for how they are seen and treated.Dementia and personal appearanceOur work focuses on patients living with dementia admitted to acute hospital wards. Here, they are a large group, present alongside older patients unaffected by dementia, as well as younger patients. This mixed population provides a useful setting to consider the impact of personal appearance on different patient groups.The role of appearance in the presentation of the self has been explored extensively by Tseëlon,12 13 drawing on Goffman’s kamagra wholesale work on stigma5 and the presentation of the self14 using interactionist approaches. Drawing on the experiences on women in the UK, Tseëlon argues Goffman’s interactionist approach best supports how we understand the relationship appearance plays in self presentation, and its relationships with other signs and interactions surrounding it.

Tseëlon suggests that understandings in this area, in the role appearance and clothing have in the presentation of the self, have been restricted by the perceived trivialities of the topic and limited to the field of fashion studies.15The personal appearance of older patients, and patients living with dementia in particular, has, more recently, been shown to be worthy of attention and of particular significance. Older people are often assumed to be left out of fashion, yet kamagra wholesale a concern with appearance remains.16 17 Lack of attention to clothing and to personal care may be one sign of the varied symptoms associated with cognitive impairment or dementia, and so conversely, attention to appearance is one way of combatting the stigma associated with dementia. Families and carers may also feel the importance of personal appearance. The significant kamagra wholesale body of work by Twigg and Buse in this field in particular draws attention to the role clothing has on preserving the identity and dignity or people living with dementia, while also constraining and enabling elements of care within long-term community settings.16–19 Within this paper, we examine the ways in which these phenomena can be even more acutely felt within the impersonal setting of the acute hospital.Work has also shown how people living with dementia strongly retain a felt, bodily appreciation for the importance of personal appearance.

The comfort and sensuous feel of familiar clothing may remain, even after cognitive capacities such as the ability to recognise oneself in a mirror, or verbal fluency, are lost.18 More strongly still, Kontos,20–22 drawing on the work of Merleau-Ponty and of Bourdieu, has convincingly argued that this attention to clothing and personal appearance is an important aspect of the maintenance of a bodily sense of self, which is also socially mediated, in part via such attention to appearance. Our observations lend support to Kontos’ hypothesis.Much of this previous work has considered clothing in the everyday life of people living with dementia in the context of community or long-term residential care.18 Here, we look at the visual impact of clothing and appearance in the different setting of the hospital ward and consider the consequent implications for patient care. This setting enables us to consider how the short-term and unfamiliar environments of the acute ward, together with the contrast between personal and institutional attire, impact on the perception of the patient by self and by others.There is a body of literature that examines the work of restoring the appearance of residents within long-term community care settings, for instance Ward et al’s work that demonstrates the importance of hair and grooming as a key component of care.23 24 The work of Iltanen-Tähkävuori25 examines the usage of garments designed for long-term care settings, exploring the conflict between clothing used to prevent undressing or facilitate the delivery of care, kamagra wholesale and the distress such clothing can cause, being powerfully symbolic of lower social status and associated with reduced autonomy.26 27Within this literature, there has also been a significant focus on the role of clothing, appearance and the tasks of personal care surrounding it, on the older female body. A corpus of feminist literature has examined the ageing process and the use of clothing to conceal ageing, the presentation of a younger self, or a ‘certain’ age28 It argues that once the ability to conceal the ageing process through clothing and grooming has been lost, the aged person must instead conceal themselves, dressing to hide themselves and becoming invisible in the process.29 This paper will explore how institutional clothing within hospital wards affects both the male and female body, the presentation of the ageing body and its role in reinforcing the invisibility of older people, at a time when they are paradoxically most visible, unclothed and undressed, or wearing institutional clothing within the hospital ward.Institutional clothing is designed and used to fulfil a practical function.

Its use may therefore perhaps incline us towards a ‘task-based’ mode of attention, which as McGilchrist argues,10 while having a vital place in our understanding of the world, may on occasion interfere with the forms of attention that may be needed to deliver good person-oriented care responsive to individual needs.MethodsEthnography involves the in-depth study of people’s actions and accounts within their natural everyday setting, collecting relatively unstructured data from a range of sources.30 Importantly, it can take into account the perspectives of patients, carers and hospital staff.31 Our approach to ethnography is informed by the symbolic interactionist research tradition, which aims to provide an interpretive understanding of the social world, with an emphasis on interaction, focusing on understanding how action and meaning are constructed within a setting.32 The value of this approach is the depth of understanding and theory generation it can provide.33The goal of ethnography is to identify social processes within the data. There are multiple complex and nuanced interactions within these clinical settings that are capable of ‘communicating many messages at once, even of subverting on one level what it appears to be “saying” on kamagra wholesale another’.34 Thus, it is important to observe interaction and performance. How everyday care work is organised and delivered. By obtaining observational data from within each institution on the everyday work of hospital wards, their family carers and the nursing and healthcare assistants (HCAs) who kamagra wholesale carry out this work, we can explore the ways in which hospital organisation, procedures and everyday care impact on care during a hospital admission.

It remedies a common weakness in many qualitative studies, that what people say in interviews may differ from what they do or their private justifications to others.35Data collection (observations and interviews) and analysis were informed by the analytic tradition of grounded theory.36 There was no prior hypothesis testing and we used the constant comparative method and theoretical sampling whereby data collection (observation and interview data) and analysis are inter-related,36 37 and are carried out concurrently.38 39 The flexible nature of this approach is important, because it can allow us to increase the ‘analytic incisiveness’35 of the study. Preliminary analysis of data collected from individual sites informed the focus of later stages of sampling, data collection and analysis in other sites.Thus, sampling requires a flexible, pragmatic approach and purposive and maximum variation sampling (theoretical sampling) was used. This included five hospitals selected to represent a range of hospitals types, geographies and socioeconomic kamagra wholesale catchments. Five hospitals were purposefully selected to represent a range of hospitals types.

Two large university teaching hospitals, two medium-sized general hospitals and one smaller general hospital. This included one urban, two inner city and two hospitals covering a mix of rural and suburban kamagra wholesale catchment areas, all situated within England and Wales.These sites represented a range of expertise and interventions in caring for people with dementia, from no formal expertise to the deployment of specialist dementia workers. Fractures, nutritional disorders, urinary tract and pneumonia40 41 are among the principal causes of admission to acute hospital settings among people with dementia. Thus, we kamagra wholesale focused observation within trauma and orthopaedic wards (80 days) and medical assessment units (MAU.

75 days).Across these sites, 155 days of observational fieldwork were carried out. At each of the five sites, a minimum of 30 days observation took place, split between the two ward types. Observations were carried out by two researchers, each working in clusters of 2–4 days over a kamagra wholesale 6-week period at each site. A single day of observation could last a minimum of 2 hours and a maximum of 12 hours.

A total of 684 hours of observation were conducted for this study. This produced approximately 600 000 words of observational fieldnotes that were transcribed, kamagra wholesale cleaned and anonymised (by KF and AN). We also carried out ethnographic (during observation) interviews with trauma and orthopaedic ward (192 ethnographic interviews and 22 group interviews) and MAU (222 ethnographic interviews) staff (including nurses, HCAs, auxiliary and support staff and medical teams) as they cared for this patient group. This allowed us to question what they are doing and why, and what are the caring practices of ward staff when interacting with people living with dementia.Patients within kamagra wholesale these settings with a diagnosis of dementia were identified through ward nursing handover notes, patient records and board data with the assistance of ward staff.

Following the provision of written and verbal information about the study, and the expression of willingness to take part, written consent was taken from patients, staff and visitors directly observed or spoken to as part of the study.To optimise the generalisability of our findings,42 our approach emphasises the importance of comparisons across sites,43 with theoretical saturation achieved following the search for negative cases, and on exploring a diverse and wide range of data. When no additional empirical data were found, we concluded that the analytical categories were saturated.36 44Grounded theory and ethnography are complementary traditions, with grounded theory strengthening the ethnographic aims of achieving a theoretical interpretation of the data, while the ethnographic approach prevents a rigid application of grounded theory.35 Using an ethnographic approach can mean that everything within a setting is treated as data, which can lead to large volumes of unconnected data and a descriptive analysis.45 This approach provides a middle ground in which the ethnographer, often seen as a passive observer of the social world, uses grounded theory to provide a systematic approach to data collection and analysis that can be used to develop theory to address the interpretive realities of participants within this setting.35Patient and public involvementThe data presented in this paper are drawn from a wider ethnographic study supported by an advisory group of people living with dementia and their family carers. It was this advisory group that informed us of the need of a better understanding of the impacts of the everyday kamagra wholesale care received by people living with dementia in acute hospital settings. The authors met with this group on a regular basis throughout the study, and received guidance on both the design of the study and the format of written materials used to recruit participants to the study.

The external oversight group for this study included, and was chaired, by carers of people living with dementia. Once data kamagra wholesale analysis was complete, the advisory group commented on our initial findings and recommendations. During and on completion of the analysis, a series of public consultation events were held with people living with dementia and family carers to ensure their involvement in discussing, informing and refining our analysis.FindingsWithin this paper, we focus on exploring the medical gaze through the embedded institutional cultures of patient clothing, and the implications this have for patients living with dementia within acute hospital wards. These findings emerged from our wider analysis of our ethnographic study examining ward cultures of care and the experiences of people living kamagra wholesale with dementia.

Here, we examine the ways in which the cultures of clothing within wards impact on the visibility of patients within it, what clothing and identity mean within the ward and the ways in which clothing can be a source of distress. We will look at how personal grooming and appearance can affect status within the ward, and finally explore the removal of clothing, and the impacts of its absence.Ward clothing culturesAcross our sites, there was variation in the cultures of patient clothing and dress. Within many wards, it was typical for all older patients to be dressed in hospital-issued institutional gowns and pyjamas (typically in pastel blue, pink, green or peach), paired with hospital supplied kamagra wholesale socks (usually bright red, although there was some small variation) with non-slip grip soles, while in other wards, it was standard practice for people to be supported to dress in their own clothes. Across all these wards, we observed that younger patients (middle aged/working age) were more likely to be able to wear their own clothes while admitted to a ward, than older patients and those with a dementia diagnosis.Among key signifiers of social status and individuality are the material things around the person, which in these hospital wards included the accoutrements around the bedside.

Significantly, it was observed that people living with dementia were more likely to be wearing an institutional hospital gown or institutional pyjamas, and to have little to individuate the person at the bedside, on either their cabinet or the mobile tray table at their bedside. The wearing of institutional clothing was typically connected to fewer personal items on display kamagra wholesale or within reach of the patient, with any items tidied away out of sight. In contrast, younger working age patients often had many personal belongings, cards, gadgets, books, media players, with young adults also often having a range of ‘get well soon’ gifts, balloons and so on from the hospital gift shop) on display. This both afforded some elements of familiarity, but also marked the person out as someone with individuality and a certain social standing and place.Visibility of patients on a wardThe significance kamagra wholesale of the obscurity or invisibility of the patient in artworks depicting doctors has been commented on.4 Likewise, we observed that some patients within these wards were much more ‘visible’ to staff than others.

It was often apparent how the wearing of personal clothing could make the patient and their needs more readily visible to others as a person. This may be especially so given the contrast in appearance clothing may produce in this particular setting. On occasion, this may be remarked on by staff, and the resulting attention received favourably by the patient.A member of the bay team returned to a patient and found her freshly dressed in a white tee shirt, navy slacks and black velvet slippers and exclaimed aloud kamagra wholesale and appreciatively, ‘Wow, look at you!. €™ The patient looked pleased as she sat and combed her hair [site 3 day 1].Such a simple act of recognition as someone with a socially approved appearance takes on a special significance in the context of an acute hospital ward, and for patients living with dementia whose personhood may be overlooked in various ways.46This question of visibility of patients may also be particularly important when people living with dementia may be less able to make their needs and presence known.

In this example, a whole bay of patients was seemingly ‘invisible’. Here, the ethnographer is observing a four-bed bay occupied by male patients living with dementia.The man kamagra wholesale in bed 17 is sitting in his bedside chair. He is dressed in green hospital issue pyjamas and yellow grip socks. At 10 a.m., the physiotherapy team come and kamagra wholesale see him.

The physiotherapist crouches down in front of him and asks him how he is. He says he is unhappy, and the physiotherapist explains that she’ll be back later to see him again. The nurse checks on him, asks him if he wants a pillow, and puts it behind his head explaining to him, ‘You kamagra wholesale need to sit in the chair for a bit’. She pulls his bedside trolley near to him.

With the help of a Healthcare Assistant they make the bed. The Healthcare Assistant chats to him, puts cake out for him, and puts a blanket over his legs kamagra wholesale. He is shaking slightly and I wonder if he is cold.The nurse explains to me, ‘The problem is this is a really unstimulating environment’, then says to the patient, ‘All done, let’s have a bit of a tidy up,’ before wheeling the equipment out.The neighbouring patient in bed 18, is now sitting in his bedside chair, wearing (his own) striped pyjamas. His eyes kamagra wholesale are open, and he is looking around.

After a while, he closes his eyes and dozes. The team chat to patient 19 behind the curtains. He says he doesn’t want to sit, and kamagra wholesale they say that is fine unless the doctors tell them otherwise.The nurse puts music on an old radio with a CD player which is at the doorway near the ward entrance. It sounds like music from a musical and the ward it is quite noisy suddenly.

She turns down the volume a bit, but it is very jaunty and upbeat. The man in bed 19 quietly sings along to the songs kamagra wholesale. €˜I am going to see my baby when I go home on victory day…’At ten thirty, the nurse goes off on her break. The rest of the team are spread around the other kamagra wholesale bays and side rooms.

There are long distances between bays within this ward. After all the earlier activity it is now very calm and peaceful in the bay. Patient 20 is kamagra wholesale sitting in the chair tapping his feet to the music. He has taken out a large hessian shopping bag out of his cabinet and is sorting through the contents.

There is a lot of paperwork in it which he is kamagra wholesale reading through closely and sorting.Opposite, patient 17 looks very uncomfortable. He is sitting with two pillows behind his back but has slipped down the chair. His head is in his hands and he suddenly looks in pain. He hasn’t touched his tea, and is talking to himself kamagra wholesale.

The junior medic was aware that 17 was not comfortable, and it had looked like she was going to get some advice, but she hasn’t come back. 18 drinks his tea and looks at a wool twiddle mitt sleeve, puts it down, and dozes. 19 has finished all his coffee and manages to put the cup down on the trolley.Everyone is tapping their feet or wiggling their kamagra wholesale toes to the music, or singing quietly to it, when a student nurse, who is working at the computer station in the corridor outside the room, comes in. She has a strong purposeful stride and looks irritated as she switches the music off.

It feels like a jolt to the kamagra wholesale room. She turns and looks at me and says, ‘Sorry were you listening to it?. €™ I tell her that I think these gentlemen were listening to it.She suddenly looks very startled and surprised and looks at the men in the room for the first time. They have all stopped tapping their toes and kamagra wholesale stopped singing along.

She turns it back on but asks me if she can turn it down. She leaves and goes back to her paperwork outside. Once it is turned back on everyone starts tapping their toes again kamagra wholesale. The music plays on.

€˜There’ll be bluebirds over the white cliffs of Dover, just you wait and see…’[Site 3 day 3]The music was played by staff to help combat the drab and unstimulating environment of this hospital ward for the patients, the kamagra wholesale very people the ward is meant to serve. Yet for this member of ward staff the music was perceived as a nuisance, the men for whom the music was playing seemingly did not register to her awareness. Only an individual of ‘higher’ status, the researcher, sitting at the end of this room was visible to her. This example illustrates the general question of the visibility or otherwise of patients kamagra wholesale.

Focusing on our immediate topic, there may be complex pathways through which clothing may impact on how patients living with dementia are perceived, and on their self-perception.Clothing and identityOn these wards, we also observed how important familiar aspects of appearance were to relatives. Family members may be distressed if they find the person they knew so well, looking markedly different. In the example below, a mother and two adult daughters visit the father of the family, who is not visible to them as kamagra wholesale the person they were so familiar with. His is not wearing his glasses, which are missing, and his daughters find this very difficult.

Even though he looks very different following his admission—he has lost a large amount of weight and has sunken cheekbones, and kamagra wholesale his skin has taken on a darker hue—it is his glasses which are a key concern for the family in their recognition of their father:As I enter the corridor to go back to the ward, I meet the wife and daughter of the patient in bed 2 in the hall and walk with them back to the ward. Their father looks very frail, his head is back, and his face is immobile, his eyes are closed, and his mouth is open. His skin looks darker than before, and his cheekbones and eye sockets are extremely prominent from weight loss. €˜I am like a kamagra wholesale bird I want to fly away…’ plays softly in the radio in the bay.

I sit with them for a bit and we chat—his wife holds his hand as we talk. His wife has to take two busses to get to the hospital and we talk about the potential care home they expect her husband will be discharged to. They hope it will be kamagra wholesale close because she does not drive. He isn’t wearing his glasses and his daughter tells me that they can’t find them.

We look in the kamagra wholesale bedside cabinet. She has never seen her dad without his glasses. €˜He doesn’t look like my dad without his glasses’ [Site 2 day 15].It was often these small aspects of personal clothing and grooming that prompted powerful responses from visiting family members. Missing glasses and missing teeth were notable in this regard (and with the follow-up visits from the relatives of discharged patients trying to retrieve these now lost objects) kamagra wholesale.

The location of these possessions, which could have a medical purpose in the case of glasses, dental prosthetics, hearing aids or accessories which contained personal and important aspects of a patient’s identity, such as wallets or keys, and particularly, for female patients, handbags, could be a prominent source of distress for individuals. These accessories to personal clothing were notable on these wards by their everyday absence, hidden away in bedside cupboards or simply not brought in with the patient at admission, and by the frequency with which patients requested and called out for them or tried to look for them, often in repetitive cycles that indicated their underlying anxiety about these belongings, but which would become invisible to staff, becoming an everyday background intrusion to the work of the wards.When considering the visibility and recognition of individual persons, missing glasses, especially glasses for distance vision, have a particular significance, for without them, a person may be less able to recognise and interact visually with others. Their presence facilitates the subject of the gaze, in gazing back, and hence helps to ground meaningful and reciprocal relationships kamagra wholesale of recognition. This may be one factor behind the distress of relatives in finding their loved ones’ glasses to be absent.Clothing as a source of distressAcross all sites, we observed patients living with dementia who exhibited obvious distress at aspects of their institutional apparel and at the absence of their own personal clothing.

