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IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ buy viagra online without a prescription in the composition of the multidisciplinary teams that provide care for patients who http://www.jazzspecial.dk/female-viagra-for-sale/ have a DSD.11 14 Several projects have now worked to resolve this variability in care. The European Cooperation in Science and Technology (EU COST) action BM1303 ‘A systematic elucidation of differences of sex development’ has been a platform to achieve European agreement on harmonisation of clinical management and laboratory practices.15–17 Another such initiative involved an update of the 2006 DSD consensus document by an international group of professionals and patient representatives.18 These initiatives have highlighted how cultural and financial aspects and buy viagra online without a prescription the availability of resources differ significantly between countries and societies, a situation that hampers supranational agreement on common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them. Nonetheless, four DSD (expert) centres located in buy viagra online without a prescription the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with similarly structured healthcare systems and similar resources. Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues.

International networks such as the European Reference Network for rare endocrine conditions (EndoERN), in which DSD is embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature buy viagra online without a prescription thus far because they reflect evolving technologies or less visible stakeholders. For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant referral to buy viagra online without a prescription a specialised team may be challenging, especially for professionals with limited experience in DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written for these healthcare providers. Moreover, this enables DSD specialists to refer to the guideline when advising a referral. Transition from the prenatal to buy viagra online without a prescription the postnatal team and from the paediatric to the adult team requires optimal communication between the specialists involved.

Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor buy viagra online without a prescription the guideline revision, an interdisciplinary multicentre group was formed with all members responsible for updating the literature for a specific part of the guideline. Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is buy viagra online without a prescription often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper.

Abstracts had to be written in English and were identified using a broad range of Medical Subject Headings terms (eg, DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, buy viagra online without a prescription guideline, multidisciplinary care). Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were excluded, as were articles that were not open access buy viagra online without a prescription or retrievable through institutional access. Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft was discussed by the writing committee and, after having obtained agreement on remaining points of discussion, buy viagra online without a prescription revised into a final draft.

This version was sent to a broad group of professionals from academic centres and DSD teams whose members had volunteered to review the draft guideline. After receiving and incorporating their buy viagra online without a prescription input, the final version was presented to the paediatric and genetic associations for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur earlier, for example, when a buy viagra online without a prescription commercial ultrasound is performed at the request of the parents.Another way DSD can be diagnosed before birth is when invasive prenatal genetic testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex and the phenotypic sex seen by ultrasound. In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately.

More often, the discrepancy will be due to sex-chromosome mosaicism or a true buy viagra online without a prescription form of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic sex revealed by non-invasive prenatal testing (NIPT), which is now available to high-risk pregnant women in the Netherlands and to all pregnant women in Belgium, and later ultrasound findings. NIPT screens for CNVs in the fetus. However, depending on legal buy viagra online without a prescription restrictions and/or ethical considerations, the X and Y chromosomes are not always included in NIPT analysis and reports. If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the time that buy viagra online without a prescription NIPT is performed (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team.

After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on the ultrasound findings and the limitations of buy viagra online without a prescription this technique. The procedure(s) that can be followed, including the risks associated with an amniocentesis. And the type of information genetic testing can and buy viagra online without a prescription cannot provide. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved.

The clinical geneticist should be experienced in prenatal counselling and well informed about the diagnostic possibilities given the limited time span in which test results need to be available to allow parents to make a well-informed decision about whether or not to continue the buy viagra online without a prescription pregnancy. Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting parents may also consider termination of pregnancy, which, although considered controversial by some, is legal in Belgium and the buy viagra online without a prescription Netherlands. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress buy viagra online without a prescription of not knowing exactly what the child’s genitalia will look like and uncertainty about the diagnosis, treatment and prognosis cannot be avoided completely. Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images.

In our experience, parents appreciate having already spoken to some members of buy viagra online without a prescription the DSD team during pregnancy and having a contact person before birth.After expert prenatal counselling, a significant number of pregnant couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist. The terminology used in communication with parents should be carefully chosen,22 23 and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed in figure buy viagra online without a prescription 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array. It was recently estimated that >30% of individuals who have a DSD have additional structural anomalies, with cardiac and neurological anomalies and fetal growth restriction being particularly common.27 28 If additional anomalies are seen, the geneticist can consider specific gene defects that may underlie a known genetic buy viagra online without a prescription syndrome or carry out NGS.

NGS-based techniques have also now made their appearance in prenatal diagnosis of congenital anomalies.29 30 Panels using these techniques can be specific for genes involved in DSD, or be larger panels covering multiple congenital anomalies, and are usually employed with trio-analysis to compare variants identified in the child with the parents’ genetics.29–31 Finding a genetic cause before delivery can help reduce parental stress in the neonatal period and speed up decisions regarding gender assignment. In such cases there is no tight time limit, and we propose completing the analysis well before the expected delivery.Disorders/differences of buy viagra online without a prescription sex development (DSD) in the prenatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

Conventional karyotyping can be useful. NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 1 Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

Conventional karyotyping can be useful. NGS, next-generation sequencing.First contact by a professional less experienced in DSDWhereas most current guidelines start from the point when an individual has been referred to the DSD team,1 15 the Dutch-Flemish guideline dedicates a chapter to healthcare professionals less experienced in DSD as they are often the first to suspect or identify such a condition. Apart from the paper of Indyk,7 little guidance is available for these professionals about how to act in such a situation. The chapter in the Dutch-Flemish guideline summarises the various clinical presentations that a DSD can have and provides information on how to communicate with parents and/or patients about the findings of the physical examination, the first-line investigations and the need for prompt referral to a specialised centre for further evaluation. Clinical examples are offered to illustrate some of these recurring situations.

The medical issues in DSD can be very challenging, and the social and psychological impact is high. For neonates with ambiguous genitalia, sex assignment is an urgent and crucial issue, and it is mandatory that parents are informed that it is possible to postpone registration of their child’s sex. In cases where sex assignment has already taken place, the message that the development of the gonads or genitalia is still atypical is complicated and distressing for patients and parents or carers. A list of contact details for DSD centres and patient organisations in the Netherlands and Flanders is attached to the Dutch-Flemish guideline. Publishing such a list, either in guidelines or online, can help healthcare professionals find the nearest centres for consultations and provide patients and patient organisations with an overview of the centres where expertise is available.Timing and place of genetic testing using NGS-based gene panelsThe diagnostic workup that is proposed for 46,XX and 46,XY DSD is shown in figures 2 and 3, respectively.

Even with the rapidly expanding molecular possibilities, a (family) history and a physical examination remain the essential first steps in the diagnostic process. Biochemical and hormonal screening aim at investigating serum electrolytes, renal function and the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes. Ultrasound screening of kidneys and internal genitalia, as well as establishing genotypic sex, should be accomplished within 48 hours and complete the baseline diagnostic work-up of a child born with ambiguous genitalia.1 16 32 3346,XX disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. NGS, next-generation sequencing.

CAH, Congenital adrenal hyperplasia. AMH, Anti-Müllerian Hormone." data-icon-position data-hide-link-title="0">Figure 2 46,XX disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia.

AMH, Anti-Müllerian Hormone.46,XY disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. * SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 3 46,XY disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

NGS, next-generation sequencing.Very recently, a European position paper has been published focusing on the genetic workup of DSD.16 It highlights the limitations and drawbacks of NGS-based tests, which include the chance of missing subtle structural variants such as CNVs and mosaicism and the fact that NGS cannot detect methylation defects or other epigenetic changes.16 28 31 Targeted DNA analysis is preferred in cases where hormonal investigations suggest a block in steroidogenesis (eg, 11-β-hydroxylase deficiency, 21-hydroxylase deficiency), or in the context of a specific clinical constellation such as the often coincidental finding of Müllerian structures in a boy with normal external genitalia or cryptorchidism, that is, persistent Müllerian duct syndrome.33 34 Alternative tests should also be considered depending on the available information. Sometimes, a simple mouth swab for FISH analysis can detect mosaic XY/X in a male with hypospadias or asymmetric gonadal development or in a female with little or no Turner syndrome stigmata and a normal male molecular karyotyping profile or peripheral blood karyotype. Such targeted testing avoids incidental findings and is cheaper and faster than analysis of a large NGS-based panel, although the cost difference is rapidly declining.However, due to the genetic and phenotypic heterogeneity of DSD conditions, the most cost-effective next steps in the majority of cases are whole exome sequencing followed by panel analysis of genes involved in genital development and function or trio-analysis of a large gene panel (such as a Mendeliome).16 35–38 Pretest genetic counselling involves discussing what kind of information will be reported to patients or parents and the chance of detecting VUS, and the small risk of incidental findings when analysing a DSD panel should be mentioned. Laboratories also differ in what class of variants they report.39 In our experience, the fear of incidental findings is a major reason why some parents refrain from genetic testing.Timing of the DSD gene panel analysis is also important. While some patients or parents prefer that all diagnostic procedures be performed as soon as possible, others need time to reflect on the complex information related to more extensive genetic testing and on its possible consequences.

If parents or patients do not consent to panel-based genetic testing, analysis of specific genes, such as WT1, should be considered when appropriate in view of the clinical consequences if a mutation is present (eg, clinical surveillance of renal function and screening for Wilms’ tumour in the case of WT1 mutations). Genes that are more frequently involved in DSD (eg, SRY, NR5A1) and that match the specific clinical and hormonal features in a given patient could also be considered for sequencing. Targeted gene analysis may also be preferred in centres located in countries that do not have the resources or technical requirements to perform NGS panel-based genetic testing. Alternatively, participation by these centres in international collaborative networks may allow them to outsource the molecular genetic workup abroad.Gene panels differ between centres and are regularly updated based on scientific progress. A comparison of DSD gene panels used in recent studies can be found at https://www.nature.com/articles/s41574-018-0010-8%23Sec46.15 The panels currently used at the coauthors’ institutions can be found on their respective websites.

Given the pace of change, it is important to regularly consider repeating analysis in patients with an unexplained DSD, for example, when they transition into adult care or when they move from one centre to another. This also applies to patients in whom a clinical diagnosis has never been genetically confirmed. Confusion may arise when the diagnosis cannot be confirmed or when a mutation is identified in a different gene, for example, NR5A1 in someone with a clinical diagnosis of CAIS that has other consequences for relatives. Hence, new genetic counselling should always accompany new diagnostic endeavours.Class 3 variants and histopathological examinationsThe rapidly evolving diagnostic possibilities raise new questions. What do laboratories report?.

How should we deal with the frequent findings of mainly unique VUS or class 3 variants (ACMG recommendation) in the many different DSD-related genes in the diagnostic setting?. Reporting VUS can be a source of uncertainty for parents, but not reporting these variants precludes further investigations to determine their possible pathogenicity. It can also be difficult to prove variant pathogenicity, both on gene-level and variant-level.39 Moreover, given the gonad-specific expression of some genes and the variable phenotypic spectrum and reduced penetrance, segregation analysis is not always informative. A class 3 variant that does not fit the clinical presentation may be unrelated to the observed phenotype, but it could also represent a newly emerging phenotype. This was recently demonstrated by the identification of the NR5A1 mutation, R92W, in individuals with 46,XX testicular and ovotesticular DSD.40 This gene had previously been associated with 46,XY DSD.

In diagnostic laboratories, there is usually no capacity or expertise to conduct large-scale functional studies to determine pathogenicity of these unique class 3 VUS in the different genes involved in DSD. Functional validation of variants identified in novel genes may be more attractive in a research context. However, for individual families with VUS in well-established DSD genes such as AR or HSD17B3, functional analysis may provide a confirmed diagnosis that implies for relatives the option of undergoing their own DNA analysis and estimating the genetic risk of their own future offspring. This makes genetic follow-up important in these cases and demonstrates the usefulness of international databases and networks and the centralisation of functional studies of genetic variants in order to reduce costs and maximise expertise.The same is true for histopathological description, germ-cell tumour risk assessment in specific forms of DSD and classification of gonadal samples. Germ-cell tumour risk is related to the type of DSD (among other factors), but it is impossible to make risk estimates in individual cases.41–44 Gonadectomy may be indicated in cases with high-risk dysgenetic abdominal gonads that cannot be brought into a stable superficial (ie, inguinal, labioscrotal) position that allows clinical or radiological surveillance, or to avoid virilisation due to 5-alpha reductase deficiency in a 46,XY girl with a stable female gender identity.45 Pathological examination of DSD gonads requires specific expertise.

For example, the differentiation between benign germ cell abnormalities, such as delayed maturation and (pre)malignant development of germ cells, is crucial for clinical management but can be very troublesome.46 Centralised pathological examination of gonadal biopsy and gonadectomy samples in one centre, or a restricted number of centres, on a national scale can help to overcome the problem of non-uniform classification and has proven feasible in the Netherlands and Belgium. We therefore believe that uniform assessment and classification of gonadal differentiation patterns should also be addressed in guidelines on DSD management.International databases of gonadal tissues are crucial for learning more about the risk of malignancy in different forms of DSD, but they are only reliable if uniform criteria for histological classification are strictly applied.46 These criteria could be incorporated in many existing networks such as the I-DSD consortium, the Disorders of Sex Development Translational Research Network, the European Reference Network on Urogenital Diseases (eUROGEN), the EndoERN and COST actions.15–17 47Communication at the transition from paediatric to adult carePaediatric and adult teams need to collaborate closely to facilitate a well-organised transition from paediatric to adult specialist care.15 48–50 Both teams need to exchange information optimally and should consider transition as a longitudinal process rather than a fixed moment in time. Age-appropriate information is key at all ages, and an overview of topics to be discussed at each stage is described by Cools et al.15 Table 1 shows an example of how transition can be organised.View this table:Table 1 Example of transition table as used in the DSD clinic of the Erasmus Medical CenterPsychological support and the continued provision of information remains important for individuals with a DSD at all ages.15 22 In addition to the information given by the DSD team members, families and patients can benefit from resources such as support groups and information available on the internet.47 Information available online should be checked for accuracy and completeness when referring patients and parents to internet sites.Recommendations for future actionsMost guidelines and articles on the diagnosis and management of DSD are aimed at specialists and are only published in specialist journals or on websites for endocrinologists, urologists or geneticists. Yet there is a need for guidelines directed towards first-line and second-line healthcare workers that summarise the recommendations about the first crucial steps in the management of DSD. These should be published in widely available general medical journals and online, along with a national list of DSD centres.

Furthermore, DSD (expert) centres should provide continuous education to all those who may be involved in the identification of individuals with a DSD in order to enable these healthcare professionals to recognise atypical genitalia, to promptly refer individuals who have a DSD and to inform the patient and parents about this and subsequent diagnostic procedures.As DSD continues to be a rare condition, it will take time to evaluate the effects of having such a guideline on the preparedness of first-line and second-line healthcare workers to recognise DSD conditions. One way to evaluate this might be the development and use of questionnaires asking patients, carers and families and referring physicians how satisfied they were with the initial medical consultation and referral and what could be improved. A helpful addition to existing international databases that collect information on genetic variations would be a list of centres that offer suitable functional studies for certain genes, ideally covering the most frequently mutated genes (at minimum).Patient organisations can also play an important role in informing patients about newly available diagnostic or therapeutic strategies and options, and their influence and specific role has now been recognised and discussed in several publications.17 47 However, it should be kept in mind that these organisations do not represent all patients, as a substantial number of patients and parents are not member of such an organisation.Professionals have to provide optimal medical care based on well-established evidence, or at least on broad consensus. Yet not everything can be regulated by recommendations and guidelines. Options, ideas and wishes should be openly discussed between professionals, patients and families within their confidential relationship.

This will enable highly individualised holistic care tailored to the patient’s needs and expectations. Once they are well-informed of all available options, parents and/or patients can choose what they consider the optimal care for their children or themselves.15 16ConclusionThe Dutch-Flemish guideline uniquely addresses some topics that are under-represented in the literature, thus adding some key aspects to those addressed in recent consensus papers and guidelines.15–17 33 47As more children with a DSD are now being identified prenatally, and the literature on prenatal diagnosis of DSD remains scarce,20 21 we propose a prenatal diagnostic algorithm and emphasise the importance of having a prenatal specialist involved in or collaborating with DSD (expert) centres.We also stress that good communication between all involved parties is essential. Professionals should be well informed about protocols and communication. Collaboration between centres is necessary to optimise aspects of care such as uniform interpretation of gonadal pathology and functional testing of class 3 variants found by genetic testing. Guidelines can provide a framework within which individualised patient care should be discussed with all stakeholders.AcknowledgmentsThe authors would like to thank the colleagues of the DSD teams for their input in and critical reading of the Dutch-Flemish guideline.

Amsterdam University Center (AMC and VU), Maastricht University Medical Center, Erasmus Medical Center Rotterdam, Radboud University Medical Center Nijmegen, University Medical Center Groningen, University Medical Center Utrecht, Ghent University Hospital. The authors would like to thank Kate McIntyre for editing the revised manuscript and Tom de Vries Lentsch for providing the figures as a PDF. Three of the authors of this publication are members of the European Reference Network for rare endocrine diseases—Project ID 739543.IntroductionEndometrial cancer is the most common gynaecological malignancy in the developed world.1 Its incidence has risen over the last two decades as a consequence of the ageing population, fewer hysterectomies for benign disease and the obesity epidemic. In the USA, it is estimated that women have a 1 in 35 lifetime risk of endometrial cancer, and in contrast to cancers of most other sites, cancer-specific mortality has risen by approximately 2% every year since 2008 related to the rapidly rising incidence.2Endometrial cancer has traditionally been classified into type I and type II based on morphology.3 The more common subtype, type I, is mostly comprised of endometrioid tumours and is oestrogen-driven, arises from a hyperplastic endometrium, presents at an early stage and has an excellent 5 year survival rate.4 By contrast, type II includes non-endometrioid tumours, specifically serous, carcinosarcoma and clear cell subtypes, which are biologically aggressive tumours with a poor prognosis that are often diagnosed at an advanced stage.5 Recent efforts have focused on a molecular classification system for more accurate categorisation of endometrial tumours into four groups with distinct prognostic profiles.6 7The majority of endometrial cancers arise through the interplay of familial, genetic and lifestyle factors. Two inherited cancer predisposition syndromes, Lynch syndrome and the much rarer Cowden syndrome, substantially increase the lifetime risk of endometrial cancer, but these only account for around 3–5% of cases.8–10 Having first or second degree relative(s) with endometrial or colorectal cancer increases endometrial cancer risk, although a large European twin study failed to demonstrate a strong heritable link.11 The authors failed to show that there was greater concordance in monozygotic than dizygotic twins, but the study was based on relatively small numbers of endometrial cancers.

Lu and colleagues reported an association between common single nucleotide polymorphisms (SNPs) and endometrial cancer risk, revealing the potential role of SNPs in explaining part of the risk in both the familial and general populations.12 Thus far, many SNPs have been reported to modify susceptibility to endometrial cancer. However, much of this work predated genome wide association studies and is of variable quality. Understanding genetic predisposition to endometrial cancer could facilitate personalised risk assessment with a view to targeted prevention and screening interventions.13 This emerged as the most important unanswered research question in endometrial cancer according to patients, carers and healthcare professionals in our recently completed James Lind Womb Cancer Alliance Priority Setting Partnership.14 It would be particularly useful for non-endometrioid endometrial cancers, for which advancing age is so far the only predictor.15We therefore conducted a comprehensive systematic review of the literature to provide an overview of the relationship between SNPs and endometrial cancer risk. We compiled a list of the most robust endometrial cancer-associated SNPs. We assessed the applicability of this panel of SNPs with a theoretical polygenic risk score (PRS) calculation.

We also critically appraised the meta-analyses investigating the most frequently reported SNPs in MDM2. Finally, we described all SNPs reported within genes and pathways that are likely involved in endometrial carcinogenesis and metastasis.MethodsOur systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) collaboration 2009 recommendations. The registered protocol is available through PROSPERO (CRD42018091907).16Search strategyWe searched Embase, MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases via the Healthcare Databases Advanced Search (HDAS) platform, from 2007 to 2018, to identify studies reporting associations between polymorphisms and endometrial cancer risk. Key words including MeSH (Medical Subject Heading) terms and free-text words were searched in both titles and abstracts. The following terms were used.