Some older patients were clearly able to verbalise their understandings of the impacts kamagra wholesale of wearing institutional clothing. One patient remarked to a nurse of her hospital blue tracksuit. €˜I look like an Olympian or Wentworth prison in this outfit!. The latter I expect…’ The staff laughed as they walked her out of the kamagra wholesale bay (site 3 day 1).Institutional clothing may be a source of distress to patients, although they may be unable to express this verbally.

Kontos has shown how people living with dementia may retain an awareness at a bodily level of the demands of etiquette.20 Likewise, in our study, a man living with dementia, wearing a very large institutional pyjama top, which had no collar and a very low V neck, continually tried to pull it up to cover his chest. The neckline was particularly low, because the pyjamas were far too large for him. He continued to fiddle with his very low-necked top even when his lunch tray was placed in front of him kamagra wholesale. He clearly felt very uncomfortable with such clothing.

He continued using his hands to try to pull it up to cover his exposed kamagra wholesale chest, during and after the meal was finished (site 3 day 5).For some patients, the communication of this distress in relation to clothing may be liable to misinterpretation and may have further impacts on how they are viewed within the ward. Here, a patient living with dementia recently admitted to this ward became tearful and upset after having a shower. She had no fresh clothes, and so the team had provided her with a pink hospital gown to wear.‘I want my trousers, where is my bra, I’ve got no bra on.’ It is clear she doesn’t feel right without her own clothes on. The one-to-one healthcare assistant assigned to this patient tells her, ‘Your bra is dirty, do you want to wear that? kamagra wholesale.

€™ She replies, ‘No I want a clean one. Where are my trousers?. I want them, I’ve lost them.’ The healthcare assistant repeats the explaination that her clothes are dirty, and asks her, ‘Do you kamagra wholesale want your dirty ones?. €™ She is very teary ‘No, I want my clean ones.’ The carer again explains that they are dirty.The cleaner who always works in the ward arrives to clean the floor and sweeps around the patient as she sits in her chair, and as he does this, he says ‘Hello’ to her.

She is very teary and explains that she has lost her kamagra wholesale clothes. The cleaner listens sympathetically as she continues ‘I am all confused. I have lost my clothes. I am kamagra wholesale all confused.

How am I going to go to the shops with no clothes on!. €™ (site 5 day 5).This person experienced significant distress because of her absent clothes, but this would often be simply attributed to confusion, seen as a feature of her dementia. This then may solidify staff perceptions kamagra wholesale of her condition. However, we need to consider that rather than her condition (her diagnosis of dementia) causing distress about clothing, the direction of causation may be the reverse.

The absence of her own familiar clothing contributes significantly to her distress and kamagra wholesale disorientation. Others have argued that people with limited verbal capacity and limited cognitive comprehension will have a direct appreciation of the grounding familiarity of wearing their own clothes, which give a bodily felt notion of comfort and familiarity.18 47 Familiar clothing may then be an essential prop to anchor the wearer within a recognisable social and meaningful space. To simply see clothing from a task-oriented point of view, as fulfilling a simply mechanical function, and that all clothing, whether personal or institutional have the same value and role, might be to interpret the desire to wear familiar clothing as an ‘optional extra’. However, for those patients most at risk of disorientation and distress within an unfamiliar environment, it could kamagra wholesale be a valuable necessity.Personal grooming and social statusIncluding in our consideration of clothing, we observed other aspects of the role of personal grooming.

Personal grooming was notable by its absence beyond the necessary cleaning required for reasons of immediate hygiene and clinical need (such as the prevention of pressure ulcers). Older patients, and particular those living with dementia who were unable to carry out ‘self-care’ independently and were not able to request support with personal grooming, could, over their admission, become visibly unkempt and scruffy, hair could be left unwashed, uncombed and unstyled, while men could become hirsute through a lack of shaving. The simple act of a visitor dressing and grooming a patient as they prepared for discharge could transform their appearance and leave that patient looking more alert, appear to having increased capacity, than when sitting ungroomed kamagra wholesale in their bed or bedside chair.It is important to consider the impact of appearance and of personal care in the context of an acute ward. Kontos’ work examining life in a care home, referred to earlier, noted that people living with dementia may be acutely aware of transgressions in grooming and appearance, and noted many acts of self-care with personal appearance, such as stopping to apply lipstick, and conformity with high standards of table manners.

Clothing, etiquette and personal grooming are important indicators of social class and hence an kamagra wholesale aspect of belonging and identity, and of how an individual relates to a wider group. In Kontos’ findings, these rituals and standards of appearance were also observed in negative reactions, such as expressions of disgust, towards those residents who breached these standards. Hence, even in cases where an individual may be assessed as having considerable cognitive impairment, the importance of personal appearance must not be overlooked.For some patients within these wards, routine practices of everyday care at the bedside can increase the potential to influence whether they feel and appear socially acceptable. The delivery of routine timetabled care at the bedside kamagra wholesale can impact on people’s appearance in ways that may mark them out as failing to achieve accepted standards of embodied personhood.

The task-oriented timetabling of mealtimes may have significance. It was a typical observed feature of this routine, when a mealtime has ended, that people living with dementia were left with visible signs and features of the mealtime through spillages on faces, clothes, bed sheets and bedsides, that leave them at risk of being assessed as less socially acceptable and marked as having reduced independence. For example, a volunteer attempts to ‘feed’ a person living with dementia, when she gives up and leave the bedside (this woman living with dementia has resisted her attempts and explicitly kamagra wholesale says ‘no’), remnants of the food is left spread around her mouth (site E). In a different ward, the mealtime has ended, yet a large white plastic bib to prevent food spillages remains attached around the neck of a person living with dementia who is unable to remove it (site X).Of note, an adult would not normally wear a white plastic bib at home or in a restaurant.

It signifies a task-based apparel that is demeaning to an kamagra wholesale individual’s social status. This example also contrasts poignantly with examples from Kontos’ work,20 such as that of a female who had little or no ability to verbalise, but who nonetheless would routinely take her pearl necklace out from under her bib at mealtimes, showing she retained an acute awareness of her own appearance and the ‘right’ way to display this symbol of individuality, femininity and status. Likewise, Kontos gives the example of a resident who at mealtimes ‘placed her hand on her chest, to prevent her blouse from touching the food as she leaned over her plate’.20Patients who are less robust, who have cognitive impairments, who may be liable to disorientation and whose agency and personhood are most vulnerable are thus those for whom appropriate and familiar clothing may be most advantageous. However, we kamagra wholesale found the ‘Matthew effect’ to be frequently in operation.

To those who have the least, even that which they have will be taken away.48 Although there may be institutional and organisational rationales for putting a plastic cover over a patient, leaving it on for an extended period following a meal may act as a marker of dehumanising loss of social status. By being able to maintain familiar clothing and adornment to visually display social standing and identity, a person living with dementia may maintain a continuity of selfhood.However, it is also possible that dressing and grooming an older person may itself be a task-oriented institutional activity in certain contexts, as discussed by Lee-Treweek49 in the context of a nursing home preparing residents for ‘lounge view’ where visitors would see them, using residents to ‘create a visual product for others’ sometimes to the detriment of residents’ needs. Our observations regarding the importance of patient appearance must therefore be considered as part of the care of the whole person and a significant feature of the institutional culture.Patient status and appearanceWithin these wards, a new grouping of class could become imposed on patients kamagra wholesale. We understand class not simply as socioeconomic class but as an indicator of the strata of local social organisation to which an individual belongs.

Those in the lowest classes may have limited opportunities to participate in society, and we observed the ways in which this applied to the people living with kamagra wholesale dementia within these acute wards. The differential impact of clothing as signifiers of social status has also been observed in a comparison of the white coat and the patient gown.4 It has been argued that while these both may help to mask individuality, they have quite different effects on social status on a ward. One might say that the white coat increases visibility as a person of standing and the attribution of agency, the patient gown diminishes both of these. (Within these wards, although white coats were not to be found, the dress code of medical staff did make them stand out kamagra wholesale.

For male doctors, for example, the uniform rarely strayed beyond chinos paired with a blue oxford button down shirt, sleeves rolled up, while women wore a wider range of smart casual office wear.) Likewise, we observed that the same arrangement of attire could be attributed to entirely different meanings for older patients with or without dementia.Removal of clothes and exposureWithin these wards, we observed high levels of behaviour perceived by ward staff as people living with dementia displaying ‘resistance’ to care.50 This included ‘resistance’ towards institutional clothing. This could include pulling up or removing hospital gowns, removing institutional pyjama trousers or pulling up gowns, and standing with gowns untied and exposed at the back (although this last example is an unavoidable design feature of the clothing itself). Importantly, the kamagra wholesale removal of clothing was limited to institutional gowns and pyjamas and we did not see any patients removing their own clothing. This also included the removal of institutional bedding, with instances of patients pulling or kicking sheets from their bed.

These acts could and was often interpreted by kamagra wholesale ward staff as a patient’s ‘resistance’ to care. There was some variation in this interpretation. However, when an individual patient response to their institutional clothing and bedding was repeated during a shift, it was more likely to be conceived by the ward team as a form of resistance to their care, and responded to by the replacement and reinforcement of the clothing and bedding to recover the person.The removal of gowns, pyjamas and bedsheets often resulted in a patient exposing their genitalia or continence products (continence pads could be visible as a large diaper or nappy or a pad visibly held in place by transparent net pants), and as such, was disruptive to the norms and highly visible to staff and other visitor to these wards. Notably, unlike other behaviours considered by staff to be disruptive or inappropriate within these wards such kamagra wholesale as shouting or crying out, the removal of bedsheets and the subsequent bodily exposure would always be immediately corrected, the sheet replaced and the patient covered by either the nurse or HCA.

The act of removal was typically interpreted by ward staff as representing a feature of the person’s dementia and staff responses were framed as an issue of patient dignity, or the dignity and embarrassment of other patients and visitors to the ward. However, such responses to removal could lead to further cycles of removal and replacement, leading to kamagra wholesale an escalation of distress in the person. This was important, because the recording of ‘refusal of care’, or presumed ‘confusion’ associated with this, could have significant impacts on the care and discharge pathways available and prescribed for the individual patient.Consider the case of a woman living with dementia who is 90 years old (patient 1), in the example below. Despite having no immediate medical needs, she has been admitted to the MAU from a care home (following her husband’s stroke, he could no longer care for her).

Across the previous evening and morning shift, she was shouting, refusing all food and care and has received assistance from the specialist dementia care worker kamagra wholesale. However, during this shift, she has become calmer following a visit from her husband earlier in the day, has since eaten and requested drinks. Her care home would not readmit her, which meant she was not able to be discharged from the unit (an overflow unit due to a high number of admissions to the emergency department during a patch of exceptionally hot weather) until alternative arrangements could be made by social services.During our observations, she remains calm for the first 2 hours. When she does talk, she kamagra wholesale is very loud and high pitched, but this is normal for her and not a sign of distress.

For staff working on this bay, their attention is elsewhere, because of the other six patients on the unit, one is ‘on suicide watch’ and another is ‘refusing their medication’ (but does not have a diagnosis of dementia). At 15:10 patient 1 kamagra wholesale begins to remove her sheets:15:10. The unit seems chaotic today. Patient 1 has begun to loudly drum her fingers on the tray table.

She still has not been brought more milk, which she requested from the HCA kamagra wholesale an hour earlier. The bay that patient 1 is admitted to is a temporary overflow unit and as a result staff do not know where things are. 1 has moved her sheets off her legs, her bare knees peeking out over the top of piled sheets.15:15. The nurse in charge says, ‘Hello,’ when kamagra wholesale she walks past 1’s bed.

1 looks across and smiles back at her. The nurse in charge explains to her that she kamagra wholesale needs to shuffle up the bed. 1 asks the nurse about her husband. The nurse reminds 1 that her husband was there this morning and that he is coming back tomorrow.

1 says that he hasn’t been and she kamagra wholesale does not believe the nurse.15:25. I overhear the nurse in charge question, under her breath to herself, ‘Why 1 has been left on the unit?. €™ 1 has started asking for somebody to come and see her. The nurse in charge tells 1 that she needs to do kamagra wholesale some jobs first and then will come and talk to her.15:30.

1 has once again kicked her sheets off of her legs. A social worker comes kamagra wholesale onto the unit. 1 shouts, ‘Excuse me’ to her. The social worker replies, ‘Sorry I’m not staff, I don’t work here’ and leaves the bay.15:40.

1 keeps kicking sheets off her bed, kamagra wholesale otherwise the unit is quiet. She now whimpers whenever anyone passes her bed, which is whenever anyone comes through the unit’s door. 1 is the only elderly patient on the unit. Again, the nurse in charge is heard sympathizing that this is not the right place kamagra wholesale for her.16:30.

A doctor approaches 1, tells her that she is on her list of people to say hello to, she is quite friendly. 1 tells kamagra wholesale her that she has been here for 3 days, (the rest is inaudible because of pitch). The doctor tries to cover 1 up, raising her bed sheet back over the bed, but 1 loudly refuses this. The doctor responds by ending the interaction, ‘See you later’, and leaves the unit.16:40.

1 attempts to kamagra wholesale talk to the new nurse assigned to the unit. She goes over to 1 and says, ‘What’s up my darling?. €™ It’s hard to follow 1 now as she sounds very upset. The RN’s first instinct, kamagra wholesale like with the doctor and the nurse in charge, is to cover up 1 s legs with her bed sheet.

When 1 reacts to this she talks to her and they agree to cover up her knees. 1 is talking about how her kamagra wholesale husband won’t come and visit her, and still sounds really upset about this. [Site 3, Day 13]Of note is that between days 6 and 15 at this site, observed over a particularly warm summer, this unit was uncomfortably hot and stuffy. The need to be uncovered could be viewed as a reasonable response, and in fact was considered acceptable for patients without a classification of dementia, provided they were otherwise clothed, such as the hospital gown patient 1 was wearing.

This is an example of an aspect of care where the choice and autonomy granted to patients assessed as having (or assumed to have) cognitive capacity is not available to people who are considered to have impaired cognitive capacity (a diagnosis of dementia) and carries the kamagra wholesale additional moral judgements of the appropriateness of behaviour and bodily exposure. In the example given above, the actions were linked to the patient’s resistance to their admission to the hospital, driven by her desire to return home and to be with her husband. Throughout observations over this 10-day period, patients perceived by staff as rational agents were allowed to strip down their bedding for comfort, whereas patients living with dementia who responded in this way were often viewed by staff as ‘undressing’, which would be interpreted as a feature of their condition, to be challenged and corrected by staff.Note how the same visual data triggered opposing interpretations of personal autonomy. Just as in the example above where distress over loss of familiar clothing may be interpreted as an aspect of confusion, yet lead to, or kamagra wholesale exacerbate, distress and disorientation.

So ‘deviant’ bedding may be interpreted, for some patients only, in ways that solidify notions of lack of agency and confusion, is another example of the Matthew effect48 at work through the organisational expectations of the clothed appearance of patients.Within wards, it is not unusual to see patients, especially those with a diagnosis of dementia http://half-witpoet.com/?p=41 or cognitive impairment, walking in the corridor inadvertently in some state of undress, typically exposed from behind by their hospital gowns. This exposure in itself is of course, kamagra wholesale an intrinsic functional feature of the design of the flimsy back-opening institutional clothing the patient has been placed in. This task-based clothing does not even fulfil this basic function very adequately. However, this inadvertent exposure could often be interpreted as an overt act of resistance to the ward and towards staff, especially when it led to exposed genitalia or continence products (pads or nappies).We speculate that the interpretation of resistance may be triggered by the visual prompt of disarrayed clothing and the meanings assumed to follow, where lack of decorum in attire is interpreted as indicating more general behavioural incompetence, cognitive impairment and/or standing outside the social order.DiscussionPrevious studies examining the significance of the visual, particularly Twigg and Buse’s work16–19 exploring the materialities of appearance, emphasise its key role in self-presentation, visibility, dignity and autonomy for older people and especially those living with dementia in care home settings.

Similarly, care home studies have demonstrated that institutional clothing, designed to facilitate task-based care, can be potentially dehumanising or and distressing.25 26 Our findings resonate with this work, but find that for people living with dementia within a key site of care, the acute ward, the impact of institutional clothing on the individual patient living with dementia, is poorly recognised, but is significant for the quality and humanity of their care.Our ethnographic approach enabled the researchers to kamagra wholesale observe the organisation and delivery of task-oriented fast-paced nature of the work of the ward and bedside care. Nonetheless, it should also be emphasised the instances in which staff such as HCAs and specialist dementia staff within these wards took time to take note of personal appearance and physical caring for patients and how important this can be for overall well-being. None of our observations should be read as critical of any individual staff, but reflects longstanding institutional cultures.Our previous work has examined how readily a person living with dementia within a hospital wards is vulnerable to dehumanisation,51 and to their behaviour within these wards being interpreted as a feature of their condition, rather than a response to the ways in which timetabled care is delivered at their bedside.50 We have also examined the ways in which visual stimuli within these wards in the form of signs and symbols indicating a diagnosis of dementia may inadvertently focus attention away from the individual patient and may incline towards simplified and inaccurate categorisation of both needs and the diagnostic category of dementia.52Our work supports the analysis of the two forms of attention arising from McGilchrist’s work.10 The institutional culture of the wards produces an organisational task-based technical attention, which we found appeared to compete with and reduce the opportunity for ward staff to seek a finer emotional attunement to the person they are caring for and their needs. Focus on kamagra wholesale efficiency, pace and record keeping that measures individual task completion within a timetable of care may worsen all these effects.