€œendomet*”,“uter*”, “womb”, “cancer(s)”, “neoplasm(s)”, “endometrium tumour”, “carcinoma”, “adenosarcoma”, “clear cell carcinoma”, “carcinosarcoma”, “SNP”, “single nucleotide polymorphism”, “GWAS”, and “genome-wide association study/ies”. No other restrictions were applied. The search was repeated with time restrictions between 2018 and June 2019 to capture any recent publications.Eligibility criteriaStudies were selected for full-text evaluation if they were primary articles investigating a relationship between endometrial cancer and SNPs. Study outcome was either the increased or decreased risk of endometrial cancer relative to controls reported as an odds ratio (OR) with corresponding 95% confidence intervals (95% CIs).Study selectionThree independent reviewers screened all articles uploaded to a screening spreadsheet developed by Helena VonVille.17 Disagreements were resolved by discussion. Chronbach’s α score was calculated between reviewers and indicated high consistency at 0.92.

Case–control, prospective and retrospective studies, genome-wide association studies (GWAS), and both discovery and validation studies were selected for full-text evaluation. Non-English articles, editorials, conference abstracts and proceedings, letters and correspondence, case reports and review articles were excluded.Candidate-gene studies with at least 100 women and GWAS with at least 1000 women in the case arm were selected to ensure reliability of the results, as explained by Spencer et al.18 To construct a panel of up to 30 SNPs with the strongest evidence of association, those with the strongest p values were selected. For the purpose of an SNP panel, articles utilising broad European or multi-ethnic cohorts were selected. Where overlapping populations were identified, the most comprehensive study was included.Data extraction and synthesisFor each study, the following data were extracted. SNP ID, nearby gene(s)/chromosome location, OR (95% CI), p value, minor or effect allele frequency (MAF/EAF), EA (effect allele) and OA (other allele), adjustment, ethnicity and ancestry, number of cases and controls, endometrial cancer type, and study type including discovery or validation study and meta-analysis.

For risk estimates, a preference towards most adjusted results was applied. For candidate-gene studies, a standard p value of<0.05 was applied and for GWAS a p value of <5×10-8, indicating genome-wide significance, was accepted as statistically significant. However, due to the limited number of SNPs with p values reaching genome-wide significance, this threshold was then lowered to <1×10-5, allowing for marginally significant SNPs to be included. As shown by Mavaddat et al, for breast cancer, SNPs that fall below genome-wide significance may still be useful for generating a PRS and improving the models.19We estimated the potential value of a PRS based on the most significant SNPs by comparing the predicted risk for a woman with a risk score in the top 1% of the distribution to the mean predicted risk. Per-allele ORs and MAFs were taken from the publications and standard errors (SEs) for the lnORs were derived from published 95% CIs.

The PRS was assumed to have a Normal distribution, with mean 2∑βipI and SE, σ, equal to √2∑βi2pI(1−pi), according to the binomial distribution, where the summation is over all SNPs in the risk score. Hence the relative risk (RR) comparing the top 1% of the distribution to the mean is given by exp(Z0.01σ), where Z is the inverse of the standard normal cumulative distribution.ResultsThe flow chart of study selection is illustrated in figure 1. In total, 453 text articles were evaluated and, of those, 149 articles met our inclusion criteria. One study was excluded from table 1, for having an Asian-only population, as this would make it harder to compare with the rest of the results which were all either multi-ethnic or Caucasian cohorts, as stated in our inclusion criteria for the SNP panel.20 Any SNPs without 95% CIs were also excluded from any downstream analysis. Additionally, SNPs in linkage disequilibrium (r2 >0.2) with each other were examined, and of those in linkage disequilibrium, the SNP with strongest association was reported.

Per allele ORs were used unless stated otherwise.View this table:Table 1 List of top SNPs most likely to contribute to endometrial cancer risk identified through systematic review of recent literature21–25Study selection flow diagram. *Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from.

Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement. PLoS Med 6(6). E1000097.

Doi:10.1371/journal.pmed1000097." data-icon-position data-hide-link-title="0">Figure 1 Study selection flow diagram. *Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from.

Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement. PLoS Med 6(6). E1000097.

Doi:10.1371/journal.pmed1000097.Top SNPs associated with endometrial cancer riskFollowing careful interpretation of the data, 24 independent SNPs with the lowest p values that showed the strongest association with endometrial cancer were obtained (table 1).21–25 These SNPs are located in or around genes coding for transcription factors, cell growth and apoptosis regulators, and enzymes involved in the steroidogenesis pathway. All the SNPs presented here were reported on the basis of a GWAS or in one case, an exome-wide association study, and hence no SNPs from candidate-gene studies made it to the list. This is partly due to the nature of larger GWAS providing more comprehensive and powered results as opposed to candidate gene studies. Additionally, a vast majority of SNPs reported by candidate-gene studies were later refuted by large-scale GWAS such as in the case of TERT and MDM2 variants.26 27 The exception to this is the CYP19 gene, where candidate-gene studies reported an association between variants in this gene with endometrial cancer in both Asian and broad European populations, and this association was more recently confirmed by large-scale GWAS.21 28–30 Moreover, a recent article authored by O’Mara and colleagues reviewed the GWAS that identified most of the currently known SNPs associated with endometrial cancer.31Most of the studies represented in table 1 are GWAS and the majority of these involved broad European populations. Those having a multi-ethnic cohort also consisted primarily of broad European populations.

Only four of the variants in table 1 are located in coding regions of a gene, or in regulatory flanking regions around the gene. Thus, most of these variants would not be expected to cause any functional effects on the gene or the resulting protein. An eQTL search using GTEx Portal showed that some of the SNPs are significantly associated (p<0.05) with modified transcription levels of the respective genes in various tissues such as prostate (rs11263761), thyroid (rs9668337), pituitary (rs2747716), breast mammary (rs882380) and testicular (rs2498794) tissue, as summarised in table 2.View this table:Table 2 List of eQTL hits for the selected panel of SNPsThe only variant for which there was an indication of a specific association with non-endometrioid endometrial cancer was rs148261157 near the BCL11A gene. The A allele of this SNP had a moderately higher association in the non-endometrioid arm (OR 1.64, 95% CI 1.32 to 2.04. P=9.6×10-6) compared with the endometrioid arm (OR 1.25, 95% CI 1.14 to 1.38.

P=4.7×10-6).21Oestrogen receptors α and β encoded by ESR1 and ESR2, respectively, have been extensively studied due to the assumed role of oestrogens in the development of endometrial cancer. O’Mara et al reported a lead SNP (rs79575945) in the ESR1 region that was associated with endometrial cancer (p=1.86×10-5).24 However, this SNP did not reach genome-wide significance in a more recent larger GWAS.21 No statistically significant associations have been reported between endometrial cancer and SNPs in the ESR2 gene region.AKT is an oncogene linked to endometrial carcinogenesis. It is involved in the PI3K/AKT/mTOR pro-proliferative signalling pathway to inactivate apoptosis and allow cell survival. The A allele of rs2494737 and G allele of rs2498796 were reported to be associated with increased and decreased risk of endometrial cancer in 2016, respectively.22 30 However, this association was not replicated in a larger GWAS in 2018.21 Nevertheless, given the previous strong indications, and biological basis that could explain endometrial carcinogenesis, we decided to include an AKT1 variant (rs2498794) in our results.PTEN is a multi-functional tumour suppressor gene that regulates the AKT/PKB signalling pathway and is commonly mutated in many cancers including endometrial cancer.32 Loss-of-function germline mutations in PTEN are responsible for Cowden syndrome, which exerts a lifetime risk of endometrial cancer of up to 28%.9 Lacey and colleagues studied SNPs in the PTEN gene region. However, none showed significant differences in frequency between 447 endometrial cancer cases and 439 controls of European ancestry.33KRAS mutations are known to be present in endometrial cancer.

These can be activated by high levels of KLF5 (transcriptional activator). Three SNPs have been identified in or around KLF5 that are associated with endometrial cancer. The G allele of rs11841589 (OR 1.15, 95% CI 1.11 to 1.21. P=4.83×10-11), the A allele of rs9600103 (OR 1.23, 95% CI 1.16 to 1.30. P=3.76×10-12) and C allele of rs7981863 (OR 1.16, 95% CI 1.12 to 1.20.

P=2.70×10-17) have all been found to be associated with an increased likelihood of endometrial cancer in large European cohorts.21 30 34 It is worth noting that these SNPs are not independent, and hence they quite possibly tag the same causal variant.The MYC family of proto-oncogenes encode transcription factors that regulate cell proliferation, which can contribute to cancer development if dysregulated. The recent GWAS by O’Mara et al reported three SNPs within the MYC region that reached genome-wide significance with conditional p values reaching at least 5×10–8.35To test the utility of these SNPs as predictive markers, we devised a theoretical PRS calculation using the log ORs and EAFs per SNP from the published data. The results were very encouraging with an RR of 3.16 for the top 1% versus the mean, using all the top SNPs presented in table 1 and 2.09 when using only the SNPs that reached genome-wide significance (including AKT1).Controversy surrounding MDM2 variant SNP309MDM2 negatively regulates tumour suppressor gene TP53, and as such, has been extensively studied in relation to its potential role in predisposition to endometrial cancer. Our search identified six original studies of the association between MDM2 SNP rs2279744 (also referred to as SNP309) and endometrial cancer, all of which found a statistically significant increased risk per copy of the G allele. Two more original studies were identified through our full-text evaluation.