Indeed, other work has shown that in some contexts, attention to visual appearance may itself be little more than a ‘task’ to achieve.49 McGilchrist makes clear, and we agree, that both forms of attention are vital, but more needs to be done to enable staff to find a balance.Previous work has shown how important appearance is to older people, and to people living with dementia in particular, both in terms of how they are perceived by others, but also how for this group, people living with dementia, clothing and personal grooming may act as a particularly important anchor into a familiar social world. These twin aspects of clothing and appearance—self-perception and perception by others—may be especially important in the fast-paced context of an acute ward environment, where patients living with dementia may be struggling with the kamagra wholesale impacts of an additional acute medical condition within in a highly timetabled and regimented and unfamiliar environment of the ward, and where staff perceptions of them may feed into clinical assessments of their condition and subsequent treatment and discharge pathways. We have seen above, for instance, how behaviour in relation to appearance may be seen as ‘resisting care’ in one group of patients, but as the natural expression of personal preference in patients viewed as being without cognitive impairments. Likewise, personal grooming might impact favourably on a patient’s alertness, visibility and status within the ward.Prior work has demonstrated the importance of the medical gaze for the perceptions of the patient.

Other work has also shown how older people, and in kamagra wholesale particular people living with dementia, may be thought to be beyond concern for appearance, yet this does not accurately reflect the importance of appearance we found for this patient group. Indeed, we argue that our work, along with the work of others such as Kontos,20 21 shows that if anything, visual appearance is especially important for people living with dementia particularly within clinical settings. In considering the task of washing the patient, Pols53 considered ‘dignitas’ in terms of aesthetic values, in comparison to humanitas conceived as citizen values of equality between persons. Attention to dignitas in the form of appearance may be a way of facilitating the treatment by others of a person with humanitas, and helping to realise dignity kamagra wholesale of patients.Data availability statementNo data are available.

Data are unavailable to protect anonymity.Ethics statementsPatient consent for publicationNot required.Ethics approvalEthics committee approval for the study was granted by the NHS Research Ethics Service (15/WA/0191).AcknowledgmentsThe authors acknowledge funding support from the NIHR.Notes1. Devan Stahl (2013) kamagra wholesale. €œLiving into the imagined body. How the diagnostic image confronts the lived body.” Medical Humanities.

Medhum-2012–010286.2. Joyce Zazulak et al. (2017). "The art of medicine.

Arts-based training in observation and mindfulness for fostering the empathic response in medical residents.” Medical Humanities. Medhum-2016-011180.3. E Forde (2018). "Using photography to enhance GP trainees’ reflective practice and professional development." Medical Humanities.

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Blackwell.9. S Weil (1953). Gravity and Grace. U of Nebraska Press.10.

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Iain McGilchrist (2011). €œPaying attention to the bipartite brain.” The Lancet 377 (9771). 1068–1069.12. Efrat Tseëlon (1992).

€œSelf presentation through appearance. A manipulative vs a dramaturgical approach”. Symbolic Interaction, 15(4). 501–514.13.

E Tseëlon (1995). The masque of femininity. The presentation of woman in everyday life. London.

Sage.14. E Goffman (1990b). The Presentation of Self in Everyday Life Penguin15. Efrat Tseëlon (2001).

€œFashion research and its discontents”. Fashion Theory, 5 (4). 435–451.16. Julia Twigg (2010a).

€œClothing and dementia. A neglected dimension?. € Journal of Ageing Studies 24(4). 223–230.17.

Julia Twigg and Christina E Buse (2013). €œDress, dementia and the embodiment of identity.” Dementia 12(3). 326–336.18. C.

E Buse and J. Twigg (2015). €œClothing, embodied identity and dementia. Maintaining the self through dress.” Age, Culture, Humanities (2).19.

Christina Buse and Julia Twigg (2018). €œDressing disrupted. Negotiating care through the materiality of dress in the context of dementia.” Sociology of Health &. Illness, 40(2).

340-352.20. PIA C Kontos (2004). Ethnographic reflections on selfhood, embodiment and Alzheimer's disease. Ageing &.

Society, 24(6). 829–849.21. P. C Kontos (2005).

€œEmbodied selfhood in Alzheimer's disease. Rethinking person-centred care.” Dementia 4 (4). 553–570.22. P.

C Kontos and G. Naglie (2007). €œBridging theory and practice. Imagination, the body, and person-centred dementia care.” Dementia 6 (4).

549–569.23. Richard Ward et al. (2016a). €œâ€˜Gonna make yer gorgeous’.

Everyday transformation, resistance and belonging in the care-based hair salon.” Dementia, 15(3). 395–413.24. Richard Ward, Sarah Campbell, and John Keady (2016b). €œAssembling the salon.

Learning from alternative forms of body work in dementia care.” Sociology of Health &. Illness, 38(8). 1287–1302.25. Sonja Iltanen-Tähkävuori, Minttu Wikberg, and Päivi Topo (2012).

Design and dementia. A case of garments designed to prevent undressing. Dementia, 11(1). 49–59.26.

Päivi Topo and Sonja Iltanen-Tähkävuori (2010). €œScripting patienthood with patient clothing.” Social Science &. Medicine, 70(11). 1682–1689.27.

Julia Twigg (2010b). €œWelfare embodied. The materiality of hospital dress. A commentary on Topo and Iltanen-Tähkävuori”.

Social Science and Medicine, 70(11), 1690–1692.28. Kathleen Woodward (2006). €œPerforming age, performing gender” National Women’s Studies Association (NWSA) Journal 18(1). 162–89.29.

K.M Woodward (1999). Introduction. In K.M. Woodward (ed.), Figuring Age.

Women, Bodies and Generations (pp. Ix-xxix). Bloomington. Indiana University Press.30.

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Routledge.31. V. J Caracelli (2006). Enhancing the policy process through the use of ethnography and other study frameworks.

A mixed-method strategy. Research in the Schools, 13(1). 84–92.32. W Housley and P Atkinson (2003).

Interactionism, Sage33. M Hammersley (1987) What's Wrong with Ethnography?. Methodological Explorations. London.

Routledge34. V Turner and E Bruner (1986). The Anthropology of Experience New York. PAJ Publications.

2435. K Charmaz and RG Mitchell (2001). €˜Grounded theory in ethnography’ in Atkinson P. (Ed) Handbook of Ethnography, 2001.

160-174. Sage. London36. B Glaser and A Strauss (1967).

The Discovery of Grounded Theory. London. Weidenfeld and Nicholson, 24(25). 288–30437.

Juliet M. Corbin and Anselm Strauss (1990). Grounded theoryrResearch. Procedures, canons, and evaluative criteria.

J Green (1998). Commentary. Grounded theory and the constant comparative method. BMJ (Clinical research ed.), 316 (7137),:1064.39.

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Firestone (1983) “Multisite qualitative policy research. Optimising description and generalizability”. Education Research 12:14–1943. F Vogt (2002).

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IntroductionThere has been considerable interest in elucidating the contribution of genetic factors to the development of common diseases and using this information for better prediction of disease Discover More risk kamagra melbourne. The common disease common variant hypothesis predicts that variants that are common in the population play a role in disease susceptibility.1 Genome-wide association studies (GWAS) using single nucleotide polymorphism (SNP) kamagra melbourne arrays were developed as a mechanism by which to investigate these genetic factors and it was hoped this would lead to identification of variants associated with disease risk and subsequent development of predictive tests. Variants identified as associated with particular traits by these studies, for the large part, are SNPs that individually have a minor effect on disease risk and hence, by themselves, cannot be reliably used in disease prediction. Looking at the aggregate impact of these kamagra melbourne SNPs in the form of a polygenic score (PGS) appeared to be one possible means of using this information to predict disease.2 It is thought this will be of benefit as our genetic make-up is largely stable from birth and dictates a ‘baseline risk’ on which external influences act and modulate. Therefore, PGS are a potential mechanism to act as a risk predictor by capturing information on this genetic liability.The use of PGS as a predictive biomarker is being explored in a number of different disease areas, including cancer,3 4 psychiatric disorders,5–7 metabolic disorders (diabetes,8 obesity9) and coronary artery disease (CAD).10 The proposed applications range from aiding disease diagnosis, informing selection of therapeutic interventions, improvement of risk prediction, informing disease screening and, on a personal level, informing life planning.

Therefore, genetic risk information in the form of a PGS is considered to have potential in informing both clinical and individual-level decision-making.Recent advances in statistical techniques, improved computational power and the availability of large data sets have led to rapid developments kamagra melbourne in this area over the past few years. This has resulted in a variety of approaches to construction of models for score calculation and the investigation of these scores for prediction of common diseases.11 Several review articles aimed at researchers with a working knowledge of this field have been produced.6 11–17 In this article, we provide an overview of the key aspects of PGS construction to assist clinicians and researchers in other areas of academia to gain an understanding of the processes involved in score construction. We also consider the implications of evolving kamagra melbourne methodologies for the development of applications of PGS in healthcare.Evolution in polygenic model construction methodologiesTerminology with respect to PGS has evolved over time, reflecting evolving approaches and methodology. Other terms include PGS, polygenic risk score, polygenic load, genotype score, genetic burden, polygenic hazard score, genetic risk score (GRS), metaGRS and allelic risk score. Throughout this article we use the terms polygenic models to refer to the method used kamagra melbourne to calculate an output in the form of a PGS.

Different polygenic models can be used to calculate a PGS and analysis of these scores can be used to examine associations with particular markers or to predict an individuals risk of diseases.12Usual practice in calculating PGS is as a weighted sum of a number of risk alleles carried by an individual, where the risk alleles and their weights are defined by SNPs and their measured effects (figure 1).11 Polygenic models have been constructed using a few, hundreds or thousands of SNPs, and more recently SNPs across the whole genome. Consequently, determining which SNPs to include and the disease-associated weighting to assign to SNPs are important aspects of model construction (figure 2).18 These aspects are kamagra melbourne influenced by available genotype data and effect size estimates as well as the methodology employed in turning this information into model parameters (ie, weighted SNPs).Polygenic score calculation. This calculation aggregates the SNPs and their weights selected for a polygenic score. Common diseases are thought to be influenced by many genetic variants with small individual effect sizes, such that meaningful risk prediction necessitates examining the aggregated impact of these multiple variants including their kamagra melbourne weightings. PGS, polygenic score." data-icon-position data-hide-link-title="0">Figure 1 Polygenic score calculation.

This calculation aggregates the SNPs and their kamagra melbourne weights selected for a polygenic score. Common diseases kamagra melbourne are thought to be influenced by many genetic variants with small individual effect sizes, such that meaningful risk prediction necessitates examining the aggregated impact of these multiple variants including their weightings. PGS, polygenic score.Construction of a polygenic score. In the process of developing a polygenic score, numerous models are tested and then compared kamagra melbourne. The model that performs best (as determined by one or more measures) is then selected for validation in the external data set.

GWAS, genome-wide association studies." data-icon-position data-hide-link-title="0">Figure 2 Construction kamagra melbourne of a polygenic score. In the process of developing a polygenic score, numerous models are tested and then compared. The model that performs best (as determined by one or more measures) is then selected for validation in the external data set kamagra melbourne. GWAS, genome-wide association studies.Changes in data availability over time have had an impact on the approach taken in SNP selection and weighting. Early studies to identify variants associated with common diseases took the form kamagra melbourne of candidate gene studies.

The small size of candidate gene studies, the limitation of technologies available for genotyping and stringent significance thresholds meant that these studies investigated fewer variants and those that were identified with disease associations had relatively large effect sizes.19 Taken together, this meant that a relatively small number of variants were available for consideration for inclusion in a polygenic model.20 21 Furthermore, weighting parameters for these few variants were often simplistic, such as counts of the number of risk alleles carried, ignoring their individual effect sizes.16The advent of GWAS enabled assessment of SNPs across the genome, leading to the identification of a larger number of disease-associated variants and therefore more variants suitable for inclusion in a polygenic model. In addition, the increasing number of individuals in the association studies meant that the power of these studies increased, allowing for more precise estimates of effect sizes.19 Furthermore, some theorised that lowering stringent significance thresholds set for SNP–trait associations could also identify SNPs that might play a part in disease risk.11 16 This resulted in more options with respect to polygenic model kamagra melbourne parameters of SNPs to include and weights to assign to them. However, the inclusion of more SNPs and direct application of GWAS effect sizes as a weighting parameter does not always equate to better predictive performance.4 16 This is because GWAS do not provide perfect information with respect to the causal SNP, the effect sizes or the number of SNPs that contribute to the trait. Therefore, different methods have been developed to address these issues and optimise predictive kamagra melbourne performance of the score. Current common practice is to construct models with different iterations of SNPs and weighting, with assessment of the performance of each to identify the optimum configuration of SNPs and their weights (figure 2).Methods used in SNP selection and weighting assignmentSome methods of model development will initially involve selection of SNPs followed by optimisation of weighting, whereas others may involve optimisation of weightings for all SNPs that have been genotyped using their overall GWAS effect sizes, the linkage disequilibrium (LD) and an estimate of the proportion of SNPs that are expected to contribute to the risk.22LD is the phenomenon where some SNPs are coinherited more frequently with other SNPs due to their close proximity on the genome.

Segments with strong kamagra melbourne LD between SNPs are referred to as haplotype blocks. This phenomenon means that GWAS often identify multiple SNPs in the same haplotype block associated with disease and the true causal SNP is not known. As models have started to assess more SNPs, careful consideration is required to take into account possible correlation between SNPs as a kamagra melbourne result of this phenomenon. Correlation between SNPs can lead to double counting of SNPs and association redundancy, where multiple SNPs in a region of LD kamagra melbourne are identified as being associated with the outcome. This can lead to reduction in the predictive performance of the model.

Therefore, processes for kamagra melbourne filtering SNPs and using one SNP (tag SNP) to act as a marker in an area of high LD, through LD thinning, were developed. Through these processes SNPs correlated with other SNPs in a block are removed, by either pruning or clumping. Pruning ignores p value thresholds and ‘eliminates’ SNPs by a process kamagra melbourne of iterative comparison between a pair of SNPs to assess if they are correlated, and subsequently could remove SNPs that are deemed to have evidence of association. Clumping (also known as informed pruning) is guided by GWAS p values and chooses the most significant SNP, therefore keeping the most significant SNP within a block.23 This is all done with the aim of pinpointing relatively small areas of the genome that contribute to risk of the trait. Different significance thresholds may be used to select SNPs from this kamagra melbourne subgroup for inclusion in models.Poor performance of a model can result from imperfect tagging with the underlying causal SNP.16 This is because the causal SNP that is associated with disease might not be in LD with the tag SNP that is in the model but is in LD with another SNP which is not in the model.

This particularly occurs where the LD and variant frequency differs between population groups.24 An alternate approach to filter SNPs is stepwise regression where SNPs are selected based on how much the SNPs improve the model’s performance. This is a statistical approach and does not consider the impact of LD or effect size.As described above, early studies used simple weighting approaches or directly kamagra melbourne applied effect sizes from GWAS as weighting parameters for SNPs. However, application of effect sizes as a weighting parameter directly from a GWAS may not be optimal, due to differences in the population that the GWAS was conducted in and the target population. Also as described above, LD and the fact that not all kamagra melbourne SNPs may contribute to the trait mean that these effect sizes from GWAS are imperfect estimates. Therefore, methods have been developed that adjust effect size estimates from GWAS using statistical techniques which make assumptions about factors such as the number of causal SNPs, level of LD between SNPs or knowledge of their potential function to better reflect their impact on a trait.

Numerous statistical methodologies have been developed to improve weighting with a view to enhancing the discriminative power of a PGS.25 26 Examples of some methodological approaches are LDpred,22 winner’s curse correction,23 empirical Bayes estimation,27 shrinkage regression (Lasso),28 linear mixed models,29 with more being developed or tested kamagra melbourne. An additional improvement on the methods is to embed non-genetic information (eg, age-specific ORs).6 Determination of which methodology or hybrid of methodologies is most appropriate for various settings and conditions is continuously being explored and is evolving with new statistical approaches developing at a rapid pace.In summary, model development has evolved in an attempt to gain the most from available GWAS data and address some of the issues that arise due to working with data sets which cannot be directly translated into parameters for prediction models. The different approaches taken in SNP kamagra melbourne selection and weighting, and the impact on the predictive performance of a model are important to consider when assessing different models. This is because different approaches to PGS modelling can achieve the same or a similar level of prediction. From a health system implementation perspective, particular approaches may be preferred kamagra melbourne following practical considerations and trade-offs between obtaining genotype data, processes for score construction and model performance.

In addition, the degree to which these parameters need to be optimised kamagra melbourne will also be impacted by the input data and validation data set, and the quality control procedures that need to be applied to these data sets.12Sources of input data for score constructionKey to the development of a polygenic model is the availability of data sets that can provide input parameters for model construction. Genotype data used in model construction can either be available as raw GWAS data or provided as GWAS summary statistics. Data in the raw format are individual-level data from a SNP array and may not have undergone basic quality control such kamagra melbourne as assessment of missingness, sex discrepancy checks, deviation from Hardy-Weinberg equilibrium, heterozygosity rate, relatedness or assessment for outliers.30 31 Availability of raw GWAS data allows for different polygenic models to be developed because of the richness of the data, however computational issues arise because of the size of the data sets. Data based on genome sequencing, as opposed to SNP arrays, could also be used in model construction. There have been limited studies of PGS developed from this form of data due to limitations in data availability, which is mainly due to cost restraints.15 32 Individual-level genomic data are also often not available to researchers due to privacy concerns.Due to these issues, the focus of polygenic model development has therefore been on using well-powered GWAS summary statistics.33 These are available from open access repositories and contain summary information such as the allele positions, ORs, CIs and allele frequency, without kamagra melbourne containing confidential information on individuals.

These data sets have usually been through the basic quality control measures mentioned above. There are, however, no standards for publicly available files, meaning some further processing steps may be required, in particular when various kamagra melbourne data sets are combined for a meta-analysis. Quality control on summary statistics is only possible if information such as missing genotype rate, minor allele frequency, Hardy-Weinberg equilibrium failures and non-Mendelian transmission rates is provided.12Processing of GWAS data may include additional quality control steps, imputation and filtering of the SNP information, which can be done at the level of genotype or summary statistics data. SNP arrays used in GWAS only have common SNPs represented on them as they rely on LD between SNPs kamagra melbourne to cover the entire genome. As described above, one tag SNP on the array can represent many other SNPs.