However, these were not included here as they did not meet our inclusion criteria—one due to small sample size, the other due to studying rs2279744 status dependent on another SNP.36 37 Even so, the two studies were described in multiple meta-analyses that are listed in table 3. Different permutations of these eight original studies appear in at least eight published meta-analyses. However, even the largest meta-analysis contained <2000 cases (table 3)38View this table:Table 3 Characteristics of studies that examined MDM2 SNP rs2279744In comparison, a GWAS including nearly 13 000 cases found no evidence of an association with OR and corresponding 95% CI of 1.00 (0.97 to 1.03) and a p value of 0.93 (personal communication).21 Nevertheless, we cannot completely rule out a role for MDM2 variants in endometrial cancer predisposition as the candidate-gene studies reported larger effects in Asians, whereas the GWAS primarily contained participants of European ancestry. There is also some suggestion that the SNP309 variant is in linkage disequilibrium with another variant, SNP285, which confers an opposite effect.It is worth noting that the SNP285C/SNP309G haplotype frequency was observed in up to 8% of Europeans, thus requiring correction for the confounding effect of SNP285C in European studies.39 However, aside from one study conducted by Knappskog et al, no other study including the meta-analyses corrected for the confounding effect of SNP285.40 Among the studies presented in table 3, Knappskog et al (2012) reported that after correcting for SNP285, the OR for association of this haplotype with endometrial cancer was much lower, though still significant. Unfortunately, the meta-analyses which synthesised Knappskog et al (2012), as part of their analysis, did not correct for SNP285C in the European-based studies they included.38 41 42 It is also concerning that two meta-analyses using the same primary articles failed to report the same result, in two instances.38 42–44DiscussionThis article represents the most comprehensive systematic review to date, regarding critical appraisal of the available evidence of common low-penetrance variants implicated in predisposition to endometrial cancer.

We have identified the most robust SNPs in the context of endometrial cancer risk. Of those, only 19 were significant at genome-wide level and a further five were considered marginally significant. The largest GWAS conducted in this field was the discovery- and meta-GWAS by O’Mara et al, which utilised 12 096 cases and 108 979 controls.21 Despite the inclusion of all published GWAS and around 5000 newly genotyped cases, the total number did not reach anywhere near what is currently available for other common cancers such as breast cancer. For instance, BCAC (Breast Cancer Association Consortium) stands at well over 200 000 individuals with more than half being cases, and resulted in identification of ~170 SNPs in relation to breast cancer.19 45 A total of 313 SNPs including imputations were then used to derive a PRS for breast cancer.19 Therefore, further efforts should be directed to recruit more patients, with deep phenotypic clinical data to allow for relevant adjustments and subgroup analyses to be conducted for better precision.A recent pre-print study by Zhang and colleagues examined the polygenicity and potential for SNP-based risk prediction for 14 common cancers, including endometrial cancer, using available summary-level data from European-ancestry datasets.46 They estimated that there are just over 1000 independent endometrial cancer susceptibility SNPs, and that a PRS comprising all such SNPs would have an area under the receiver-operator curve of 0.64, similar to that predicted for ovarian cancer, but lower than that for the other cancers in the study. The modelling in the paper suggests that an endometrial cancer GWAS double the size of the current largest study would be able to identify susceptibility SNPs together explaining 40% of the genetic variance, but that in order to explain 75% of the genetic variance it would be necessary to have a GWAS comprising close to 150 000 cases and controls, far in excess of what is currently feasible.We found that the literature consists mainly of candidate-gene studies with small sample sizes, meta-analyses reporting conflicting results despite using the same set of primary articles, and multiple reports of significant SNPs that have not been validated by any larger GWAS.

The candidate-gene studies were indeed the most useful and cheaper technique available until the mid to late 2000s. However, a lack of reproducibility (particularly due to population stratification and reporting bias), uncertainty of reported associations, and considerably high false discovery rates make these studies much less appropriate in the post-GWAS era. Unlike the candidate-gene approach, GWAS do not require prior knowledge, selection of genes or SNPs, and provide vast amounts of data. Furthermore, both the genotyping process and data analysis phases have become cheaper, the latter particularly due to faster and open-access pre-phasing and imputation tools being made available.It is clear from table 1 that some SNPs were reported with wide 95% CI, which can be directly attributed to small sample sizes particularly when restricting the cases to non-endometrioid histology only, low EAF or poor imputation quality. Thus, these should be interpreted with caution.

Additionally, most of the SNPs reported by candidate-gene studies were not detected by the largest GWAS to date conducted by O’Mara et al.21 However, this does not necessarily mean that the possibility of those SNPs being relevant should be completely dismissed. Moreover, meta-analyses were attempted for other variants. However, these showed no statistically significant association and many presented with high heterogeneity between the respective studies (data not shown). Furthermore, as many studies utilised the same set of cases and/or controls, conducting a meta-analysis was not possible for a good number of SNPs. It is therefore unequivocal that the literature is crowded with numerous small candidate-gene studies and conflicting data.

This makes it particularly hard to detect novel SNPs and conduct meaningful meta-analyses.We found convincing evidence for 19 variants that indicated the strongest association with endometrial cancer, as shown in table 1. The associations between endometrial cancer and variants in or around HNF1B, CYP19A1, SOX4, MYC, KLF and EIF2AK found in earlier GWAS were then replicated in the latest and largest GWAS. These SNPs showed promising potential in a theoretical PRS we devised based on published data. Using all 24 or genome-wide significant SNPs only, women with a PRS in the top 1% of the distribution would be predicted to have a risk of endometrial cancer 3.16 and 2.09 times higher than the mean risk, respectively.However, the importance of these variants and relevance of the proximate genes in a functional or biological context is challenging to evaluate. Long distance promoter regulation by enhancers may disguise the genuine target gene.

In addition, enhancers often do not loop to the nearest gene, further complicating the relevance of nearby gene(s) to a GWAS hit. In order to elucidate biologically relevant candidate target genes in endometrial cancer, O’Mara et al looked into promoter-associated chromatin looping using a modern HiChIP approach.47 The authors utilised normal and tumoural endometrial cell lines for this analysis which showed significant enrichment for endometrial cancer heritability, with 103 candidate target genes identified across the 13 risk loci identified by the largest ECAC GWAS. Notable genes identified here were CDKN2A and WT1, and their antisense counterparts. The former was reported to be nearby of rs1679014 and the latter of rs10835920, as shown in table 1. Moreover, of the 36 candidate target genes, 17 were found to be downregulated while 19 were upregulated in endometrial tumours.The authors also investigated overlap between the 13 endometrial cancer risk loci and top eQTL variants for each target gene.47 In whole blood, of the two particular lead SNPs, rs8822380 at 17q21.32 was a top eQTL for SNX11 and HOXB2, whereas rs937213 at 15q15.1 was a top eQTL for SRP14.

In endometrial tumour, rs7579014 at 2p16.1 was found to be a top eQTL for BCL11A. This is particularly interesting because BCL11A was the only nearby/candidate gene that had a GWAS association reported in both endometrioid and non-endometrioid subtypes. The study looked at protein–protein interactions between endometrial cancer drivers and candidate target gene products. Significant interactions were observed with TP53 (most significant), AKT, PTEN, ESR1 and KRAS, among others. Finally, when 103 target candidate genes and 387 proteins were combined together, 462 pathways were found to be significantly enriched.

Many of these are related to gene regulation, cancer, obesity, insulinaemia and oestrogen exposure. This study clearly showed a potential biological relevance for some of the SNPs reported by ECAC GWAS in 2018.Most of the larger included studies used cohorts primarily composed of women of broad European descent. Hence, there are negligible data available for other ethnicities, particularly African women. This is compounded by the lack of reference genotype data available for comparative analysis, making it harder for research to be conducted in ethnicities other than Europeans. This poses a problem for developing risk prediction models that are equally valuable and predictive across populations.

Thus, our results also are of limited applicability to non-European populations.Furthermore, considering that non-endometrioid cases comprise a small proportion (~20%) of all endometrial cancer cases, much larger cohort sizes are needed to detect any genuine signals for non-endometrioid tumours. Most of the evaluated studies looked at either overall/mixed endometrial cancer subtypes or endometrioid histology, and those that looked at variant associations with non-endometrioid histology were unlikely to have enough power to detect any signal with statistical significance. This is particularly concerning because non-endometrioid subtypes are biologically aggressive tumours with a much poorer prognosis that contribute disproportionately to mortality from endometrial cancer. It is particularly important that attempts to improve early detection and prevention of endometrial cancer focus primarily on improving outcomes from these subtypes. It is also worth noting that, despite the current shift towards a molecular classification of endometrial cancer, most studies used the overarching classical Bokhman’s classification system, type I versus type II, or no histological classification system at all.

Therefore, it is important to create and follow a standardised and comprehensive classification system for reporting tumour subtypes for future studies.This study compiled and presented available information for an extensively studied, yet unproven in large datasets, SNP309 variant in MDM2. Currently, there is no convincing evidence for an association between this variant and endometrial cancer risk. Additionally, of all the studies, only one accounted for the opposing effect of a nearby variant SNP285 in their analyses. Thus, we conclude that until confirmed by a sufficiently large GWAS, this variant should not be considered significant in influencing the risk of endometrial cancer and therefore not included in a PRS. This is also true for the majority of the SNPs reported in candidate-gene studies, as the numbers fall far short of being able to detect genuine signals.This systematic review presents the most up-to-date evidence for endometrial cancer susceptibility variants, emphasising the need for further large-scale studies to identify more variants of importance, and validation of these associations.

Until data from larger and more diverse cohorts are available, the top 24 SNPs presented here are the most robust common genetic variants that affect endometrial cancer risk. The multiplicative effects of these SNPs could be used in a PRS to allow personalised risk prediction models to be developed for targeted screening and prevention interventions for women at greatest risk of endometrial cancer..

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An infographic summarizes key findings from the evidence review addressing this issue. Other publications in the Health viagra precio Workforce Strategies for California Series include the following. A research brief on efforts to expand postbaccalaureate programs to help train health professionals so that the workforce better reflects California’s demographics A research brief on expanding teaching hospitals in underserved regions of the state A research brief on identifying strategies to increase the number of health care professionals who speak the same language as their patientsHHS Technology Group, LLC™ (HTG) and Mathematica announced their collaboration on a new health assessment platform that will account for individual health factors to provide a personalized risk score for helping individuals estimate their personal probability of contracting erectile dysfunction treatment as a result of engaging in common activities, such as attending sporting events and dining in restaurants. The comprehensive digital health tool for smart phones, tablets and personal computers will compute personal health risk beyond a simple red, yellow or green threat. This unique solution will enable individuals to perform a health self-assessment as a means of protecting themselves against erectile dysfunction treatment, as viagra precio local economies around the country re-open.