Imputation of kamagra melbourne SNPs is common in GWAS and describes the process of predicting genotypes that have not been directly genotyped but are statistically inferred (imputed) based on haplotype blocks from a reference sequence.33–35 Often association tests between the imputed SNPs and trait are repeated. As genotype imputation requires individual-level data, researchers have proposed summary statistics imputation as a mechanism to infer the association between untyped SNPs and a trait. The performance of imputation has been evaluated and shown that, with certain limitations, summary statistics imputation is an efficient and cost-effective methodology to identify loci associated with traits when compared with imputation done on genotypes.36An alternative source of input data for the selection of SNPs and kamagra melbourne their weightings is through literature or in existing databases, where already known trait-associated SNPs and their effect sizes are used as the input parameters in model development. A number of studies have taken this approach37 38 and it is possible to use multiple sources when developing various polygenic models and establishing the preferred parameters to use.Currently, there does not appear to be one methodology that works across all contexts and traits, each trait will need to be assessed to determine which method is the most suitable for the trait being evaluated. For example, four different polygenic model construction strategies were explored for three skin cancer subtypes4 by using data on SNPs and their effect sizes from different sources, such as the latest GWAS meta-analysis results, the National Human Genome Research Institute (NHGRI) kamagra melbourne EBI GWAS catalogue, UK Biobank GWAS summary statistics with different thresholds and GWAS summary statistics with LDpred.

In this setting for basal cell carcinoma and melanoma, the meta-analysis and catalogue-derived models were found to perform similarly but that the latter was ultimately used as it included more SNPs. For squamous cell carcinoma the meta-analysis-derived model kamagra melbourne performed better than the catalogue-derived model. This demonstrates how each disease subtype, model construction strategy and data set can have their own limitations and advantages.Knowledge of the kamagra melbourne sources of input data and its subsequent use in model development is important in understanding the limitations of available models. Models that are developed using data sets that reflect the population in which prediction is to be carried out will perform better. For example, data collected from a symptomatic or high-risk population may not be suitable as an input data set for the development of a polygenic model that will kamagra melbourne be used for disease prediction in the general population.

Large GWAS studies were previously focused on high-risk individuals, such as patients with breast cancer with a strong family history or known pathogenic variants in BRCA1 or BRCA2. These studies would not be suitable for the development of PGS for use in kamagra melbourne the general population but can inform risk assessment in high-risk individuals. The source of the data for SNP selection and weighting also has implications for downstream uses and validation. For example, variant frequency and LD patterns can vary between populations and this can translate to poor performance of the polygenic model if the external validation population is different from that of the input data set.39–41 Furthermore, the power and validity of polygenic kamagra melbourne analyses are influenced by the input data sources.12 42From a model to a scorePGS can be calculated using one of the methodologies discussed above. The resulting PGS units of measurement depend on which measurement is used for the weighting.12 For example, the weightings may have been calculated based on logOR for discrete traits or linear regression coefficient (β/beta) in continuous traits from univariate regression tests carried out in the GWAS.

The resulting scores are then usually transformed to a standard normal distribution to give scores ranging from −1 to kamagra melbourne 1, or 0 to 100 for ease of interpretation. This enables further examination of the association between the score and a trait and the predictive ability of different scores generated by different models. Similar to other biomarker analyses, this involves using the PGS as a predictor of a trait kamagra melbourne with other covariates (eg, age, smoking, and so on) added, if appropriate, in a target sample. Examination of differences in the distribution of scores in cases and controls, or by examining differences in traits between different strata of PGS can enable assessment of predictive ability (figure 3). Common practice is for individual-level PGS values to kamagra melbourne be used to stratify populations into distinct groups of risk based on percentile cut-off or threshold values (eg, the top 1%).Example distribution of polygenic scores across a population.

Thresholds can be set to stratify risk as low (some), average (most) and high (some)." data-icon-position data-hide-link-title="0">Figure 3 Example distribution of polygenic scores across a population. Thresholds can be set to stratify risk as low (some), average (most) and high (some).Model validationPolygenic model development is reliant on further data sets for model testing and validation and the kamagra melbourne composition of these data sets is important in ensuring that the models are appropriate for a particular purpose. The development of a model to calculate kamagra melbourne a PGS involves refinement of the previously discussed input parameters, and selection of the ‘best’ of several models based on performance (figure 2). Therefore, a testing/training data set is often required to assess the model’s ability to accurately predict the trait of interest. This is kamagra melbourne often a data set that is independent of the base/input/discovery data set.

It may comprise a subset of the discovery data set that is only used for testing and was not included in the initial development of the model but should ideally be a separate independent data set.Genotype and phenotype data are needed in these data sets. Polygenic models are used to calculate PGS for individuals in kamagra melbourne the training data set and regression analysis is performed with the PGS as a predictor of a trait. Other covariates may also be included, if appropriate. This testing phase can be considered a process kamagra melbourne for identifying models with better overall performance and/or informing refinements needed. Hence, this phase often involves comparison of different models that are developed using the same input data set to identify those models that have optimal performance.The primary purpose is to determine which model best discriminates between cases and controls.

The area under the curve (AUC) or the C-statistic is the most commonly used measure in assessing kamagra melbourne discriminative ability. It has been criticised as being an insensitive measure that is not able to fully capture all aspects of predictive ability. For instance, in some kamagra melbourne instances, AUC can remain unchanged between models but the individuals within are categorised into a different risk group.43 Alternative metrics that have been used to evaluate model performance include increase in risk difference, integrated discrimination improvement, R2 (estimate of variance explained by the PGS after covariate adjustment), net classification index and the relative risk (highest percentile vs lowest percentile). A clear understanding on how to interpret the performance within various settings is important in determining which model is most suitable.44As per normal practice when developing any prediction model, polygenic models with the optimal performance in a testing/training data set should be further validated in external data sets. External data sets are critical in validation of models and assessment of generalisability, hence must kamagra melbourne also conform to the desired situations in which a model is to be used.

The goal is to find a model with suitable parameters of predictive performance in data sets outside of those in which it was developed. Ideally, external kamagra melbourne validation requires replication in independent data sets. Few existing polygenic models have been validated to this extent, the focus being rather on the development of new models rather than evaluation of existing ones. One example where replication has been carried out is in kamagra melbourne the field of CAD, where the GPSCAD45 and metaGRSCAD10 polygenic models (both developed using UK Biobank data) were evaluated in a Finnish population cohort.46 Predictive ability was found to be lower in the Finnish population. This is likely to be due kamagra melbourne to the differences in genetic structure of this population and the population of the data set used for polygenic model development.

Research is ongoing to evaluate polygenic models in other populations and strategies are being developed to ensure the same performance when used more widely, possibly through reweighting and adjustment of the scores.47Moving towards clinical applicationsPGS are thought to be useful information that could improve risk estimation and provide an avenue for disease prevention and deciding treatment strategies. There are indications from a number of fields that genetic information in the form of PGS can act as independent biomarkers and aid stratification.11 16 48 kamagra melbourne However, the clinical benefits of stratification using a PGS and the implications for clinical practice are only just beginning to be examined. The use of PGS as part of existing risk prediction tools or as a stand-alone predictor has been suggested. This latter option may be true for diseases where knowledge or predictive ability kamagra melbourne with other risk factors is limited, such as in prostate cancer.49 In either case, polygenic models need to be individually examined to determine suitability and applicability for the specific clinical question.50 Despite some commercial companies developing PGS,51 52 currently PGS are not an established part of clinical practice.Integration into clinical practice requires evaluation of a PGS-based test. An important concept to consider in this regard is the distinction between an assay and a test.

This has been previously discussed with respect to genetic test evaluation.53 54 It is worth examining kamagra melbourne this concept as applied to PGS, as their evaluation is reliant on a clear understanding of the test to be offered. As outlined by Zimmern and Kroese,54 the method used to analyse a substance in a sample is considered the assay, whereas a test is the use of an assay within a specific context. With respect to PGS, the process of developing a model to derive a score can be considered the assay, while the use of this model for a particular disease, population and purpose can be considered kamagra melbourne the test. This distinction is important when assessing if studies are reporting on assay performance as opposed to test performance. It is our view that, with respect to polygenic models, progress kamagra melbourne has been made with respect to assay development, but PGS-based tests are yet to be developed and evaluated.

This can enable a clearer understanding of their potential clinical utility and issues that may arise for clinical implementation.11 18 55 It is clear that this is still an evolving field, and going forward different models may be required for different traits due to their underlying genetic architecture,26 different clinical contexts and needs.Clinical contexts where risk stratification is already established practice are most likely where implementation of PGS will occur first. Risk prediction models based on non-genetic factors have been developed for many conditions and are used in clinical care, for example, in cardiovascular disease over 100 such models exist.56 In such contexts, how a PGS and its ability to predict risk compared with, or improves on, these existing models is being investigated.3 44 57–61 The extent to which PGS improves prediction, as well as the cost kamagra melbourne implications of including this, is likely to impact on implementation.Integration of PGS into clinical practice, for any application, requires robust and validated mechanisms to generate these scores. Therefore, given the numerous models available, an assessment of their suitability as part of a test is required. Parameters or guidelines with respect to aspects of model performance and metrics that could assist in selecting the model to take forward as a PGS-based test are limited and kamagra melbourne need to be addressed. Currently, there are different mechanisms to generate PGS and have arisen in response to the challenges in aggregating large-scale genomic data for prediction.

For example, a review reported kamagra melbourne 29 PGS models for breast cancer from 22 publications.62 Due to there being a number of different methodologies to generate a score, numerous models may exist for the same condition and each of the resulting models could perform differently. Models may perform differently because the population, measured outcome or context of the development data sets used to generate the models is diverse, for example, a score for risk of kamagra melbourne breast cancer versus a breast cancer subtype.44 63 This diversity, alongside the lack of established best practice and standardised reporting in publications, makes comparison and evaluation of polygenic models for use in clinical settings challenging. It is clear that moving the field forward is reliant on transparent reporting and evaluation. Recommendations for best practices on the reporting of polygenic models in literature have been proposed14 64 as well as a database,65 66 which could allow for kamagra melbourne such comparisons. Statements and guidelines for risk prediction model development, such as the Genetic Risk Prediction Studies and Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD), already exist, but are not consistently used.

TRIPOD explicitly covers the development and validation of prediction models for both diagnosis and prognosis, for all medical domains.One clear issue is generalisability and drop in performance of polygenic models once they are applied in a population group different from the one in which they were developed.22 46 67–70 This is an ongoing challenge in genomics as most GWAS, from which most PGS are being developed, have been conducted in European-Caucasian populations.71 Efforts to improve representation are underway72 and there are attempts to reweight/adjust scores when applied to different population groups which are showing some potential but need further research.47 Others have demonstrated that models developed in more diverse population groups have improved performance when applied to external data sets in different populations.24 73 It is important to consider this issue when moving towards clinical applications as it may pose an ethical challenge if the PGS is not generalisable.A greater understanding of different complex traits and the impact of pleiotropy is only beginning to be investigated.74 There is growing appreciation of the role of pleiotropy as multiple variants have been identified to be associated with multiple traits and exert diverse effects, providing insight into overlapping mechanisms.75 76 kamagra melbourne This, together with the impact of population stratification, genetic relatedness, ascertainment and other sources of heterogeneity leading to spurious signals and reduced power in genetic association studies, all impacting on the predictive ability of PGS in different populations and for different diseases.While many publications report on model development and evaluation, often there is a lack of clarity on intended purpose,50 77 leading to uncertainties as to the clinical pathways in which implementation is envisaged. A clear description of intended use within clinical pathways is a central component in evaluating the use of an application with any form of PGS and in considering practical implications, such as mechanisms of obtaining the score, incorporation into health records, interpretation of scores, relevant cut-offs for intervention initiation, mechanisms for feedback of results and costs, among other issues. These parameters will kamagra melbourne also be impacted by the polygenic model that is taken forward for implementation. Meaning that there are still some important questions that need to be addressed to determine how and where PGS could work within current healthcare systems, particularly at a population level.78It is widely accepted that genotyping using arrays is a lower cost endeavour in comparison to genome sequencing, making the incorporation of PGS into routine healthcare an attractive proposition. However, we were unable to find any studies reporting on kamagra melbourne the use or associated costs of such technology for population screening.

Studies are beginning to examine use case scenarios and model cost-effectiveness, but this has only been in very few, specific investigations.79 80 Costs will also be influenced by the testing technology and by the downstream consequences of testing, which is likely to differ depending on specific applications that are developed and the pathways in which such tests are incorporated. This is particularly the case in screening or primary care kamagra melbourne settings, where such testing is currently not an established part of care pathways and may require additional resources, not least as a result of the volume of testing that could be expected. Moving forward, the clinical role of PGS needs to be developed further, including defining the clinical applications as well as supporting evidence, for example, on the effect of clinical outcomes, the feasibility for use in routine practice and cost-effectiveness.ConclusionThere is a large amount of diversity in the PGS field with respect to model development approaches, and this continues to evolve. There is rapid progress which is being driven by the availability of larger data sets, primarily from GWAS and concomitant developments in kamagra melbourne statistical methodologies. As understanding and knowledge develops, the usefulness and appropriateness of polygenic models for different diseases and contexts are being explored.

Nevertheless, this is still an emerging field, with a variable evidence base demonstrating some potential kamagra melbourne. The validity of PGS needs to be clearly demonstrated, and their applications evaluated prior to clinical implementation..

IntroductionThere has been considerable interest in elucidating the contribution of genetic factors to the development of common diseases and using this information for kamagra wholesale better prediction of disease risk. The common disease common variant hypothesis predicts that variants that are common in the population play a role in disease susceptibility.1 Genome-wide association studies (GWAS) using single nucleotide polymorphism (SNP) arrays were developed as a mechanism by which to investigate these genetic factors and it was hoped this would lead to identification of variants associated with disease risk and subsequent development of predictive kamagra wholesale tests. Variants identified as associated with particular traits by these studies, for the large part, are SNPs that individually have a minor effect on disease risk and hence, by themselves, cannot be reliably used in disease prediction. Looking at the aggregate impact of these SNPs in the form of a polygenic score (PGS) appeared to be one kamagra wholesale possible means of using this information to predict disease.2 It is thought this will be of benefit as our genetic make-up is largely stable from birth and dictates a ‘baseline risk’ on which external influences act and modulate.

Therefore, PGS are a potential mechanism to act as a risk predictor by capturing information on this genetic liability.The use of PGS as a predictive biomarker is being explored in a number of different disease areas, including cancer,3 4 psychiatric disorders,5–7 metabolic disorders (diabetes,8 obesity9) and coronary artery disease (CAD).10 The proposed applications range from aiding disease diagnosis, informing selection of therapeutic interventions, improvement of risk prediction, informing disease screening and, on a personal level, informing life planning. Therefore, genetic risk information in the form of a PGS is considered to have potential in informing both clinical and individual-level decision-making.Recent advances in statistical techniques, improved computational power and the availability of large data sets have led to rapid developments kamagra wholesale in this area over the past few years. This has resulted in a variety of approaches to construction of models for score calculation and the investigation of these scores for prediction of common diseases.11 Several review articles aimed at researchers with a working knowledge of this field have been produced.6 11–17 In this article, we provide an overview of the key aspects of PGS construction to assist clinicians and researchers in other areas of academia to gain an understanding of the processes involved in score construction. We also consider the implications of evolving methodologies for the development kamagra wholesale of applications of PGS in healthcare.Evolution in polygenic model construction methodologiesTerminology with respect to PGS has evolved over time, reflecting evolving approaches and methodology.

Other terms include PGS, polygenic risk score, polygenic load, genotype score, genetic burden, polygenic hazard score, genetic risk score (GRS), metaGRS and allelic risk score. Throughout this article we use the terms polygenic models to refer kamagra wholesale to the method used to calculate an output in the form of a PGS. Different polygenic models can be used to calculate a PGS and analysis of these scores can be used to examine associations with particular markers or to predict an individuals risk of diseases.12Usual practice in calculating PGS is as a weighted sum of a number of risk alleles carried by an individual, where the risk alleles and their weights are defined by SNPs and their measured effects (figure 1).11 Polygenic models have been constructed using a few, hundreds or thousands of SNPs, and more recently SNPs across the whole genome. Consequently, determining which SNPs to include and the disease-associated weighting to assign to SNPs are important aspects of model construction (figure 2).18 These aspects are influenced by available genotype data and effect size estimates as well as the methodology employed in turning this information kamagra wholesale into model parameters (ie, weighted SNPs).Polygenic score calculation.

This calculation aggregates the SNPs and their weights selected for a polygenic score. Common diseases are thought to be influenced by many genetic variants with small individual kamagra wholesale effect sizes, such that meaningful risk prediction necessitates examining the aggregated impact of these multiple variants including their weightings. PGS, polygenic score." data-icon-position data-hide-link-title="0">Figure 1 Polygenic score calculation. This calculation aggregates the kamagra wholesale SNPs and their weights selected for a polygenic score.

Common diseases are thought to be influenced by many genetic variants with small individual effect sizes, such that meaningful risk prediction necessitates examining the aggregated impact of these multiple variants including kamagra wholesale their weightings. PGS, polygenic score.Construction of a polygenic score. In the kamagra wholesale process of developing a polygenic score, numerous models are tested and then compared. The model that performs best (as determined by one or more measures) is then selected for validation in the external data set.

GWAS, genome-wide association studies." data-icon-position data-hide-link-title="0">Figure 2 Construction of a polygenic kamagra wholesale score. In the process of developing a polygenic score, numerous models are tested and then compared. The model that performs best (as determined by one or more measures) is then selected for validation in the external data kamagra wholesale set. GWAS, genome-wide association studies.Changes in data availability over time have had an impact on the approach taken in SNP selection and weighting.

Early studies to identify variants associated with common kamagra wholesale diseases took the form of candidate gene studies. The small size of candidate gene studies, the limitation of technologies available for genotyping and stringent significance thresholds meant that these studies investigated fewer variants and those that were identified with disease associations had relatively large effect sizes.19 Taken together, this meant that a relatively small number of variants were available for consideration for inclusion in a polygenic model.20 21 Furthermore, weighting parameters for these few variants were often simplistic, such as counts of the number of risk alleles carried, ignoring their individual effect sizes.16The advent of GWAS enabled assessment of SNPs across the genome, leading to the identification of a larger number of disease-associated variants and therefore more variants suitable for inclusion in a polygenic model. In addition, the increasing number of individuals in the association studies meant that the power of these studies increased, kamagra wholesale allowing for more precise estimates of effect sizes.19 Furthermore, some theorised that lowering stringent significance thresholds set for SNP–trait associations could also identify SNPs that might play a part in disease risk.11 16 This resulted in more options with respect to polygenic model parameters of SNPs to include and weights to assign to them. However, the inclusion of more SNPs and direct application of GWAS effect sizes as a weighting parameter does not always equate to better predictive performance.4 16 This is because GWAS do not provide perfect information with respect to the causal SNP, the effect sizes or the number of SNPs that contribute to the trait.

Therefore, different methods have been developed to address kamagra wholesale these issues and optimise predictive performance of the score. Current common practice is to construct models with different iterations of SNPs and weighting, with assessment of the performance of each to identify the optimum configuration of SNPs and their weights (figure 2).Methods used in SNP selection and weighting assignmentSome methods of model development will initially involve selection of SNPs followed by optimisation of weighting, whereas others may involve optimisation of weightings for all SNPs that have been genotyped using their overall GWAS effect sizes, the linkage disequilibrium (LD) and an estimate of the proportion of SNPs that are expected to contribute to the risk.22LD is the phenomenon where some SNPs are coinherited more frequently with other SNPs due to their close proximity on the genome. Segments with strong LD between SNPs are referred kamagra wholesale to as haplotype blocks. This phenomenon means that GWAS often identify multiple SNPs in the same haplotype block associated with disease and the true causal SNP is not known.

As models kamagra wholesale have started to assess more SNPs, careful consideration is required to take into account possible correlation between SNPs as a result of this phenomenon. Correlation between SNPs can lead kamagra wholesale to double counting of SNPs and association redundancy, where multiple SNPs in a region of LD are identified as being associated with the outcome. This can lead to reduction in the predictive performance of the model. Therefore, processes for filtering SNPs and using one kamagra wholesale SNP (tag SNP) to act as a marker in an area of high LD, through LD thinning, were developed.

Through these processes SNPs correlated with other SNPs in a block are removed, by either pruning or clumping. Pruning ignores kamagra wholesale p value thresholds and ‘eliminates’ SNPs by a process of iterative comparison between a pair of SNPs to assess if they are correlated, and subsequently could remove SNPs that are deemed to have evidence of association. Clumping (also known as informed pruning) is guided by GWAS p values and chooses the most significant SNP, therefore keeping the most significant SNP within a block.23 This is all done with the aim of pinpointing relatively small areas of the genome that contribute to risk of the trait. Different significance thresholds may be used to select SNPs from this subgroup for inclusion in models.Poor performance of a model can kamagra wholesale result from imperfect tagging with the underlying causal SNP.16 This is because the causal SNP that is associated with disease might not be in LD with the tag SNP that is in the model but is in LD with another SNP which is not in the model.

This particularly occurs where the LD and variant frequency differs between population groups.24 An alternate approach to filter SNPs is stepwise regression where SNPs are selected based on how much the SNPs improve the model’s performance. This is a statistical approach and does not consider the impact of LD or effect size.As described above, early studies used simple weighting approaches or directly applied effect sizes from GWAS as weighting kamagra wholesale parameters for SNPs. However, application of effect sizes as a weighting parameter directly from a GWAS may not be optimal, due to differences in the population that the GWAS was conducted in and the target population. Also as described above, LD and the fact that not kamagra wholesale all SNPs may contribute to the trait mean that these effect sizes from GWAS are imperfect estimates.

Therefore, methods have been developed that adjust effect size estimates from GWAS using statistical techniques which make assumptions about factors such as the number of causal SNPs, level of LD between SNPs or knowledge of their potential function to better reflect their impact on a trait. Numerous statistical methodologies have been developed kamagra wholesale to improve weighting with a view to enhancing the discriminative power of a PGS.25 26 Examples of some methodological approaches are LDpred,22 winner’s curse correction,23 empirical Bayes estimation,27 shrinkage regression (Lasso),28 linear mixed models,29 with more being developed or tested. An additional improvement on the methods is to embed non-genetic information (eg, age-specific ORs).6 Determination of which methodology or hybrid of methodologies is most appropriate for various settings and conditions is continuously being explored and is evolving with new statistical approaches developing at a rapid pace.In summary, model development has evolved in an attempt to gain the most from available GWAS data and address some of the issues that arise due to working with data sets which cannot be directly translated into parameters for prediction models. The different approaches taken in SNP selection and weighting, and the kamagra wholesale impact on the predictive performance of a model are important to consider when assessing different models.

This is because different approaches to PGS modelling can achieve the same or a similar level of prediction. From a health system implementation perspective, particular approaches may be preferred following practical considerations and trade-offs between obtaining genotype data, processes for kamagra wholesale score construction and model performance. In addition, the degree to which these parameters need to be optimised will also be impacted by the input data and validation data set, and the quality control kamagra wholesale procedures that need to be applied to these data sets.12Sources of input data for score constructionKey to the development of a polygenic model is the availability of data sets that can provide input parameters for model construction. Genotype data used in model construction can either be available as raw GWAS data or provided as GWAS summary statistics.

Data in the raw format are individual-level data from a SNP array and may not have undergone basic quality control such as assessment of missingness, sex discrepancy checks, deviation from Hardy-Weinberg equilibrium, heterozygosity rate, relatedness or assessment for outliers.30 31 Availability of raw GWAS data allows for different polygenic models to be developed because of the richness kamagra wholesale of the data, however computational issues arise because of the size of the data sets. Data based on genome sequencing, as opposed to SNP arrays, could also be used in model construction. There have been limited studies of PGS developed from this form of data due to limitations in data availability, which is mainly due to cost restraints.15 32 Individual-level genomic data are also often not available to researchers due to privacy concerns.Due to these issues, the focus of polygenic model development has therefore been on using well-powered GWAS summary statistics.33 These are available from open access repositories and contain summary information such as the allele positions, ORs, CIs and allele frequency, without containing confidential information kamagra wholesale on individuals. These data sets have usually been through the basic quality control measures mentioned above.

There are, however, no standards for publicly available files, meaning some further processing steps may be required, in particular when various data sets are combined kamagra wholesale for a meta-analysis. Quality control on summary statistics is only possible if information such as missing genotype rate, minor allele frequency, Hardy-Weinberg equilibrium failures and non-Mendelian transmission rates is provided.12Processing of GWAS data may include additional quality control steps, imputation and filtering of the SNP information, which can be done at the level of genotype or summary statistics data. SNP arrays used in GWAS only have common SNPs represented on them as they rely on kamagra wholesale LD between SNPs to cover the entire genome. As described above, one tag SNP on the array can represent many other SNPs.

Imputation of SNPs is common in GWAS and describes the process of predicting genotypes that have not kamagra wholesale been directly genotyped but are statistically inferred (imputed) based on haplotype blocks from a reference sequence.33–35 Often association tests between the imputed SNPs and trait are repeated. As genotype imputation requires individual-level data, researchers have proposed summary statistics imputation as a mechanism to infer the association between untyped SNPs and a trait. The performance of imputation has been evaluated and shown that, with certain limitations, summary statistics imputation is an kamagra wholesale efficient and cost-effective methodology to identify loci associated with traits when compared with imputation done on genotypes.36An alternative source of input data for the selection of SNPs and their weightings is through literature or in existing databases, where already known trait-associated SNPs and their effect sizes are used as the input parameters in model development. A number of studies have taken this approach37 38 and it is possible to use multiple sources when developing various polygenic models and establishing the preferred parameters to use.Currently, there does not appear to be one methodology that works across all contexts and traits, each trait will need to be assessed to determine which method is the most suitable for the trait being evaluated.

For example, four different polygenic model construction strategies were explored for three skin cancer subtypes4 by using data on SNPs and their effect sizes from different kamagra wholesale sources, such as the latest GWAS meta-analysis results, the National Human Genome Research Institute (NHGRI) EBI GWAS catalogue, UK Biobank GWAS summary statistics with different thresholds and GWAS summary statistics with LDpred. In this setting for basal cell carcinoma and melanoma, the meta-analysis and catalogue-derived models were found to perform similarly but that the latter was ultimately used as it included more SNPs. For squamous cell carcinoma the meta-analysis-derived model performed better kamagra wholesale than the catalogue-derived model. This demonstrates how each disease subtype, model kamagra wholesale construction strategy and data set can have their own limitations and advantages.Knowledge of the sources of input data and its subsequent use in model development is important in understanding the limitations of available models.

Models that are developed using data sets that reflect the population in which prediction is to be carried out will perform better. For example, data collected from a symptomatic or high-risk population may not be suitable as an input data set for the development of a polygenic model kamagra wholesale that will be used for disease prediction in the general population. Large GWAS studies were previously focused on high-risk individuals, such as patients with breast cancer with a strong family history or known pathogenic variants in BRCA1 or BRCA2. These studies would not be suitable for the development of PGS for use in the general population but can inform risk assessment in high-risk kamagra wholesale individuals.

The source of the data for SNP selection and weighting also has implications for downstream uses and validation. For example, variant frequency and LD patterns can vary between populations and this can translate to poor performance of the kamagra wholesale polygenic model if the external validation population is different from that of the input data set.39–41 Furthermore, the power and validity of polygenic analyses are influenced by the input data sources.12 42From a model to a scorePGS can be calculated using one of the methodologies discussed above. The resulting PGS units of measurement depend on which measurement is used for the weighting.12 For example, the weightings may have been calculated based on logOR for discrete traits or linear regression coefficient (β/beta) in continuous traits from univariate regression tests carried out in the GWAS. The resulting scores are then usually transformed to a standard normal distribution to give scores ranging from kamagra wholesale −1 to 1, or 0 to 100 for ease of interpretation.

This enables further examination of the association between the score and a trait and the predictive ability of different scores generated by different models. Similar to other biomarker analyses, this involves using the PGS as a predictor kamagra wholesale of a trait with other covariates (eg, age, smoking, and so on) added, if appropriate, in a target sample. Examination of differences in the distribution of scores in cases and controls, or by examining differences in traits between different strata of PGS can enable assessment of predictive ability (figure 3). Common practice is for individual-level PGS values to be used to stratify populations into distinct groups of risk based on percentile cut-off or threshold values (eg, the top 1%).Example distribution of polygenic scores across a kamagra wholesale population.

Thresholds can be set to stratify risk as low (some), average (most) and high (some)." data-icon-position data-hide-link-title="0">Figure 3 Example distribution of polygenic scores across a population. Thresholds can be set to stratify risk as low (some), average (most) and high (some).Model validationPolygenic model development is reliant on further data sets for model kamagra wholesale testing and validation and the composition of these data sets is important in ensuring that the models are appropriate for a particular purpose. The development of a model to calculate a PGS involves refinement of the previously discussed input parameters, and selection of the ‘best’ of several models based kamagra wholesale on performance (figure 2). Therefore, a testing/training data set is often required to assess the model’s ability to accurately predict the trait of interest.

This is often kamagra wholesale a data set that is independent of the base/input/discovery data set. It may comprise a subset of the discovery data set that is only used for testing and was not included in the initial development of the model but should ideally be a separate independent data set.Genotype and phenotype data are needed in these data sets. Polygenic models are used to calculate PGS for individuals in the training data set and regression analysis is performed with the PGS as a predictor of a trait kamagra wholesale. Other covariates may also be included, if appropriate.

This testing phase can be considered a process for kamagra wholesale identifying models with better overall performance and/or informing refinements needed. Hence, this phase often involves comparison of different models that are developed using the same input data set to identify those models that have optimal performance.The primary purpose is to determine which model best discriminates between cases and controls. The area under the curve (AUC) kamagra wholesale or the C-statistic is the most commonly used measure in assessing discriminative ability. It has been criticised as being an insensitive measure that is not able to fully capture all aspects of predictive ability.

For instance, in some instances, AUC can remain unchanged kamagra wholesale between models but the individuals within are categorised into a different risk group.43 Alternative metrics that have been used to evaluate model performance include increase in risk difference, integrated discrimination improvement, R2 (estimate of variance explained by the PGS after covariate adjustment), net classification index and the relative risk (highest percentile vs lowest percentile). A clear understanding on how to interpret the performance within various settings is important in determining which model is most suitable.44As per normal practice when developing any prediction model, polygenic models with the optimal performance in a testing/training data set should be further validated in external data sets. External data sets are critical in validation of models and assessment of generalisability, hence must also conform to the desired situations in kamagra wholesale which a model is to be used. The goal is to find a model with suitable parameters of predictive performance in data sets outside of those in which it was developed.

Ideally, external validation kamagra wholesale requires replication in independent data sets. Few existing polygenic models have been validated to this extent, the focus being rather on the development of new models rather than evaluation of existing ones. One example where replication has been carried out is in the field of CAD, where the GPSCAD45 and metaGRSCAD10 polygenic kamagra wholesale models (both developed using UK Biobank data) were evaluated in a Finnish population cohort.46 Predictive ability was found to be lower in the Finnish population. This is likely to be due to the differences in genetic structure of this population and the kamagra wholesale population of the data set used for polygenic model development.

Research is ongoing to evaluate polygenic models in other populations and strategies are being developed to ensure the same performance when used more widely, possibly through reweighting and adjustment of the scores.47Moving towards clinical applicationsPGS are thought to be useful information that could improve risk estimation and provide an avenue for disease prevention and deciding treatment strategies. There are indications from a number of fields that genetic information in the form of PGS can act as independent biomarkers and aid stratification.11 16 48 However, the clinical benefits of stratification kamagra wholesale using a PGS and the implications for clinical practice are only just beginning to be examined. The use of PGS as part of existing risk prediction tools or as a stand-alone predictor has been suggested. This latter option may be true for diseases where knowledge or predictive ability with other risk factors is limited, such as in prostate cancer.49 In either case, polygenic models need to be individually examined to determine suitability and applicability kamagra wholesale for the specific clinical question.50 Despite some commercial companies developing PGS,51 52 currently PGS are not an established part of clinical practice.Integration into clinical practice requires evaluation of a PGS-based test.

An important concept to consider in this regard is the distinction between an assay and a test. This has kamagra wholesale been previously discussed with respect to genetic test evaluation.53 54 It is worth examining this concept as applied to PGS, as their evaluation is reliant on a clear understanding of the test to be offered. As outlined by Zimmern and Kroese,54 the method used to analyse a substance in a sample is considered the assay, whereas a test is the use of an assay within a specific context. With respect to PGS, the process of developing a model to derive a score can be considered the kamagra wholesale assay, while the use of this model for a particular disease, population and purpose can be considered the test.

This distinction is important when assessing if studies are reporting on assay performance as opposed to test performance. It is our view that, with respect to polygenic models, progress has been made with respect to assay development, but PGS-based tests are yet to be developed and evaluated kamagra wholesale. This can enable a clearer understanding of their potential clinical utility and issues that may arise for clinical implementation.11 18 55 It is clear that this is still an evolving field, and going forward different models may be required for different traits due to their underlying genetic architecture,26 different clinical contexts and needs.Clinical contexts where risk stratification is already established practice are most likely where implementation of PGS will occur first. Risk prediction models based on non-genetic factors have been developed for many conditions and are used in clinical care, for example, in cardiovascular disease over 100 such models exist.56 In such contexts, how a PGS and its ability to predict risk compared with, or improves on, these existing models is being investigated.3 44 57–61 The extent to which PGS improves prediction, as well as the cost implications of including this, is likely to impact kamagra wholesale on implementation.Integration of PGS into clinical practice, for any application, requires robust and validated mechanisms to generate these scores.

Therefore, given the numerous models available, an assessment of their suitability as part of a test is required. Parameters or guidelines with respect to aspects of model performance and metrics that could assist kamagra wholesale in selecting the model to take forward as a PGS-based test are limited and need to be addressed. Currently, there are different mechanisms to generate PGS and have arisen in response to the challenges in aggregating large-scale genomic data for prediction. For example, a review reported 29 PGS models for breast cancer from 22 publications.62 Due to there being a number of different methodologies to generate a score, numerous models may exist for the same condition and each of kamagra wholesale the resulting models could perform differently.

Models may perform differently because the population, measured outcome or context of the development data sets used to generate the models is diverse, for example, a score for risk kamagra wholesale of breast cancer versus a breast cancer subtype.44 63 This diversity, alongside the lack of established best practice and standardised reporting in publications, makes comparison and evaluation of polygenic models for use in clinical settings challenging. It is clear that moving the field forward is reliant on transparent reporting and evaluation. Recommendations for best practices on the reporting of polygenic models in literature have been proposed14 64 as well as a database,65 66 which kamagra wholesale could allow for such comparisons. Statements and guidelines for risk prediction model development, such as the Genetic Risk Prediction Studies and Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD), already exist, but are not consistently used.