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An infographic summarizes key findings from the evidence review addressing this issue. Other publications in buy viagra online without a prescription the Health Workforce Strategies for California Series include the following. A research brief on efforts to expand postbaccalaureate programs to help train health professionals so that the workforce better reflects California’s demographics A research brief on expanding teaching hospitals in underserved regions of the state A research brief on identifying strategies to increase the number of health care professionals who speak the same language as their patientsHHS Technology Group, LLC™ (HTG) and Mathematica announced their collaboration on a new health assessment platform that will account for individual health factors to provide a personalized risk score for helping individuals estimate their personal probability of contracting erectile dysfunction treatment as a result of engaging in common activities, such as attending sporting events and dining in restaurants. The comprehensive digital health tool for smart phones, tablets and personal computers will compute personal health risk beyond a simple red, yellow or green useful reference threat. This unique solution will enable individuals buy viagra online without a prescription to perform a health self-assessment as a means of protecting themselves against erectile dysfunction treatment, as local economies around the country re-open.

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A saying often http://www.sylvanupholstery.com/seroquel-cost/ attributed to George Bernard Shaw is ‘The single biggest problem in communication is the illusion that it has taken place.’ While it has been debated viagra en farmacias who originally made this statement, this expression has been used across several industries in different ways.1–4 Communication is an essential aspect of patient safety. One could argue for expanding this proverb to emphasise the importance of viagra en farmacias recognising that communication at key moments is intrinsically valuable. The biggest problems in communication are the illusion that it has taken place and the assumption that it is not necessary.Over the past 100 years, cognitive aids for crisis events during patient care have been called for, developed, refined and examined.5–12 While much of this literature comes from high-risk industries and medical simulation, there is increasing supporting evidence from healthcare on how these tools can act as cognitive aids in clinical settings. Regarding terminology, we cite a review article on viagra en farmacias emergency manuals (EMs). €˜EMs are context-relevant viagra en farmacias sets of cognitive aids, such as crisis checklists, that are intended to provide professionals with key information for managing rare emergency events.

Synonyms and related terms include crisis checklists. Emergency checklists and cognitive aids, a much viagra en farmacias broader term, although often also used to describe tools for use during emergency events specifically.’13 Published accounts from healthcare professionals who experienced real-life events have described the power of these tools to prevent errors of omission, commission and lapses in communication.14–18 These events can be both common in large health systems and rare at the level of the individual clinician.10 It is also hard to predict when they will occur. These attributes create a meaningful role to study crisis checklists, EMs and other cognitive aids using medical simulation, particularly in healthcare settings (such as the emergency department (ED)) where they have been understudied.In this issue of BMJ Quality and Safety, Dryver et al make a major contribution to the expanding scope of these evidence-based tools into the realm of emergency medicine.19 In a simulation-based multi-institutional, multidisciplinary randomised controlled trial on the use of medical crisis checklists in the ED, the authors evaluated resuscitation teams in performing indicated emergency interventions during simulated medical crisis events (eg, anaphylactic shock, status epilepticus), with or without access to a crisis checklist for that scenario. Emergency medicine resuscitation teams, comprised of physicians (mainly residents), nurses, nursing assistants and viagra en farmacias medical secretaries, participated in these simulations. They took place during the teams’ clinical shift viagra en farmacias in the ED setting, with access to their usual equipment, medications and cognitive aids.

The checklist for each scenario was displayed on large wall-mounted or television screens and outlined possible interventions to consider during the management of that particular crisis, including for instance medications with their indication, contraindication and risks as well as dose and route of administration. The authors found, among other findings, a notable and viagra en farmacias significant difference in the median percentage of indicated emergency interventions when the checklists were available. 38.8% without checklist access and 85.7% with checklist access (p<0.001). They also found that the vast majority of participants (94%) agreed that they would viagra en farmacias use the checklists if faced with a similar case during actual patient care. Consistent with findings from prior studies in the New England Journal of Medicine (studying operating room teams) and the Journal of Critical Care (studying intensive care unit teams), Dryver et al have demonstrated yet another setting (the viagra en farmacias ED) where crisis checklists, EMs and other critical event cognitive aids may be beneficial.10 20The study should be interpreted in the context of its study design, strengths and limitations.

The study was conducted using in situ simulation, that is, the performance of medical simulation in a clinical care area pertaining to the events being studied. When done safely, this method provides opportunities for participants to practise the management of critical events in the actual location where they may encounter them during actual viagra en farmacias patient care situations.21–23 It is also a multi-institutional study that involved two EDs from an academic centre. One from a rural community hospital, and one from a large community hospital. The checklists were tailored to the medications available at each institution’s ED location as viagra en farmacias opposed to a generic pocket-card cognitive aid. The value of such local customisation has been noted across several publications on crisis checklists and EMs, also highlighting the broader factors to consider (in addition to medication details) such as the medium used (eg, paper vs digital, tablet vs computer), device models and settings (eg, transcutaneous pacemakers settings, defibrillator settings), and methods to call for help (eg, local emergency phone numbers).10 12 24This study focused on the presence or absence of a readily displayed checklist with a medical crisis made readily apparent from the simulated scenario’s introduction viagra en farmacias.

It was not aimed to evaluate the ability of teams to correctly diagnose the critical event of interest. While the authors note that this allowed the simulations to focus on treatment, other studies on crisis checklists/EMs have intentionally included scenarios where the diagnosis was unclear or not within the EM available.10 25 One simulation-based study that included scenarios not within the EM available showed variable usage of the EMs (‘with some teams not using the [emergency manual] at all’) and variable impact on team performance.25 Future studies on the use of ED crisis viagra en farmacias checklists by resuscitation teams may want to factor in the complexity of an undifferentiated medical scenario, where a patient may present with an unknown diagnosis, or where a clinical presentation may be confounded by comorbidities.Not only the range of care settings expands where cognitive aids are considered beneficial when dealing with crisis situations, ongoing work also extends the use of such tools temporally. (1) preventing the viagra en farmacias crisis and/or its manifestations from occurring in the first place, and (2) dealing with the aftermath of the crisis event. The WHO Safe Surgery Saves Lives Surgical Safety Checklist is a well-known example of the first category, containing a set of evidence-based processes of care meant to be carried out at key pause points during surgery. This tool includes a pause-point to allow anticipated critical events to be reviewed, as well as processes that could lead to a critical event if missed (eg, reviewing allergies, confirming counts are correct towards the end of a procedure).26 A systematic review of articles describing the actual use of surgical safety checklists found that they were associated with increased detection of potential safety hazards, decreased surgical complications and improved staff communication.27 Regarding the second category, dealing with the aftermath of a crisis, critical event debriefing is a long-standing practice that has been noted for its potential benefits to healthcare professionals at the individual, team and systems level.28–33 It can help mitigate the negative impact of crisis events on healthcare providers, offer opportunities for education and learning, and serve as a vehicle to identify systems gaps in overall quality and safety.33 34 Something as simple as a well-timed viagra en farmacias drop of WATER (Welfare check, Acute/short-term corrections, Team reactions and reflection, Education, and Resource awareness/longer term needs), the beginnings of a cognitive aid in itself, can have a meaningful ripple effect if used when indicated (figure 1).

Several cognitive aids for various forms of debriefing have been described. The Promoting Excellence And Reflective Learning in Simulation (PEARLS) debriefing tool was developed based on experiences in medical simulation.35 Versions of PEARLS have been adapted for healthcare debriefing and systems-focused debriefing.32 36 The Debriefing In-Situ Conversation after Emergent Resuscitation Now tool was developed in the study of resuscitations at a paediatric ED.37 An adapted version was created during the erectile dysfunction treatment viagra for end-of-shift debriefing in EDs (Debriefing In Situ erectile dysfunction treatment to Encourage Reflection and Plus-Delta in Healthcare After Shifts End).38 There is a large body of literature from medical simulation and other disciplines supporting critical event debriefing.33 34 Considerations to avoid psychological iatrogenic effects from debriefing (such as customisation to local culture and available resources/debriefing training) have been noted.33 34 39 Future research, both via simulation and after real events, can help inform ways to improve the quality and frequency of debriefing after the very events that viagra en farmacias have been studied with crisis checklists and EMs.40Elements to consider for debriefing just after a perioperative critical event. These elements are not meant to be comprehensive viagra en farmacias. Customisation to local culture and available resources is essential.33 34 The responsibility for interpretation/application lies with the reader. Image.

Restivo D. Water Drop impact on water surface. Available at https://commons.wikimedia.org/wiki/File:Water_drop_impact_on_a_water-surface_-_(5).jpg. Accessed 13 Feb 2021. With permission via Creative Commons CC BY-SA 2.0 License (https://creativecommons.org/licenses/by-sa/2.0/legalcode).

QI, quality improvement." data-icon-position data-hide-link-title="0">When translating these interventions from medical simulation to the point of care, there are many lessons to be learnt from the implementation sciences. Editorials and perspective pieces have called for checklists to be viewed within a broader sociocultural or sociotechnical context, including factors such as team training and thoughtful implementation.41 42 Original research on team training initiatives that include surgical safety checklists has been associated with improved patient outcomes.43 Crisis checklists and EMs are substantially less effective if they are sitting in a drawer collecting dust during an emergency. To minimise the likelihood of this happening, it is important that their implementation is approached with the same rigour as all good quality improvement work. Including conducting a needs assessment, customising the cognitive aids, obtaining key stakeholder buy-in, establishing implementation champions, developing training programmes, evaluation and ongoing measurement and iterative improvement, which all have been well described.11 44 45 As another example of an implementation framework, the Consolidated Framework for Implementation Research is composed of five major domains. Intervention characteristics, outer setting, inner setting, characteristics of the individuals involved and the process of implementation.46 Another popular example is the plan–do–study–act model.47 48 Specific to crisis checklists and EMs, Goldhaber-Fiebert and Howard proposed four vital elements for widespread and successful implementation.