TRIPOD explicitly covers the development and validation of prediction models for both diagnosis and prognosis, for all medical domains.One clear issue is generalisability and drop in kamagra wholesale performance of polygenic models once they are applied in a population group different from the one in which they were developed.22 46 67–70 This is an ongoing challenge in genomics as most GWAS, from which most PGS are being developed, have been conducted in European-Caucasian populations.71 Efforts to improve representation are underway72 and there are attempts to reweight/adjust scores when applied to different population groups which are showing some potential but need further research.47 Others have demonstrated that models developed in more diverse population groups have improved performance when applied to external data sets in different populations.24 73 It is important to consider this issue when moving towards clinical applications as it may pose an ethical challenge if the PGS is not generalisable.A greater understanding of different complex traits and the impact of pleiotropy is only beginning to be investigated.74 There is growing appreciation of the role of pleiotropy as multiple variants have been identified to be associated with multiple traits and exert diverse effects, providing insight into overlapping mechanisms.75 76 This, together with the impact of population stratification, genetic relatedness, ascertainment and other sources of heterogeneity leading to spurious signals and reduced power in genetic association studies, all impacting on the predictive ability of PGS in different populations and for different diseases.While many publications report on model development and evaluation, often there is a lack of clarity on intended purpose,50 77 leading to uncertainties as to the clinical pathways in which implementation is envisaged. A clear description of intended use within clinical pathways is a central component in evaluating the use of an application with any form of PGS and in considering practical implications, such as mechanisms of obtaining the score, incorporation into health records, interpretation of scores, relevant cut-offs for intervention initiation, mechanisms for feedback of results and costs, among other issues. These parameters will also be impacted by the polygenic model that is taken forward for kamagra wholesale implementation. Meaning that there are still some important questions that need to be addressed to determine how and where PGS could work within current healthcare systems, particularly at a population level.78It is widely accepted that genotyping using arrays is a lower cost endeavour in comparison to genome sequencing, making the incorporation of PGS into routine healthcare an attractive proposition.

However, we were unable to find any studies reporting kamagra wholesale on the use or associated costs of such technology for population screening. Studies are beginning to examine use case scenarios and model cost-effectiveness, but this has only been in very few, specific investigations.79 80 Costs will also be influenced by the testing technology and by the downstream consequences of testing, which is likely to differ depending on specific applications that are developed and the pathways in which such tests are incorporated. This is particularly the case in screening or primary care settings, kamagra wholesale where such testing is currently not an established part of care pathways and may require additional resources, not least as a result of the volume of testing that could be expected. Moving forward, the clinical role of PGS needs to be developed further, including defining the clinical applications as well as supporting evidence, for example, on the effect of clinical outcomes, the feasibility for use in routine practice and cost-effectiveness.ConclusionThere is a large amount of diversity in the PGS field with respect to model development approaches, and this continues to evolve.

There is rapid progress which is being driven by the availability of larger data kamagra wholesale sets, primarily from GWAS and concomitant developments in statistical methodologies. As understanding and knowledge develops, the usefulness and appropriateness of polygenic models for different diseases and contexts are being explored. Nevertheless, this is still an emerging kamagra wholesale field, with a variable evidence base demonstrating some potential. The validity of PGS needs to be clearly demonstrated, and their applications evaluated prior to clinical implementation..

Kamagra jelly amazon

IntroductionThere has been considerable interest in elucidating the contribution of genetic factors to the kamagra jelly amazon development of common diseases and using this information for better prediction of disease risk where to get kamagra. The common disease common variant hypothesis predicts that variants that are common in the population play a role in disease susceptibility.1 Genome-wide association studies (GWAS) kamagra jelly amazon using single nucleotide polymorphism (SNP) arrays were developed as a mechanism by which to investigate these genetic factors and it was hoped this would lead to identification of variants associated with disease risk and subsequent development of predictive tests. Variants identified as associated with particular traits by these studies, for the large part, are SNPs that individually have a minor effect on disease risk and hence, by themselves, cannot be reliably used in disease prediction.

Looking at the aggregate impact of these SNPs in the form of a polygenic score (PGS) appeared to be one possible means of using this information to predict disease.2 It is thought this will be of benefit as our genetic make-up is largely stable kamagra jelly amazon from birth and dictates a ‘baseline risk’ on which external influences act and modulate. Therefore, PGS are a potential mechanism to act as a risk predictor by capturing information on this genetic liability.The use of PGS as a predictive biomarker is being explored in a number of different disease areas, including cancer,3 4 psychiatric disorders,5–7 metabolic disorders (diabetes,8 obesity9) and coronary artery disease (CAD).10 The proposed applications range from aiding disease diagnosis, informing selection of therapeutic interventions, improvement of risk prediction, informing disease screening and, on a personal level, informing life planning. Therefore, genetic risk information in the form of a PGS is considered kamagra jelly amazon to have potential in informing both clinical and individual-level decision-making.Recent advances in statistical techniques, improved computational power and the availability of large data sets have led to rapid developments in this area over the past few years.

This has resulted in a variety of approaches to construction of models for score calculation and the investigation of these scores for prediction of common diseases.11 Several review articles aimed at researchers with a working knowledge of this field have been produced.6 11–17 In this article, we provide an overview of the key aspects of PGS construction to assist clinicians and researchers in other areas of academia to gain an understanding of the processes involved in score construction. We also consider the implications of evolving methodologies for the development of applications of PGS in healthcare.Evolution in polygenic model construction methodologiesTerminology with respect to PGS has evolved over time, reflecting evolving approaches and kamagra jelly amazon methodology. Other terms include PGS, polygenic risk score, polygenic load, genotype score, genetic burden, polygenic hazard score, genetic risk score (GRS), metaGRS and allelic risk score.

Throughout this article we use the terms polygenic models to refer to the method used to calculate an output in kamagra jelly amazon the form of a PGS. Different polygenic models can be used to calculate a PGS and analysis of these scores can be used to examine associations with particular markers or to predict an individuals risk of diseases.12Usual practice in calculating PGS is as a weighted sum of a number of risk alleles carried by an individual, where the risk alleles and their weights are defined by SNPs and their measured effects (figure 1).11 Polygenic models have been constructed using a few, hundreds or thousands of SNPs, and more recently SNPs across the whole genome. Consequently, determining which SNPs to include and the disease-associated weighting to assign to SNPs are important aspects of model construction (figure 2).18 These aspects are influenced by available genotype data and effect size estimates as well as the methodology employed in turning this information into model kamagra jelly amazon parameters (ie, weighted SNPs).Polygenic score calculation.

This calculation aggregates the SNPs and their weights selected for a polygenic score. Common diseases are thought to be kamagra jelly amazon influenced by many genetic variants with small individual effect sizes, such that meaningful risk prediction necessitates examining the aggregated impact of these multiple variants including their weightings. PGS, polygenic score." data-icon-position data-hide-link-title="0">Figure 1 Polygenic score calculation.

This calculation aggregates the SNPs and their weights selected for a kamagra jelly amazon polygenic score. Common diseases are thought to be influenced by many genetic variants with small individual effect sizes, such that meaningful risk prediction necessitates examining the aggregated impact of kamagra jelly amazon these multiple variants including their weightings. PGS, polygenic score.Construction of a polygenic score.

In the kamagra jelly amazon process of developing a polygenic score, numerous models are tested and then compared. The model that performs best (as determined by one or more measures) is then selected for validation in the external data set. GWAS, genome-wide kamagra jelly amazon association studies." data-icon-position data-hide-link-title="0">Figure 2 Construction of a polygenic score.

In the process of developing a polygenic score, numerous models are tested and then compared. The model that performs best (as determined by one kamagra jelly amazon or more measures) is then selected for validation in the external data set. GWAS, genome-wide association studies.Changes in data availability over time have had an impact on the approach taken in SNP selection and weighting.

Early studies to identify variants associated with common diseases took the kamagra jelly amazon form of candidate gene studies. The small size of candidate gene studies, the limitation of technologies available for genotyping and stringent significance thresholds meant that these studies investigated fewer variants and those that were identified with disease associations had relatively large effect sizes.19 Taken together, this meant that a relatively small number of variants were available for consideration for inclusion in a polygenic model.20 21 Furthermore, weighting parameters for these few variants were often simplistic, such as counts of the number of risk alleles carried, ignoring their individual effect sizes.16The advent of GWAS enabled assessment of SNPs across the genome, leading to the identification of a larger number of disease-associated variants and therefore more variants suitable for inclusion in a polygenic model. In addition, the increasing number of individuals in the association studies meant that the power of these studies increased, allowing for more precise estimates of effect sizes.19 Furthermore, some theorised that kamagra jelly amazon lowering stringent significance thresholds set for SNP–trait associations could also identify SNPs that might play a part in disease risk.11 16 This resulted in more options with respect to polygenic model parameters of SNPs to include and weights to assign to them.

However, the inclusion of more SNPs and direct application of GWAS effect sizes as a weighting parameter does not always equate to better predictive performance.4 16 This is because GWAS do not provide perfect information with respect to the causal SNP, the effect sizes or the number of SNPs that contribute to the trait. Therefore, different methods kamagra jelly amazon have been developed to address these issues and optimise predictive performance of the score. Current common practice is to construct models with different iterations of SNPs and weighting, with assessment of the performance of each to identify the optimum configuration of SNPs and their weights (figure 2).Methods used in SNP selection and weighting assignmentSome methods of model development will initially involve selection of SNPs followed by optimisation of weighting, whereas others may involve optimisation of weightings for all SNPs that have been genotyped using their overall GWAS effect sizes, the linkage disequilibrium (LD) and an estimate of the proportion of SNPs that are expected to contribute to the risk.22LD is the phenomenon where some SNPs are coinherited more frequently with other SNPs due to their close proximity on the genome.

Segments with kamagra jelly amazon strong LD between SNPs are referred to as haplotype blocks. This phenomenon means that GWAS often identify multiple SNPs in the same haplotype block associated with disease and the true causal SNP is not known. As models have started to assess more SNPs, careful consideration is required to take into account possible correlation between SNPs as a kamagra jelly amazon result of this phenomenon.

Correlation between SNPs can lead to double counting of SNPs and association kamagra jelly amazon redundancy, where multiple SNPs in a region of LD are identified as being associated with the outcome. This can lead to reduction in the predictive performance of the model. Therefore, processes for filtering SNPs and using one SNP (tag SNP) to act as a kamagra jelly amazon marker in an area of high LD, through LD thinning, were developed.

Through these processes SNPs correlated with other SNPs in a block are removed, by either pruning or clumping. Pruning ignores p value thresholds and ‘eliminates’ SNPs by a process of iterative comparison between a pair of SNPs to assess if they are correlated, and subsequently could remove SNPs that are deemed kamagra jelly amazon to have evidence of association. Clumping (also known as informed pruning) is guided by GWAS p values and chooses the most significant SNP, therefore keeping the most significant SNP within a block.23 This is all done with the aim of pinpointing relatively small areas of the genome that contribute to risk of the trait.

Different significance thresholds may be used to select SNPs from this subgroup for inclusion in models.Poor performance of a model can result from imperfect tagging kamagra jelly amazon with the underlying causal SNP.16 This is because the causal SNP that is associated with disease might not be in LD with the tag SNP that is in the model but is in LD with another SNP which is not in the model. This particularly occurs where the LD and variant frequency differs between population groups.24 An alternate approach to filter SNPs is stepwise regression where SNPs are selected based on how much the SNPs improve the model’s performance. This is a statistical approach and does not consider the impact of kamagra jelly amazon LD or effect size.As described above, early studies used simple weighting approaches or directly applied effect sizes from GWAS as weighting parameters for SNPs.

However, application of effect sizes as a weighting parameter directly from a GWAS may not be optimal, due to differences in the population that the GWAS was conducted in and the target population. Also as kamagra jelly amazon described above, LD and the fact that not all SNPs may contribute to the trait mean that these effect sizes from GWAS are imperfect estimates. Therefore, methods have been developed that adjust effect size estimates from GWAS using statistical techniques which make assumptions about factors such as the number of causal SNPs, level of LD between SNPs or knowledge of their potential function to better reflect their impact on a trait.

Numerous statistical methodologies have been developed to improve weighting with a view to enhancing the discriminative power of a PGS.25 26 Examples of some methodological approaches are LDpred,22 winner’s curse correction,23 empirical Bayes estimation,27 shrinkage regression (Lasso),28 linear mixed models,29 with kamagra jelly amazon more being developed or tested. An additional improvement on the methods is to embed non-genetic information (eg, age-specific ORs).6 Determination of which methodology or hybrid of methodologies is most appropriate for various settings and conditions is continuously being explored and is evolving with new statistical approaches developing at a rapid pace.In summary, model development has evolved in an attempt to gain the most from available GWAS data and address some of the issues that arise due to working with data sets which cannot be directly translated into parameters for prediction models. The different approaches taken in kamagra jelly amazon SNP selection and weighting, and the impact on the predictive performance of a model are important to consider when assessing different models.

This is because different approaches to PGS modelling can achieve the same or a similar level of prediction. From a health system implementation perspective, kamagra jelly amazon particular approaches may be preferred following practical considerations and trade-offs between obtaining genotype data, processes for score construction and model performance. In addition, the degree to which these parameters need to be optimised will also be impacted by the input data and validation data set, and the quality control procedures that need to be applied to these data sets.12Sources of input data for score constructionKey to the development of a polygenic model is the availability kamagra jelly amazon of data sets that can provide input parameters for model construction.

Genotype data used in model construction can either be available as raw GWAS data or provided as GWAS summary statistics. Data in the raw format are individual-level data from a SNP array and may not have undergone basic quality control such as assessment of missingness, sex discrepancy checks, deviation from Hardy-Weinberg equilibrium, heterozygosity rate, relatedness or assessment for outliers.30 31 Availability of raw GWAS data allows for different polygenic models to be developed because of the kamagra jelly amazon richness of the data, however computational issues arise because of the size of the data sets. Data based on genome sequencing, as opposed to SNP arrays, could also be used in model construction.

There have kamagra jelly amazon been limited studies of PGS developed from this form of data due to limitations in data availability, which is mainly due to cost restraints.15 32 Individual-level genomic data are also often not available to researchers due to privacy concerns.Due to these issues, the focus of polygenic model development has therefore been on using well-powered GWAS summary statistics.33 These are available from open access repositories and contain summary information such as the allele positions, ORs, CIs and allele frequency, without containing confidential information on individuals. These data sets have usually been through the basic quality control measures mentioned above. There are, kamagra jelly amazon however, no standards for publicly available files, meaning some further processing steps may be required, in particular when various data sets are combined for a meta-analysis.

Quality control on summary statistics is only possible if information such as missing genotype rate, minor allele frequency, Hardy-Weinberg equilibrium failures and non-Mendelian transmission rates is provided.12Processing of GWAS data may include additional quality control steps, imputation and filtering of the SNP information, which can be done at the level of genotype or summary statistics data. SNP arrays used in GWAS only kamagra jelly amazon have common SNPs represented on them as they rely on LD between SNPs to cover the entire genome. As described above, one tag SNP on the array can represent many other SNPs.

Imputation of SNPs is common in GWAS and describes the process of predicting genotypes that have not been directly genotyped but are statistically inferred (imputed) based on haplotype blocks from a reference sequence.33–35 Often association tests kamagra jelly amazon between the imputed SNPs and trait are repeated. As genotype imputation requires individual-level data, researchers have proposed summary statistics imputation as a mechanism to infer the association between untyped SNPs and a trait. The performance of imputation has kamagra jelly amazon been evaluated and shown that, with certain limitations, summary statistics imputation is an efficient and cost-effective methodology to identify loci associated with traits when compared with imputation done on genotypes.36An alternative source of input data for the selection of SNPs and their weightings is through literature or in existing databases, where already known trait-associated SNPs and their effect sizes are used as the input parameters in model development.

A number of studies have taken this approach37 38 and it is possible to use multiple sources when developing various polygenic models and establishing the preferred parameters to use.Currently, there does not appear to be one methodology that works across all contexts and traits, each trait will need to be assessed to determine which method is the most suitable for the trait being evaluated. For example, four different polygenic model construction strategies were explored for three skin cancer subtypes4 by using data on SNPs and their effect sizes from different sources, such as the latest GWAS meta-analysis results, the National Human Genome Research Institute (NHGRI) EBI GWAS catalogue, UK Biobank GWAS summary statistics with different thresholds and GWAS summary statistics with kamagra jelly amazon LDpred. In this setting for basal cell carcinoma and melanoma, the meta-analysis and catalogue-derived models were found to perform similarly but that the latter was ultimately used as it included more SNPs.

For squamous cell carcinoma the meta-analysis-derived model performed better than check my blog the catalogue-derived kamagra jelly amazon model. This demonstrates how each disease subtype, kamagra jelly amazon model construction strategy and data set can have their own limitations and advantages.Knowledge of the sources of input data and its subsequent use in model development is important in understanding the limitations of available models. Models that are developed using data sets that reflect the population in which prediction is to be carried out will perform better.

For example, data collected from a symptomatic or high-risk population may not be suitable as an input data set for kamagra jelly amazon the development of a polygenic model that will be used for disease prediction in the general population. Large GWAS studies were previously focused on high-risk individuals, such as patients with breast cancer with a strong family history or known pathogenic variants in BRCA1 or BRCA2. These studies kamagra jelly amazon would not be suitable for the development of PGS for use in the general population but can inform risk assessment in high-risk individuals.

The source of the data for SNP selection and weighting also has implications for downstream uses and validation. For example, variant frequency and LD patterns can vary between populations and this can translate to poor performance of the polygenic model if the external validation population is different from that of the input data set.39–41 Furthermore, kamagra jelly amazon the power and validity of polygenic analyses are influenced by the input data sources.12 42From a model to a scorePGS can be calculated using one of the methodologies discussed above. The resulting PGS units of measurement depend on which measurement is used for the weighting.12 For example, the weightings may have been calculated based on logOR for discrete traits or linear regression coefficient (β/beta) in continuous traits from univariate regression tests carried out in the GWAS.

The resulting scores are then usually transformed to a standard normal distribution to give scores ranging from kamagra jelly amazon −1 to 1, or 0 to 100 for ease of interpretation. This enables further examination of the association between the score and a trait and the predictive ability of different scores generated by different models. Similar to other biomarker analyses, this involves using the PGS as a predictor of a trait with other covariates (eg, age, smoking, and so on) added, if appropriate, in a target kamagra jelly amazon sample.

Examination of differences in the distribution of scores in cases and controls, or by examining differences in traits between different strata of PGS can enable assessment of predictive ability (figure 3). Common practice is for individual-level PGS values to kamagra jelly amazon be used to stratify populations into distinct groups of risk based on percentile cut-off or threshold values (eg, the top 1%).Example distribution of polygenic scores across a population. Thresholds can be set to stratify risk as low (some), average (most) and high (some)." data-icon-position data-hide-link-title="0">Figure 3 Example distribution of polygenic scores across a population.

Thresholds can be set to stratify risk as low (some), average (most) and high (some).Model validationPolygenic model development is reliant on further data sets for model testing and validation and the composition of these data sets is important in ensuring that the models are appropriate for a particular purpose kamagra jelly amazon. The development of a model to calculate a PGS involves refinement of the previously discussed input kamagra jelly amazon parameters, and selection of the ‘best’ of several models based on performance (figure 2). Therefore, a testing/training data set is often required to assess the model’s ability to accurately predict the trait of interest.

This is often a data set that kamagra jelly amazon is independent of the base/input/discovery data set. It may comprise a subset of the discovery data set that is only used for testing and was not included in the initial development of the model but should ideally be a separate independent data set.Genotype and phenotype data are needed in these data sets. Polygenic models are used to kamagra jelly amazon calculate PGS for individuals in the training data set and regression analysis is performed with the PGS as a predictor of a trait.

Other covariates may also be included, if appropriate. This testing phase can be considered a process for identifying models with kamagra jelly amazon better overall performance and/or informing refinements needed. Hence, this phase often involves comparison of different models that are developed using the same input data set to identify those models that have optimal performance.The primary purpose is to determine which model best discriminates between cases and controls.

The area under the curve (AUC) kamagra jelly amazon or the C-statistic is the most commonly used measure in assessing discriminative ability. It has been criticised as being an insensitive measure that is not able to fully capture all aspects of predictive ability. For instance, in some instances, AUC can remain unchanged between models but the individuals within are categorised into a different risk group.43 Alternative metrics that have been used to evaluate model performance include increase in risk difference, kamagra jelly amazon integrated discrimination improvement, R2 (estimate of variance explained by the PGS after covariate adjustment), net classification index and the relative risk (highest percentile vs lowest percentile).

A clear understanding on how to interpret the performance within various settings is important in determining which model is most suitable.44As per normal practice when developing any prediction model, polygenic models with the optimal performance in a testing/training data set should be further validated in external data sets. External data sets are critical kamagra jelly amazon in validation of models and assessment of generalisability, hence must also conform to the desired situations in which a model is to be used. The goal is to find a model with suitable parameters of predictive performance in data sets outside of those in which it was developed.

Ideally, external kamagra jelly amazon validation requires replication in independent data sets. Few existing polygenic models have been validated to this extent, the focus being rather on the development of new models rather than evaluation of existing ones. One example where replication has been carried out is in the field of CAD, where the GPSCAD45 and metaGRSCAD10 polygenic models (both developed using UK Biobank data) were evaluated in a Finnish population cohort.46 Predictive ability was found to be lower in the kamagra jelly amazon Finnish population.

This is likely to be due to the differences in genetic structure of kamagra jelly amazon this population and the population of the data set used for polygenic model development. Research is ongoing to evaluate polygenic models in other populations and strategies are being developed to ensure the same performance when used more widely, possibly through reweighting and adjustment of the scores.47Moving towards clinical applicationsPGS are thought to be useful information that could improve risk estimation and provide an avenue for disease prevention and deciding treatment strategies. There are indications from a number of fields that kamagra jelly amazon genetic information in the form of PGS can act as independent biomarkers and aid stratification.11 16 48 However, the clinical benefits of stratification using a PGS and the implications for clinical practice are only just beginning to be examined.

The use of PGS as part of existing risk prediction tools or as a stand-alone predictor has been suggested. This latter option may be true for diseases where knowledge or predictive ability with other risk factors is limited, such as in prostate cancer.49 In either case, polygenic models need to be individually examined to determine suitability and applicability for the specific clinical question.50 Despite some commercial companies developing PGS,51 52 currently PGS are not an established part kamagra jelly amazon of clinical practice.Integration into clinical practice requires evaluation of a PGS-based test. An important concept to consider in this regard is the distinction between an assay and a test.

This has been previously discussed with respect to genetic test evaluation.53 54 It is worth examining this concept as applied to PGS, as their evaluation kamagra jelly amazon is reliant on a clear understanding of the test to be offered. As outlined by Zimmern and Kroese,54 the method used to analyse a substance in a sample is considered the assay, whereas a test is the use of an assay within a specific context. With respect to PGS, the process of developing a model to derive a score can kamagra jelly amazon be considered the assay, while the use of this model for a particular disease, population and purpose can be considered the test.

This distinction is important when assessing if studies are reporting on assay performance as opposed to test performance. It is our view that, with respect to polygenic models, progress has been made with respect to assay development, kamagra jelly amazon but PGS-based tests are yet to be developed and evaluated. This can enable a clearer understanding of their potential clinical utility and issues that may arise for clinical implementation.11 18 55 It is clear that this is still an evolving field, and going forward different models may be required for different traits due to their underlying genetic architecture,26 different clinical contexts and needs.Clinical contexts where risk stratification is already established practice are most likely where implementation of PGS will occur first.

Risk prediction models based on non-genetic factors have been developed for many conditions and are used in clinical care, for example, in cardiovascular disease over 100 such models exist.56 In such contexts, how a PGS and its ability to predict kamagra jelly amazon risk compared with, or improves on, these existing models is being investigated.3 44 57–61 The extent to which PGS improves prediction, as well as the cost implications of including this, is likely to impact on implementation.Integration of PGS into clinical practice, for any application, requires robust and validated mechanisms to generate these scores. Therefore, given the numerous models available, an assessment of their suitability as part of a test is required. Parameters or guidelines with respect to aspects of model performance and metrics that could kamagra jelly amazon assist in selecting the model to take forward as a PGS-based test are limited and need to be addressed.

Currently, there are different mechanisms to generate PGS and have arisen in response to the challenges in aggregating large-scale genomic data for prediction. For example, a review reported 29 PGS models for breast cancer from 22 publications.62 Due to there being a number of different methodologies to generate a score, numerous models may exist kamagra jelly amazon for the same condition and each of the resulting models could perform differently. Models may perform differently because the population, measured outcome or context of the development data sets used to generate the models is diverse, for example, a score for risk of breast cancer versus a breast cancer subtype.44 63 This diversity, alongside the lack kamagra jelly amazon of established best practice and standardised reporting in publications, makes comparison and evaluation of polygenic models for use in clinical settings challenging.

It is clear that moving the field forward is reliant on transparent reporting and evaluation. Recommendations for best practices on the kamagra jelly amazon reporting of polygenic models in literature have been proposed14 64 as well as a database,65 66 which could allow for such comparisons. Statements and guidelines for risk prediction model development, such as the Genetic Risk Prediction Studies and Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD), already exist, but are not consistently used.

TRIPOD explicitly covers the development and validation of prediction models for both diagnosis and prognosis, for all medical domains.One clear issue is generalisability and drop in performance of polygenic models once they are applied in a population group different from the one in which they were developed.22 46 67–70 This is an ongoing challenge in genomics as most GWAS, from which most PGS are being developed, have been conducted in European-Caucasian populations.71 Efforts to improve representation are underway72 and there are attempts to reweight/adjust scores when applied to different population groups which are showing some potential but need further research.47 Others have demonstrated that models developed in more diverse population groups have improved performance when applied to external data sets in different populations.24 73 It is important to consider this issue when moving towards clinical applications as it may pose an ethical challenge if the PGS is not generalisable.A greater understanding of different complex traits and the impact of pleiotropy is only beginning to be investigated.74 There is growing appreciation of the role of pleiotropy as multiple variants have been identified to be associated with multiple traits and exert diverse effects, providing insight into overlapping mechanisms.75 76 This, together with the impact of population stratification, kamagra jelly amazon genetic relatedness, ascertainment and other sources of heterogeneity leading to spurious signals and reduced power in genetic association studies, all impacting on the predictive ability of PGS in different populations and for different diseases.While many publications report on model development and evaluation, often there is a lack of clarity on intended purpose,50 77 leading to uncertainties as to the clinical pathways in which implementation is envisaged. A clear description of intended use within clinical pathways is a central component in evaluating the use of an application with any form of PGS and in considering practical implications, such as mechanisms of obtaining the score, incorporation into health records, interpretation of scores, relevant cut-offs for intervention initiation, mechanisms for feedback of results and costs, among other issues. These parameters will also be impacted by the polygenic model that kamagra jelly amazon is taken forward for implementation.

Meaning that there are still some important questions that need to be addressed to determine how and where PGS could work within current healthcare systems, particularly at a population level.78It is widely accepted that genotyping using arrays is a lower cost endeavour in comparison to genome sequencing, making the incorporation of PGS into routine healthcare an attractive proposition. However, we kamagra jelly amazon were unable to find any studies reporting on the use or associated costs of such technology for population screening. Studies are beginning to examine use case scenarios and model cost-effectiveness, but this has only been in very few, specific investigations.79 80 Costs will also be influenced by the testing technology and by the downstream consequences of testing, which is likely to differ depending on specific applications that are developed and the pathways in which such tests are incorporated.

This is particularly the case in screening or primary care settings, where such testing is currently not an established part of care pathways and may require additional resources, not least as a result of the volume of testing kamagra jelly amazon that could be expected. Moving forward, the clinical role of PGS needs to be developed further, including defining the clinical applications as well as supporting evidence, for example, on the effect of clinical outcomes, the feasibility for use in routine practice and cost-effectiveness.ConclusionThere is a large amount of diversity in the PGS field with respect to model development approaches, and this continues to evolve. There is rapid progress kamagra jelly amazon which is being driven by the availability of larger data sets, primarily from GWAS and concomitant developments in statistical methodologies.

As understanding and knowledge develops, the usefulness and appropriateness of polygenic models for different diseases and contexts are being explored. Nevertheless, this kamagra jelly amazon is still an emerging field, with a variable evidence base demonstrating some potential. The validity of PGS needs to be clearly demonstrated, and their applications evaluated prior to clinical implementation..

IntroductionThere has been considerable interest in elucidating the contribution of genetic factors to the development of common diseases and kamagra wholesale using this information for better prediction https://www.gaertnerei-berger.at/pflanzen/ of disease risk. The common disease common variant hypothesis predicts that variants that are common in the population play a role in disease susceptibility.1 Genome-wide association kamagra wholesale studies (GWAS) using single nucleotide polymorphism (SNP) arrays were developed as a mechanism by which to investigate these genetic factors and it was hoped this would lead to identification of variants associated with disease risk and subsequent development of predictive tests. Variants identified as associated with particular traits by these studies, for the large part, are SNPs that individually have a minor effect on disease risk and hence, by themselves, cannot be reliably used in disease prediction. Looking at kamagra wholesale the aggregate impact of these SNPs in the form of a polygenic score (PGS) appeared to be one possible means of using this information to predict disease.2 It is thought this will be of benefit as our genetic make-up is largely stable from birth and dictates a ‘baseline risk’ on which external influences act and modulate. Therefore, PGS are a potential mechanism to act as a risk predictor by capturing information on this genetic liability.The use of PGS as a predictive biomarker is being explored in a number of different disease areas, including cancer,3 4 psychiatric disorders,5–7 metabolic disorders (diabetes,8 obesity9) and coronary artery disease (CAD).10 The proposed applications range from aiding disease diagnosis, informing selection of therapeutic interventions, improvement of risk prediction, informing disease screening and, on a personal level, informing life planning.

Therefore, genetic risk information in the form of a PGS is considered to have potential in informing both clinical and individual-level decision-making.Recent advances in statistical techniques, improved computational power and the availability of large data sets have led to rapid kamagra wholesale developments in this area over the past few years. This has resulted in a variety of approaches to construction of models for score calculation and the investigation of these scores for prediction of common diseases.11 Several review articles aimed at researchers with a working knowledge of this field have been produced.6 11–17 In this article, we provide an overview of the key aspects of PGS construction to assist clinicians and researchers in other areas of academia to gain an understanding of the processes involved in score construction. We also consider the implications of evolving methodologies for the development of applications of PGS in healthcare.Evolution in polygenic model construction methodologiesTerminology kamagra wholesale with respect to PGS has evolved over time, reflecting evolving approaches and methodology. Other terms include PGS, polygenic risk score, polygenic load, genotype score, genetic burden, polygenic hazard score, genetic risk score (GRS), metaGRS and allelic risk score. Throughout this article we use the terms polygenic models to refer kamagra wholesale to the method used to calculate an output in the form of a PGS.

Different polygenic models can be used to calculate a PGS and analysis of these scores can be used to examine associations with particular markers or to predict an individuals risk of diseases.12Usual practice in calculating PGS is as a weighted sum of a number of risk alleles carried by an individual, where the risk alleles and their weights are defined by SNPs and their measured effects (figure 1).11 Polygenic models have been constructed using a few, hundreds or thousands of SNPs, and more recently SNPs across the whole genome. Consequently, determining which SNPs to include and the disease-associated weighting to assign to SNPs kamagra wholesale are important aspects of model construction (figure 2).18 These aspects are influenced by available genotype data and effect size estimates as well as the methodology employed in turning this information into model parameters (ie, weighted SNPs).Polygenic score calculation. This calculation aggregates the SNPs and their weights selected for a polygenic score. Common diseases are thought to be influenced by many genetic variants with small individual effect sizes, such that meaningful risk prediction necessitates kamagra wholesale examining the aggregated impact of these multiple variants including their weightings. PGS, polygenic score." data-icon-position data-hide-link-title="0">Figure 1 Polygenic score calculation.

This calculation aggregates the SNPs and their weights selected for kamagra wholesale a polygenic score. Common diseases are thought to be influenced by many genetic variants with small individual effect sizes, such that meaningful risk prediction necessitates examining the aggregated impact of these multiple variants kamagra wholesale including their weightings. PGS, polygenic score.Construction of a polygenic score. In the process kamagra wholesale of developing a polygenic score, numerous models are tested and then compared. The model that performs best (as determined by one or more measures) is then selected for validation in the external data set.

GWAS, genome-wide association studies." data-icon-position data-hide-link-title="0">Figure 2 Construction kamagra wholesale of a polygenic score. In the process of developing a polygenic score, numerous models are tested and then compared. The model that performs best (as determined by one or more measures) is then selected for validation in the external data kamagra wholesale set. GWAS, genome-wide association studies.Changes in data availability over time have had an impact on the approach taken in SNP selection and weighting. Early studies to identify variants associated with common diseases took the form of candidate kamagra wholesale gene studies.

The small size of candidate gene studies, the limitation of technologies available for genotyping and stringent significance thresholds meant that these studies investigated fewer variants and those that were identified with disease associations had relatively large effect sizes.19 Taken together, this meant that a relatively small number of variants were available for consideration for inclusion in a polygenic model.20 21 Furthermore, weighting parameters for these few variants were often simplistic, such as counts of the number of risk alleles carried, ignoring their individual effect sizes.16The advent of GWAS enabled assessment of SNPs across the genome, leading to the identification of a larger number of disease-associated variants and therefore more variants suitable for inclusion in a polygenic model. In addition, the increasing number of individuals in the association studies meant that kamagra wholesale the power of these studies increased, allowing for more precise estimates of effect sizes.19 Furthermore, some theorised that lowering stringent significance thresholds set for SNP–trait associations could also identify SNPs that might play a part in disease risk.11 16 This resulted in more options with respect to polygenic model parameters of SNPs to include and weights to assign to them. However, the inclusion of more SNPs and direct application of GWAS effect sizes as a weighting parameter does not always equate to better predictive performance.4 16 This is because GWAS do not provide perfect information with respect to the causal SNP, the effect sizes or the number of SNPs that contribute to the trait. Therefore, different methods have been kamagra wholesale developed to address these issues and optimise predictive performance of the score. Current common practice is to construct models with different iterations of SNPs and weighting, with assessment of the performance of each to identify the optimum configuration of SNPs and their weights (figure 2).Methods used in SNP selection and weighting assignmentSome methods of model development will initially involve selection of SNPs followed by optimisation of weighting, whereas others may involve optimisation of weightings for all SNPs that have been genotyped using their overall GWAS effect sizes, the linkage disequilibrium (LD) and an estimate of the proportion of SNPs that are expected to contribute to the risk.22LD is the phenomenon where some SNPs are coinherited more frequently with other SNPs due to their close proximity on the genome.

Segments with strong LD between SNPs are referred to as haplotype kamagra wholesale blocks. This phenomenon means that GWAS often identify multiple SNPs in the same haplotype block associated with disease and the true causal SNP is not known. As models have started to kamagra wholesale assess more SNPs, careful consideration is required to take into account possible correlation between SNPs as a result of this phenomenon. Correlation between SNPs can lead to double counting of SNPs and association redundancy, where multiple SNPs in a region kamagra wholesale of LD are identified as being associated with the outcome. This can lead to reduction in the predictive performance of the model.

Therefore, processes for filtering SNPs and using one SNP (tag SNP) to act as a marker in an area of high LD, kamagra wholesale through LD thinning, were developed. Through these processes SNPs correlated with other SNPs in a block are removed, by either pruning or clumping. Pruning ignores p value thresholds and ‘eliminates’ SNPs by a process of iterative comparison between a pair of SNPs to assess if they are correlated, and subsequently could remove SNPs that are deemed to have evidence of association kamagra wholesale. Clumping (also known as informed pruning) is guided by GWAS p values and chooses the most significant SNP, therefore keeping the most significant SNP within a block.23 This is all done with the aim of pinpointing relatively small areas of the genome that contribute to risk of the trait. Different significance thresholds may be used to select SNPs from this subgroup for inclusion in models.Poor performance of kamagra wholesale a model can result from imperfect tagging with the underlying causal SNP.16 This is because the causal SNP that is associated with disease might not be in LD with the tag SNP that is in the model but is in LD with another SNP which is not in the model.