Create, familiarise, use and integrate.11 12 Agarwala et al reported an institutional case study of perioperative EM implementation that centred around three goals. (1) place EMs in every anaesthetising location, (2) create interprofessional engagement and (3) demonstrate that a majority of anaesthesia clinicians would use the EMs in some way within the first year.49 Factors such as leadership support and dedicated time to train staff can be essential.45 50 51 More successful implementation of crisis checklists and EMs has been reported when institutions used these tools to assist both during the management of the critical events and in debriefing after critical events.45 An association between the quality of implementation and improved outcomes has similarly been seen with routine surgical safety checklists.52 53 There is also value in research that considers not only whether the tool is used, but also how implementation and training strategies can be leveraged to improve thoughtful adherence to the items on the checklist and avoid issues from going unnoticed.54–56 For critical event debriefing, there is potentially a wide gap between principle and practice. Studies across different medical disciplines have reported that debriefing after critical events takes place only a fraction of the time.34 57 58 Barriers mentioned in studies and other publications include competing clinical priorities, lack of debriefing training, interpersonal dynamics and leadership buy-in.33 34 37 58–61 Several of these barriers potentially overlap with the goals of implementing crisis checklists, and there may be synergy in viewing prevention, crisis events and their aftermath within a continuum.At a fundamental level, many of the cognitive aids discussed in this editorial are designed to both improve cognition and foster interdisciplinary communication about essential best practices at key moments in time. There should not be an illusion that this communication is already taking place or an assumption that it is not necessary. There also should not be a fallacy that these critical event cognitive aids are simply ‘memory aids’.

Growing evidence of EMs during real-time use has described providers reporting the use of these tools associated with decreased stress, improved teamwork, a calmer atmosphere and better care.14 16 There is active work, including collaboration with expertise from the Human Systems Integration Division from the National Aeronautics and Space Administration, exploring how to optimise critical event cognitive aid design relative to the high cognitive load and other factors intrinsic to a crisis.62–66 Emerging research has explored whether it is beneficial to have a crisis checklist reader role, separate from the crisis event leader, when resources allow.13 67Future work on cognitive aids for medical crises should not only address whether they are present, but also how they are designed, used, simulated and implemented towards the most successful outcomes, and its effect on communication. As the scope of patient safety efforts surrounding crisis management continues to expand, there is value in thinking both spatially and temporally via both medical simulation and real events.Ethics statementsPatient consent for publicationNot required.The haemoglobin A1c (HbA1c) level has become the standard of care for monitoring type 2 diabetes as it reflects a person’s average blood glucose level over the previous 2–3 months, is correlated with risk of long-term complications and can be measured cheaply and easily. International guidelines recommend testing HbA1c every 6–12 months for those with stable type 2 diabetes, and every 3–6 months in adults with unstable type 2 diabetes until HbA1c is controlled on unchanging therapy.1–3 However, these guidelines are based on expert consensus rather than robust evidence on whether the frequency of HbA1c measurement impacts patient outcomes. To date, most studies have focused on the association between testing frequency and glycaemic control.4–6In this issue of BMJ Quality &. Safety Imai and colleagues go further, demonstrating an association between adherence to guideline-recommended testing frequency and health outcomes.7 Using data from electronic health records (EHRs), they examined adherence to guideline-recommended HbA1c testing frequency over a 5-year period in 6424 people with type 2 diabetes across 250 general practices in Australia.

An adherence rate was calculated for each person with type 2 diabetes, dividing the number of tests performed within the recommended intervals by the total number of conducted tests (minus 1). Patients were categorised into low-adherence (<33%), moderate-adherence (34%–66%) and high-adherence groups (>66%). Where there was high adherence to guideline-recommended testing frequency, HbA1c values remained stable or improved over time. In contrast, with low adherence, HbA1c values remained unstable or deteriorated over the 5-year period. The risk of developing chronic kidney disease was lower among those with high adherence compared to those with low adherence (OR 0.42, 95% CI 0.18 to 0.99).

There was no evidence of an association between the rate of adherence and the development of ischaemic heart disease. This study provides support for the importance of frequent HbA1c testing as recommended in current clinical guidelines for prevention of complications of diabetes.The study exploits an abundance of observational data on processes and outcomes of care readily available in EHRs in a real-life setting and among a general population with type two diabetes over a 5 year period. However, the authors highlight methodological challenges. Using EHRs to explore the association between adherence to testing frequency and HbA1c is susceptible to selection bias, given that patients need to have HbA1c measurements recorded to be included in the study. Imai and colleagues include ‘active patients’ defined as individuals who attended the practices three or more times in the past 2 years at the time of the visit and had two or more HbA1c tests over the study period.7 While this restriction was necessary to avoid duplication of patients across primary care practices and to study the development of complications over time, it may introduce selection bias and also reduce the generalisability of the findings.

The authors suggest their findings are conservative estimates of the association between adherence to guideline-recommended testing frequency and outcomes, given the positive association between practice visits and glycaemic control. However, those who do not attend general practice regularly differ in many other ways, which may also affect the association between adherence to guideline-recommended testing frequency and health outcomes. A recent systematic review of non-attendance at outpatient diabetes appointments, including those with a general practitioner or nurse, found that younger adults, smokers and those with financial pressures were less likely to attend.8 In addition, even among those who attend general practice regularly, differences in other aspects of care such as self-management behaviour are likely to exist between those with high-adherence versus low-adherence rates.9 In the study by Imai and colleagues, data were not available on potentially important factors, such as patients’ body mass index, smoking status and adherence to medication,7 making it difficult to attribute unstable or deteriorating HbA1c to low-adherence rates. Furthermore, the adherence rate was estimated based on average test numbers over 5 years, so adherence may vary over time. Future research could build on the work of Imai and colleagues to examine the causal relationships between a range of care processes (including testing frequency), HbA1c and health outcomes by assessing the temporality of relationships, accounting for selection bias and confounding, and exploring potential causal mechanisms such as treatment intensification.9Imai and colleagues also found that the median testing frequency in people with type 2 diabetes was less than the recommended two tests per year in Australia (median 1.6 tests per year).7 Poor adherence to recommended testing frequency is documented in several countries with similar guidelines, including countries in Europe10 11 and Asia12 as well as in the USA,13 thus raising questions about how best to improve this process of care.

Diabetes care is the subject of extensive quality improvement and implementation research,14 and a variety of interventions have been shown to improve processes and outcomes of care for people with diabetes.15 How and why these interventions work is unclear because of the range of intervention components operating at the patient, professional and system levels. Most interventions focus on a range of guideline-recommended behaviours in both health professionals and patients and are often described more broadly than changing or targeting one specific behaviour.16 For instance, adherence to HbA1c testing frequency itself is not one specific behaviour. It includes a series of behaviours by the person with diabetes, and potentially their support network, as well as behaviours by health professionals. The person with diabetes must initiate an appointment. The health professional may prompt the person to attend for regular testing.

On deciding and making the effort to attend, the person with diabetes must agree to the blood test. And the health professional must carry out the blood test and send it to a lab for analysis. To improve adherence to HbA1c testing frequency, we may have to intervene in multiple places, but first we need to identify where the process breaks down.There also needs to be a clearer understanding of why the process breaks down. To date, there has been no systematic review of the factors associated with adherence to the frequency of HbA1c testing recommended in guidelines. Individual studies, conducted in different health systems, have identified a range of patient-level factors including age, rurality, disease duration, receipt of specialist care, glycaemic control, cardiovascular risk factors and diabetes-related complications.10–13 Few studies have examined the professional, organisational and system-level determinants of adherence.

Yet we have reason to believe that factors at these levels are also important. In a qualitative synthesis of barriers to optimal diabetes management in primary care, perceived professional barriers included limited time and resources, changing professional boundaries leading to uncertainty about clinical responsibility, and a lack of confidence in knowledge of guidelines and skills.17 A meta-analysis of professional and practice-level factors associated with the quality of diabetes management in primary care identified doctor gender and age, doctor-level diabetes volume, practice deprivation and use of EHRs as significant determinants of quality, typically measured by a collection of individual indicators or a composite measure.18 Furthermore, evidence from a systematic review and meta-analysis of quality improvement interventions for diabetes suggests that strategies that intervene on the entire system of chronic disease management are associated with the largest effects irrespective of baseline HbA1c.15 Thus, to improve adherence to the frequency of HbA1c testing frequency, the problem needs to be understood in context, and solutions should incorporate professional and system-facing interventions as well as patient-facing interventions.Based on their analysis of the content of implementation interventions to support diabetes care, Presseau and colleagues call for better reporting of who needs to do what differently at all levels, including the system level, which is often underspecified.16 This, they propose, would contribute to the development of an underlying programme theory for improvement interventions linking activities to intended outcomes.19 Such an approach is relevant to many chronic conditions where disease management involves multiple actors, actions and settings. The development of testable theories and integration of causal reasoning are increasingly advocated in improvement and implementation science as a way to enhance the generalisability of interventions.20 21 Causal diagram modelling,20 the action–effect method19 and the implementation research logic model,22 facilitate the development and communication of intervention programme theory. The action effect method in particular is intended as a facilitated collaborative process to enhance the practicality of programme theory and to provide an actionable guide for quality improvement teams.19The current study by Imai and colleagues underscores the importance of the link between regular HbA1c testing, better glycaemic control and reduced risk of complications.7 While the causal mechanisms require further investigation, this study provides an important piece of the puzzle. Few interventions target Hba1c testing frequency alone, and this is unlikely to be the sole priority for people with diabetes or their health professionals, given the multiple processes recommended for optimal clinical and self-management.

However, given its centrality and profile in diabetes management, targeting HbA1c could be a lever for wider improvement. The foundation for such an intervention should be a better understanding and more precise articulation of who needs to do what differently, as well as how and why this intervention is expected to change specific processes of care and ultimately improve patient outcomes.Ethics statementsPatient consent for publicationNot required..

A saying often attributed to George Bernard Shaw is ‘The single biggest problem in communication is the illusion that it has taken place.’ While it has been debated who originally made this statement, this expression has been used across buy viagra online without a prescription several industries in different ways.1–4 Communication is an essential aspect of patient safety. One could argue for expanding this proverb to buy viagra online without a prescription emphasise the importance of recognising that communication at key moments is intrinsically valuable. The biggest problems in communication are the illusion that it has taken place and the assumption that it is not necessary.Over the past 100 years, cognitive aids for crisis events during patient care have been called for, developed, refined and examined.5–12 While much of this literature comes from high-risk industries and medical simulation, there is increasing supporting evidence from healthcare on how these tools can act as cognitive aids in clinical settings. Regarding terminology, we cite a review article buy viagra online without a prescription on emergency manuals (EMs).