This particularly occurs where the LD and variant frequency differs between population groups.24 An alternate approach to filter SNPs is stepwise regression where SNPs are selected based on how much the SNPs improve the model’s performance. This is a statistical approach and does not consider the impact of LD kamagra wholesale or effect size.As described above, early studies used simple weighting approaches or directly applied effect sizes from GWAS as weighting parameters for SNPs. However, application of effect sizes as a weighting parameter directly from a GWAS may not be optimal, due to differences in the population that the GWAS was conducted in and the target population. Also as described above, LD and the fact that not all SNPs may contribute to the trait mean that these effect sizes kamagra wholesale from GWAS are imperfect estimates. Therefore, methods have been developed that adjust effect size estimates from GWAS using statistical techniques which make assumptions about factors such as the number of causal SNPs, level of LD between SNPs or knowledge of their potential function to better reflect their impact on a trait.

Numerous statistical methodologies have been developed to improve weighting with a view to enhancing the discriminative power of a PGS.25 26 Examples of some methodological approaches are LDpred,22 winner’s curse correction,23 kamagra wholesale empirical Bayes estimation,27 shrinkage regression (Lasso),28 linear mixed models,29 with more being developed or tested. An additional improvement on the methods is to embed non-genetic information (eg, age-specific ORs).6 Determination of which methodology or hybrid of methodologies is most appropriate for various settings and conditions is continuously being explored and is evolving with new statistical approaches developing at a rapid pace.In summary, model development has evolved in an attempt to gain the most from available GWAS data and address some of the issues that arise due to working with data sets which cannot be directly translated into parameters for prediction models. The different approaches taken in SNP selection and weighting, and the impact on the predictive performance of a model are important to kamagra wholesale consider when assessing different models. This is because different approaches to PGS modelling can achieve the same or a similar level of prediction. From a health system implementation perspective, particular approaches may be preferred following practical considerations and trade-offs between obtaining genotype data, processes for score construction and model performance kamagra wholesale.

In addition, the degree to which these parameters need to be optimised will also be impacted by the input data and validation data set, and the quality control procedures that need to be applied to these data sets.12Sources of input data for score constructionKey to the development of a polygenic model is the availability of data sets that can provide input kamagra wholesale parameters for model construction. Genotype data used in model construction can either be available as raw GWAS data or provided as GWAS summary statistics. Data in the raw format are individual-level data from a SNP array and may not have undergone basic quality control such as assessment of missingness, sex discrepancy checks, deviation from Hardy-Weinberg equilibrium, heterozygosity rate, kamagra wholesale relatedness or assessment for outliers.30 31 Availability of raw GWAS data allows for different polygenic models to be developed because of the richness of the data, however computational issues arise because of the size of the data sets. Data based on genome sequencing, as opposed to SNP arrays, could also be used in model construction. There have been limited studies of PGS developed from this form of data due to limitations in data availability, which is mainly due to cost restraints.15 32 kamagra wholesale Individual-level genomic data are also often not available to researchers due to privacy concerns.Due to these issues, the focus of polygenic model development has therefore been on using well-powered GWAS summary statistics.33 These are available from open access repositories and contain summary information such as the allele positions, ORs, CIs and allele frequency, without containing confidential information on individuals.

These data sets have usually been through the basic quality control measures mentioned above. There are, however, no standards for publicly available files, meaning some further processing steps may be required, kamagra wholesale in particular when various data sets are combined for a meta-analysis. Quality control on summary statistics is only possible if information such as missing genotype rate, minor allele frequency, Hardy-Weinberg equilibrium failures and non-Mendelian transmission rates is provided.12Processing of GWAS data may include additional quality control steps, imputation and filtering of the SNP information, which can be done at the level of genotype or summary statistics data. SNP arrays used in GWAS only kamagra wholesale have common SNPs represented on them as they rely on LD between SNPs to cover the entire genome. As described above, one tag SNP on the array can represent many other SNPs.

Imputation of SNPs is common in GWAS and describes kamagra wholesale the process of predicting genotypes that have not been directly genotyped but are statistically inferred (imputed) based on haplotype blocks from a reference sequence.33–35 Often association tests between the imputed SNPs and trait are repeated. As genotype imputation requires individual-level data, researchers have proposed summary statistics imputation as a mechanism to infer the association between untyped SNPs and a trait. The performance of imputation has been evaluated and kamagra wholesale shown that, with certain limitations, summary statistics imputation is an efficient and cost-effective methodology to identify loci associated with traits when compared with imputation done on genotypes.36An alternative source of input data for the selection of SNPs and their weightings is through literature or in existing databases, where already known trait-associated SNPs and their effect sizes are used as the input parameters in model development. A number of studies have taken this approach37 38 and it is possible to use multiple sources when developing various polygenic models and establishing the preferred parameters to use.Currently, there does not appear to be one methodology that works across all contexts and traits, each trait will need to be assessed to determine which method is the most suitable for the trait being evaluated. For example, four different polygenic model construction strategies were explored for three skin cancer subtypes4 by using data on SNPs and kamagra wholesale their effect sizes from different sources, such as the latest GWAS meta-analysis results, the National Human Genome Research Institute (NHGRI) EBI GWAS catalogue, UK Biobank GWAS summary statistics with different thresholds and GWAS summary statistics with LDpred.

In this setting for basal cell carcinoma and melanoma, the meta-analysis and catalogue-derived models were found to perform similarly but that the latter was ultimately used as it included more SNPs. For squamous cell carcinoma the kamagra wholesale meta-analysis-derived model performed better than the catalogue-derived model. This demonstrates how each disease subtype, model construction strategy and data set can have their own limitations and advantages.Knowledge of the sources of input data and its kamagra wholesale subsequent use in model development is important in understanding the limitations of available models. Models that are developed using data sets that reflect the population in which prediction is to be carried out will perform better. For example, data collected from a symptomatic or high-risk population may not be suitable kamagra wholesale as an input data set for the development of a polygenic model that will be used for disease prediction in the general population.

Large GWAS studies were previously focused on high-risk individuals, such as patients with breast cancer with a strong family history or known pathogenic variants in BRCA1 or BRCA2. These studies would not be suitable for the development of PGS for use in the general population but can inform risk assessment in high-risk individuals kamagra wholesale. The source of the data for SNP selection and weighting also has implications for downstream uses and validation. For example, variant frequency and LD patterns can vary between populations and this can translate to poor performance of the polygenic model if the external validation population is different from that of the input data set.39–41 Furthermore, the power and validity of polygenic analyses are influenced by the input data sources.12 42From a model to a scorePGS kamagra wholesale can be calculated using one of the methodologies discussed above. The resulting PGS units of measurement depend on which measurement is used for the weighting.12 For example, the weightings may have been calculated based on logOR for discrete traits or linear regression coefficient (β/beta) in continuous traits from univariate regression tests carried out in the GWAS.

The resulting scores are then usually transformed to a standard normal distribution to give scores ranging from −1 to 1, or 0 to 100 for ease of interpretation kamagra wholesale. This enables further examination of the association between the score and a trait and the predictive ability of different scores generated by different models. Similar to other biomarker analyses, this involves using the PGS as a predictor of a trait with other covariates (eg, age, smoking, and so on) added, if appropriate, in a kamagra wholesale target sample. Examination of differences in the distribution of scores in cases and controls, or by examining differences in traits between different strata of PGS can enable assessment of predictive ability (figure 3). Common practice is for individual-level PGS values to be used to stratify populations into distinct groups of risk based on percentile cut-off or threshold values kamagra wholesale (eg, the top 1%).Example distribution of polygenic scores across a population.

Thresholds can be set to stratify risk as low (some), average (most) and high (some)." data-icon-position data-hide-link-title="0">Figure 3 Example distribution of polygenic scores across a population. Thresholds can be set to stratify risk as low (some), average (most) and high (some).Model validationPolygenic model development is reliant on further data kamagra wholesale sets for model testing and validation and the composition of these data sets is important in ensuring that the models are appropriate for a particular purpose. The development of kamagra wholesale a model to calculate a PGS involves refinement of the previously discussed input parameters, and selection of the ‘best’ of several models based on performance (figure 2). Therefore, a testing/training data set is often required to assess the model’s ability to accurately predict the trait of interest. This is often a data set that is independent of the base/input/discovery kamagra wholesale data set.

It may comprise a subset of the discovery data set that is only used for testing and was not included in the initial development of the model but should ideally be a separate independent data set.Genotype and phenotype data are needed in these data sets. Polygenic models are used to calculate PGS for individuals in the training data set and regression analysis is performed with the kamagra wholesale PGS as a predictor of a trait. Other covariates may also be included, if appropriate. This testing phase can be considered a process for identifying models with better overall performance and/or informing refinements needed kamagra wholesale. Hence, this phase often involves comparison of different models that are developed using the same input data set to identify those models that have optimal performance.The primary purpose is to determine which model best discriminates between cases and controls.

The area kamagra wholesale under the curve (AUC) or the C-statistic is the most commonly used measure in assessing discriminative ability. It has been criticised as being an insensitive measure that is not able to fully capture all aspects of predictive ability. For instance, in some instances, AUC can remain unchanged between models but the individuals within are categorised into a different risk group.43 Alternative metrics kamagra wholesale that have been used to evaluate model performance include increase in risk difference, integrated discrimination improvement, R2 (estimate of variance explained by the PGS after covariate adjustment), net classification index and the relative risk (highest percentile vs lowest percentile). A clear understanding on how to interpret the performance within various settings is important in determining which model is most suitable.44As per normal practice when developing any prediction model, polygenic models with the optimal performance in a testing/training data set should be further validated in external data sets. External data sets are critical in validation of models and assessment of generalisability, hence must also conform to the desired situations in which kamagra wholesale a model is to be used.

The goal is to find a model with suitable parameters of predictive performance in data sets outside of those in which it was developed. Ideally, external kamagra wholesale validation requires replication in independent data sets. Few existing polygenic models have been validated to this extent, the focus being rather on the development of new models rather than evaluation of existing ones. One example where replication has been carried out is in the field of CAD, where the GPSCAD45 and metaGRSCAD10 polygenic models (both developed using UK Biobank data) were evaluated kamagra wholesale in a Finnish population cohort.46 Predictive ability was found to be lower in the Finnish population. This is likely to kamagra wholesale be due to the differences in genetic structure of this population and the population of the data set used for polygenic model development.

Research is ongoing to evaluate polygenic models in other populations and strategies are being developed to ensure the same performance when used more widely, possibly through reweighting and adjustment of the scores.47Moving towards clinical applicationsPGS are thought to be useful information that could improve risk estimation and provide an avenue for disease prevention and deciding treatment strategies. There are indications from a number of fields that genetic information in the form of PGS can act as independent biomarkers and aid stratification.11 16 48 However, the clinical benefits of stratification using a PGS and the implications for clinical practice kamagra wholesale are only just beginning to be examined. The use of PGS as part of existing risk prediction tools or as a stand-alone predictor has been suggested. This latter option may be true for diseases where knowledge or predictive ability with other risk factors is limited, such as in kamagra wholesale prostate cancer.49 In either case, polygenic models need to be individually examined to determine suitability and applicability for the specific clinical question.50 Despite some commercial companies developing PGS,51 52 currently PGS are not an established part of clinical practice.Integration into clinical practice requires evaluation of a PGS-based test. An important concept to consider in this regard is the distinction between an assay and a test.

This has been previously discussed with respect to genetic test evaluation.53 54 It is worth examining this concept as applied to PGS, as their evaluation is reliant on a clear understanding of the test to kamagra wholesale be offered. As outlined by Zimmern and Kroese,54 the method used to analyse a substance in a sample is considered the assay, whereas a test is the use of an assay within a specific context. With respect to PGS, the process of developing a model to derive a score can be considered the assay, while the use of this model for a particular disease, population and kamagra wholesale purpose can be considered the test. This distinction is important when assessing if studies are reporting on assay performance as opposed to test performance. It is our view that, with respect kamagra wholesale to polygenic models, progress has been made with respect to assay development, but PGS-based tests are yet to be developed and evaluated.

This can enable a clearer understanding of their potential clinical utility and issues that may arise for clinical implementation.11 18 55 It is clear that this is still an evolving field, and going forward different models may be required for different traits due to their underlying genetic architecture,26 different clinical contexts and needs.Clinical contexts where risk stratification is already established practice are most likely where implementation of PGS will occur first. Risk prediction models based on non-genetic factors have been developed for many conditions and are used in clinical care, for example, in cardiovascular disease over 100 such models exist.56 In such contexts, how a PGS and kamagra wholesale its ability to predict risk compared with, or improves on, these existing models is being investigated.3 44 57–61 The extent to which PGS improves prediction, as well as the cost implications of including this, is likely to impact on implementation.Integration of PGS into clinical practice, for any application, requires robust and validated mechanisms to generate these scores. Therefore, given the numerous models available, an assessment of their suitability as part of a test is required. Parameters or guidelines with kamagra wholesale respect to aspects of model performance and metrics that could assist in selecting the model to take forward as a PGS-based test are limited and need to be addressed. Currently, there are different mechanisms to generate PGS and have arisen in response to the challenges in aggregating large-scale genomic data for prediction.

For example, a review reported 29 PGS models for breast cancer from 22 publications.62 Due to there being a number of different methodologies to generate a score, numerous models may exist for the same condition and kamagra wholesale each of the resulting models could perform differently. Models may perform differently because the population, measured outcome or context of the development data sets used to generate the models is diverse, for example, a score for risk of breast cancer versus a breast cancer subtype.44 63 This kamagra wholesale diversity, alongside the lack of established best practice and standardised reporting in publications, makes comparison and evaluation of polygenic models for use in clinical settings challenging. It is clear that moving the field forward is reliant on transparent reporting and evaluation. Recommendations for best practices on the reporting of polygenic kamagra wholesale models in literature have been proposed14 64 as well as a database,65 66 which could allow for such comparisons. Statements and guidelines for risk prediction model development, such as the Genetic Risk Prediction Studies and Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD), already exist, but are not consistently used.

TRIPOD explicitly covers the development and validation of prediction models for both diagnosis and prognosis, for all medical domains.One clear issue is generalisability and drop in performance of polygenic models once they are applied in a population group different from the one in which they were developed.22 46 67–70 This is an ongoing challenge in genomics as most GWAS, from which most PGS are being developed, have been conducted in European-Caucasian populations.71 Efforts to improve representation are underway72 and there are attempts to reweight/adjust scores when applied to different population groups which are showing some potential but need further research.47 Others have demonstrated that models developed in more diverse population groups have improved performance when applied to external data sets in different populations.24 73 It is important to consider this issue when moving towards clinical applications as it may pose an ethical challenge if the PGS is not generalisable.A greater understanding of different complex traits and the impact of pleiotropy is only beginning to be investigated.74 There is growing appreciation of the role of pleiotropy as multiple variants have been identified to be associated with multiple traits and exert diverse effects, providing insight into overlapping mechanisms.75 76 This, together with the impact of population stratification, genetic relatedness, ascertainment and other sources of heterogeneity leading to spurious signals and reduced power in genetic association studies, all impacting on the predictive ability of PGS in different populations and for different diseases.While many publications report on model development and evaluation, often there kamagra wholesale is a lack of clarity on intended purpose,50 77 leading to uncertainties as to the clinical pathways in which implementation is envisaged. A clear description of intended use within clinical pathways is a central component in evaluating the use of an application with any form of PGS and in considering practical implications, such as mechanisms of obtaining the score, incorporation into health records, interpretation of scores, relevant cut-offs for intervention initiation, mechanisms for feedback of results and costs, among other issues. These parameters will also be impacted by the polygenic model that is taken forward for implementation kamagra wholesale. Meaning that there are still some important questions that need to be addressed to determine how and where PGS could work within current healthcare systems, particularly at a population level.78It is widely accepted that genotyping using arrays is a lower cost endeavour in comparison to genome sequencing, making the incorporation of PGS into routine healthcare an attractive proposition. However, we were unable to find any studies reporting on the use or associated costs kamagra wholesale of such technology for population screening.

Studies are beginning to examine use case scenarios and model cost-effectiveness, but this has only been in very few, specific investigations.79 80 Costs will also be influenced by the testing technology and by the downstream consequences of testing, which is likely to differ depending on specific applications that are developed and the pathways in which such tests are incorporated. This is particularly the case in screening or primary care settings, where such testing is currently not an established part of care pathways and kamagra wholesale may require additional resources, not least as a result of the volume of testing that could be expected. Moving forward, the clinical role of PGS needs to be developed further, including defining the clinical applications as well as supporting evidence, for example, on the effect of clinical outcomes, the feasibility for use in routine practice and cost-effectiveness.ConclusionThere is a large amount of diversity in the PGS field with respect to model development approaches, and this continues to evolve. There is rapid progress which is being driven kamagra wholesale by the availability of larger data sets, primarily from GWAS and concomitant developments in statistical methodologies. As understanding and knowledge develops, the usefulness and appropriateness of polygenic models for different diseases and contexts are being explored.

Nevertheless, this is still an emerging field, with a variable evidence kamagra wholesale base demonstrating some potential. The validity of PGS needs to be clearly demonstrated, and their applications evaluated prior to clinical implementation..

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New York Amoxil online has kamagra wholesale asked Pfizer Inc. If the kamagra wholesale state can buy erectile dysfunction treatments directly from the company because the United States government has failed to increase supply.Cuomo said on Monday, Jan. 18 that he sent a letter to Pfizer Chairman and CEO Dr. Albert Bourla asking kamagra wholesale for the ability to purchase erectile dysfunction treatments directly from Pfizer, as the company is not bound by commitments that Moderna made under the government's Operation Warp Speed.Pfizer has headquarters in New York City and in Rockland County, in Pearl River."Pfizer is a New York company - something I am greatly proud of," Cuomo wrote in the letter."The company's decision to opt out of Operation Warp Speed, which the Biden administration plans to overhaul, puts it in a unique situation that could help us save lives right here in New York."View the letter here.✎ EditSignCuomo also issued a letter to US Health and Human Services Secretary Alex Azar demanding an explanation for the secretary's false claim that "all of the doses that had been held in physical reserve" would be shipped to states, when in fact the federal government had already distributed all of those doses and would not be increasing the supply. New York State will receive 250,000 doses this week — 50,000 less than the week prior— even though kamagra wholesale the CDC has now expanded eligibility to more than seven million New Yorkers."There needs to be full accountability of this mismanagement," Cuomo wrote in the letter, which can be viewed here✎ EditSign.

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