€˜EMs are context-relevant sets of cognitive aids, such as crisis checklists, that are intended buy viagra online without a prescription to provide professionals with key information for managing rare emergency events. Synonyms and related terms include crisis checklists. Emergency checklists and cognitive aids, a much broader term, although often also used to describe tools for use during emergency events specifically.’13 Published accounts from healthcare professionals who experienced real-life events have described the power of these tools to prevent buy viagra online without a prescription errors of omission, commission and lapses in communication.14–18 These events can be both common in large health systems and rare at the level of the individual clinician.10 It is also hard to predict when they will occur. These attributes create a meaningful role to study crisis checklists, EMs and other cognitive aids using medical simulation, particularly in healthcare settings (such as the emergency department (ED)) where they have been understudied.In this issue of BMJ Quality and Safety, Dryver et al make a major contribution to the expanding scope of these evidence-based tools into the realm of emergency medicine.19 In a simulation-based multi-institutional, multidisciplinary randomised controlled trial on the use of medical crisis checklists in the ED, the authors evaluated resuscitation teams in performing indicated emergency interventions during simulated medical crisis events (eg, anaphylactic shock, status epilepticus), with or without access to a crisis checklist for that scenario.

Emergency medicine resuscitation teams, comprised of physicians (mainly residents), nurses, nursing assistants and buy viagra online without a prescription medical secretaries, participated in these simulations. They took place during the teams’ clinical shift in the buy viagra online without a prescription ED setting, with access to their usual equipment, medications and cognitive aids. The checklist for each scenario was displayed on large wall-mounted or television screens and outlined possible interventions to consider during the management of that particular crisis, including for instance medications with their indication, contraindication and risks as well as dose and route of administration. The authors found, among other findings, buy viagra online without a prescription a notable and significant difference in the median percentage of indicated emergency interventions when the checklists were available.

38.8% without checklist access and 85.7% with checklist access (p<0.001). They also found that the vast majority of participants (94%) agreed that they would use the checklists if buy viagra online without a prescription faced with a similar case during actual patient care. Consistent with findings from prior studies in the New England Journal of Medicine (studying operating room teams) and the Journal of Critical Care (studying intensive care unit teams), Dryver et al have demonstrated yet another setting (the buy viagra online without a prescription ED) where crisis checklists, EMs and other critical event cognitive aids may be beneficial.10 20The study should be interpreted in the context of its study design, strengths and limitations. The study was conducted using in situ simulation, that is, the performance of medical simulation in a clinical care area pertaining to the events being studied.

When done safely, this method provides opportunities for participants to practise the management of critical buy viagra online without a prescription events in the actual location where they may encounter them during actual patient care situations.21–23 It is also a multi-institutional study that involved two EDs from an academic centre. One from a rural community hospital, and one from a large community hospital. The checklists were tailored to the medications available at each institution’s ED location as opposed to a generic pocket-card cognitive aid buy viagra online without a prescription. The value of such local customisation has been noted across several publications on crisis checklists and EMs, also highlighting the broader factors to consider (in addition to medication details) such as the medium used (eg, paper vs digital, tablet vs computer), device models and settings (eg, transcutaneous pacemakers settings, defibrillator settings), and methods to call for help (eg, local emergency phone numbers).10 12 buy viagra online without a prescription 24This study focused on the presence or absence of a readily displayed checklist with a medical crisis made readily apparent from the simulated scenario’s introduction.

It was not aimed to evaluate the ability of teams to correctly diagnose the critical event of interest. While the authors note that this allowed the simulations to focus on treatment, other studies on crisis checklists/EMs have intentionally included scenarios where the diagnosis was unclear or not within the EM buy viagra online without a prescription available.10 25 One simulation-based study that included scenarios not within the EM available showed variable usage of the EMs (‘with some teams not using the [emergency manual] at all’) and variable impact on team performance.25 Future studies on the use of ED crisis checklists by resuscitation teams may want to factor in the complexity of an undifferentiated medical scenario, where a patient may present with an unknown diagnosis, or where a clinical presentation may be confounded by comorbidities.Not only the range of care settings expands where cognitive aids are considered beneficial when dealing with crisis situations, ongoing work also extends the use of such tools temporally. (1) preventing the crisis and/or its manifestations buy viagra online without a prescription from occurring in the first place, and (2) dealing with the aftermath of the crisis event. The WHO Safe Surgery Saves Lives Surgical Safety Checklist is a well-known example of the first category, containing a set of evidence-based processes of care meant to be carried out at key pause points during surgery.

This tool includes a pause-point to allow anticipated critical events to be reviewed, as well as processes that could lead to a critical event if missed (eg, reviewing allergies, confirming counts are correct towards the end of a procedure).26 A systematic review of articles describing the actual use of surgical safety checklists found that they buy viagra online without a prescription were associated with increased detection of potential safety hazards, decreased surgical complications and improved staff communication.27 Regarding the second category, dealing with the aftermath of a crisis, critical event debriefing is a long-standing practice that has been noted for its potential benefits to healthcare professionals at the individual, team and systems level.28–33 It can help mitigate the negative impact of crisis events on healthcare providers, offer opportunities for education and learning, and serve as a vehicle to identify systems gaps in overall quality and safety.33 34 Something as simple as a well-timed drop of WATER (Welfare check, Acute/short-term corrections, Team reactions and reflection, Education, and Resource awareness/longer term needs), the beginnings of a cognitive aid in itself, can have a meaningful ripple effect if used when indicated (figure 1). Several cognitive aids for various forms of debriefing have been described. The Promoting Excellence And Reflective Learning in Simulation (PEARLS) debriefing tool was developed based on experiences in medical simulation.35 buy viagra online without a prescription Versions of PEARLS have been adapted for healthcare debriefing and systems-focused debriefing.32 36 The Debriefing In-Situ Conversation after Emergent Resuscitation Now tool was developed in the study of resuscitations at a paediatric ED.37 An adapted version was created during the erectile dysfunction treatment viagra for end-of-shift debriefing in EDs (Debriefing In Situ erectile dysfunction treatment to Encourage Reflection and Plus-Delta in Healthcare After Shifts End).38 There is a large body of literature from medical simulation and other disciplines supporting critical event debriefing.33 34 Considerations to avoid psychological iatrogenic effects from debriefing (such as customisation to local culture and available resources/debriefing training) have been noted.33 34 39 Future research, both via simulation and after real events, can help inform ways to improve the quality and frequency of debriefing after the very events that have been studied with crisis checklists and EMs.40Elements to consider for debriefing just after a perioperative critical event. These elements buy viagra online without a prescription are not meant to be comprehensive.

Customisation to local culture and available resources is essential.33 34 The responsibility for interpretation/application lies with the reader. Image. Restivo D. Water Drop impact on water surface.

Available at https://commons.wikimedia.org/wiki/File:Water_drop_impact_on_a_water-surface_-_(5).jpg. Accessed 13 Feb 2021. With permission via Creative Commons CC BY-SA 2.0 License (https://creativecommons.org/licenses/by-sa/2.0/legalcode). QI, quality improvement." data-icon-position data-hide-link-title="0">When translating these interventions from medical simulation to the point of care, there are many lessons to be learnt from the implementation sciences.

Editorials and perspective pieces have called for checklists to be viewed within a broader sociocultural or sociotechnical context, including factors such as team training and thoughtful implementation.41 42 Original research on team training initiatives that include surgical safety checklists has been associated with improved patient outcomes.43 Crisis checklists and EMs are substantially less effective if they are sitting in a drawer collecting dust during an emergency. To minimise the likelihood of this happening, it is important that their implementation is approached with the same rigour as all good quality improvement work. Including conducting a needs assessment, customising the cognitive aids, obtaining key stakeholder buy-in, establishing implementation champions, developing training programmes, evaluation and ongoing measurement and iterative improvement, which all have been well described.11 44 45 As another example of an implementation framework, the Consolidated Framework for Implementation Research is composed of five major domains. Intervention characteristics, outer setting, inner setting, characteristics of the individuals involved and the process of implementation.46 Another popular example is the plan–do–study–act model.47 48 Specific to crisis checklists and EMs, Goldhaber-Fiebert and Howard proposed four vital elements for widespread and successful implementation.

Create, familiarise, use and integrate.11 12 Agarwala et al reported an institutional case study of perioperative EM implementation that centred around three goals. (1) place EMs in every anaesthetising location, (2) create interprofessional engagement and (3) demonstrate that a majority of anaesthesia clinicians would use the EMs in some way within the first year.49 Factors such as leadership support and dedicated time to train staff can be essential.45 50 51 More successful implementation of crisis checklists and EMs has been reported when institutions used these tools to assist both during the management of the critical events and in debriefing after critical events.45 An association between the quality of implementation and improved outcomes has similarly been seen with routine surgical safety checklists.52 53 There is also value in research that considers not only whether the tool is used, but also how implementation and training strategies can be leveraged to improve thoughtful adherence to the items on the checklist and avoid issues from going unnoticed.54–56 For critical event debriefing, there is potentially a wide gap between principle and practice. Studies across different medical disciplines have reported that debriefing after critical events takes place only a fraction of the time.34 57 58 Barriers mentioned in studies and other publications include competing clinical priorities, lack of debriefing training, interpersonal dynamics and leadership buy-in.33 34 37 58–61 Several of these barriers potentially overlap with the goals of implementing crisis checklists, and there may be synergy in viewing prevention, crisis events and their aftermath within a continuum.At a fundamental level, many of the cognitive aids discussed in this editorial are designed to both improve cognition and foster interdisciplinary communication about essential best practices at key moments in time. There should not be an illusion that this communication is already taking place or an assumption that it is not necessary.

There also should not be a fallacy that these critical event cognitive aids are simply ‘memory aids’. Growing evidence of EMs during real-time use has described providers reporting the use of these tools associated with decreased stress, improved teamwork, a calmer atmosphere and better care.14 16 There is active work, including collaboration with expertise from the Human Systems Integration Division from the National Aeronautics and Space Administration, exploring how to optimise critical event cognitive aid design relative to the high cognitive load and other factors intrinsic to a crisis.62–66 Emerging research has explored whether it is beneficial to have a crisis checklist reader role, separate from the crisis event leader, when resources allow.13 67Future work on cognitive aids for medical crises should not only address whether they are present, but also how they are designed, used, simulated and implemented towards the most successful outcomes, and its effect on communication. As the scope of patient safety efforts surrounding crisis management continues to expand, there is value in thinking both spatially and temporally via both medical simulation and real events.Ethics statementsPatient consent for publicationNot required.The haemoglobin A1c (HbA1c) level has become the standard of care for monitoring type 2 diabetes as it reflects a person’s average blood glucose level over the previous 2–3 months, is correlated with risk of long-term complications and can be measured cheaply and easily. International guidelines recommend testing HbA1c every 6–12 months for those with stable type 2 diabetes, and every 3–6 months in adults with unstable type 2 diabetes until HbA1c is controlled on unchanging therapy.1–3 However, these guidelines are based on expert consensus rather than robust evidence on whether the frequency of HbA1c measurement impacts patient outcomes.

To date, most studies have focused on the association between testing frequency and glycaemic control.4–6In this issue of BMJ Quality &. Safety Imai and colleagues go further, demonstrating an association between adherence to guideline-recommended testing frequency and health outcomes.7 Using data from electronic health records (EHRs), they examined adherence to guideline-recommended HbA1c testing frequency over a 5-year period in 6424 people with type 2 diabetes across 250 general practices in Australia. An adherence rate was calculated for each person with type 2 diabetes, dividing the number of tests performed within the recommended intervals by the total number of conducted tests (minus 1). Patients were categorised into low-adherence (<33%), moderate-adherence (34%–66%) and high-adherence groups (>66%).

Where there was high adherence to guideline-recommended testing frequency, HbA1c values remained stable or improved over time. In contrast, with low adherence, HbA1c values remained unstable or deteriorated over the 5-year period. The risk of developing chronic kidney disease was lower among those with high adherence compared to those with low adherence (OR 0.42, 95% CI 0.18 to 0.99). There was no evidence of an association between the rate of adherence and the development of ischaemic heart disease.

This study provides support for the importance of frequent HbA1c testing as recommended in current clinical guidelines for prevention of complications of diabetes.The study exploits an abundance of observational data on processes and outcomes of care readily available in EHRs in a real-life setting and among a general population with type two diabetes over a 5 year period. However, the authors highlight methodological challenges. Using EHRs to explore the association between adherence to testing frequency and HbA1c is susceptible to selection bias, given that patients need to have HbA1c measurements recorded to be included in the study. Imai and colleagues include ‘active patients’ defined as individuals who attended the practices three or more times in the past 2 years at the time of the visit and had two or more HbA1c tests over the study period.7 While this restriction was necessary to avoid duplication of patients across primary care practices and to study the development of complications over time, it may introduce selection bias and also reduce the generalisability of the findings.

The authors suggest their findings are conservative estimates of the association between adherence to guideline-recommended testing frequency and outcomes, given the positive association between practice visits and glycaemic control. However, those who do not attend general practice regularly differ in many other ways, which may also affect the association between adherence to guideline-recommended testing frequency and health outcomes. A recent systematic review of non-attendance at outpatient diabetes appointments, including those with a general practitioner or nurse, found that younger adults, smokers and those with financial pressures were less likely to attend.8 In addition, even among those who attend general practice regularly, differences in other aspects of care such as self-management behaviour are likely to exist between those with high-adherence versus low-adherence rates.9 In the study by Imai and colleagues, data were not available on potentially important factors, such as patients’ body mass index, smoking status and adherence to medication,7 making it difficult to attribute unstable or deteriorating HbA1c to low-adherence rates. Furthermore, the adherence rate was estimated based on average test numbers over 5 years, so adherence may vary over time.

Future research could build on the work of Imai and colleagues to examine the causal relationships between a range of care processes (including testing frequency), HbA1c and health outcomes by assessing the temporality of relationships, accounting for selection bias and confounding, and exploring potential causal mechanisms such as treatment intensification.9Imai and colleagues also found that the median testing frequency in people with type 2 diabetes was less than the recommended two tests per year in Australia (median 1.6 tests per year).7 Poor adherence to recommended testing frequency is documented in several countries with similar guidelines, including countries in Europe10 11 and Asia12 as well as in the USA,13 thus raising questions about how best to improve this process of care. Diabetes care is the subject of extensive quality improvement and implementation research,14 and a variety of interventions have been shown to improve processes and outcomes of care for people with diabetes.15 How and why these interventions work is unclear because of the range of intervention components operating at the patient, professional and system levels. Most interventions focus on a range of guideline-recommended behaviours in both health professionals and patients and are often described more broadly than changing or targeting one specific behaviour.16 For instance, adherence to HbA1c testing frequency itself is not one specific behaviour. It includes a series of behaviours by the person with diabetes, and potentially their support network, as well as behaviours by health professionals.

The person with diabetes must initiate an appointment. The health professional may prompt the person to attend for regular testing. On deciding and making the effort to attend, the person with diabetes must agree to the blood test. And the health professional must carry out the blood test and send it to a lab for analysis.

To improve adherence to HbA1c testing frequency, we may have to intervene in multiple places, but first we need to identify where the process breaks down.There also needs to be a clearer understanding of why the process breaks down. To date, there has been no systematic review of the factors associated with adherence to the frequency of HbA1c testing recommended in guidelines. Individual studies, conducted in different health systems, have identified a range of patient-level factors including age, rurality, disease duration, receipt of specialist care, glycaemic control, cardiovascular risk factors and diabetes-related complications.10–13 Few studies have examined the professional, organisational and system-level determinants of adherence. Yet we have reason to believe that factors at these levels are also important.

In a qualitative synthesis of barriers to optimal diabetes management in primary care, perceived professional barriers included limited time and resources, changing professional boundaries leading to uncertainty about clinical responsibility, and a lack of confidence in knowledge of guidelines and skills.17 A meta-analysis of professional and practice-level factors associated with the quality of diabetes management in primary care identified doctor gender and age, doctor-level diabetes volume, practice deprivation and use of EHRs as significant determinants of quality, typically measured by a collection of individual indicators or a composite measure.18 Furthermore, evidence from a systematic review and meta-analysis of quality improvement interventions for diabetes suggests that strategies that intervene on the entire system of chronic disease management are associated with the largest effects irrespective of baseline HbA1c.15 Thus, to improve adherence to the frequency of HbA1c testing frequency, the problem needs to be understood in context, and solutions should incorporate professional and system-facing interventions as well as patient-facing interventions.Based on their analysis of the content of implementation interventions to support diabetes care, Presseau and colleagues call for better reporting of who needs to do what differently at all levels, including the system level, which is often underspecified.16 This, they propose, would contribute to the development of an underlying programme theory for improvement interventions linking activities to intended outcomes.19 Such an approach is relevant to many chronic conditions where disease management involves multiple actors, actions and settings. The development of testable theories and integration of causal reasoning are increasingly advocated in improvement and implementation science as a way to enhance the generalisability of interventions.20 21 Causal diagram modelling,20 the action–effect method19 and the implementation research logic model,22 facilitate the development and communication of intervention programme theory. The action effect method in particular is intended as a facilitated collaborative process to enhance the practicality of programme theory and to provide an actionable guide for quality improvement teams.19The current study by Imai and colleagues underscores the importance of the link between regular HbA1c testing, better glycaemic control and reduced risk of complications.7 While the causal mechanisms require further investigation, this study provides an important piece of the puzzle. Few interventions target Hba1c testing frequency alone, and this is unlikely to be the sole priority for people with diabetes or their health professionals, given the multiple processes recommended for optimal clinical and self-management.

However, given its centrality and profile in diabetes management, targeting HbA1c could be a lever for wider improvement. The foundation for such an intervention should be a better understanding and more precise articulation of who needs to do what differently, as well as how and why this intervention is expected to change specific processes of care and ultimately improve patient outcomes.Ethics statementsPatient consent for publicationNot required..

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In her opening statement before the Senate Judiciary Committee last week, Judge Amy Coney Barrett, President Trump's nominee to the Supreme Court, opined that courts are not policymakers.This should not be surprising -- after all, she has also said that the courts' obligation is go to this web-site not to decide what legislators meant in the words used to write venden viagra en walmart laws, only to seek out their clarity. Barrett also criticized Supreme Court Chief Justice John Roberts' majority opinion in a 2012 case upholding the Affordable Care Act (ACA), saying that he failed to follow the clear language of the statute when he decided that the fine imposed under the law for not purchasing health insurance was a "tax" allowed under Congress' taxing authority and not a penalty disallowed by the Commerce Clause.In fact, Trump is before the Supreme Court right now, with a case being argued before the justices on Nov. 10 arguing that venden viagra en walmart all of Obamacare is unconstitutional. Pundits have rightfully conjectured that he chose Barrett to do his bidding and vote to strike down the law. As Barrett's confirmation hearing began last week, Trump tweeted:"We will have Healthcare which is FAR BETTER than ObamaCare, at a FAR LOWER COST venden viagra en walmart – big premium REDUCTION, PEOPLE WITH PRE EXISTING CONDITIONS WILL BE PROTECTED AT AN EVEN HIGHER LEVEL THAN NOW.

HIGHLY UNPOPULAR AND UNFAIR INDIVIDUAL MANDATE ALREADY TERMINATED. YOU'RE WELCOME! venden viagra en walmart. "He has delivered such a message throughout his presidency, in this year alone starting with his State of the Union address, declaring support for Americans with pre-existing conditions and promising every so often that he will be introducing a spanking new healthcare plan to replace the ACA. Nothing has come forth, nor venden viagra en walmart will it. It's pure bluster and deceit.Trump's Last Chance -- Possibly -- to Destroy the ACABut a struggle now comes to bear between Barrett's views on what courts are limited in doing, and Trump wanting her to be his messenger.

Trump knows this may be his last chance to venden viagra en walmart destroy Obama's most prizeworthy legislative achievement, one that has survived 70 attempts by Republicans in Congress to kill it. Indeed, Democrats are characterizing Barrett's nomination as an attack on Americans' right to healthcare.Barrett told committee members that her prior published views disagreeing with the Supreme Court's two decisions upholding Obamacare (in another case in 2015, the Supreme Court also found the ACA constitutional) have no bearing on her thinking, because the case before the court in November deals with a different issue. Whether the individual mandate, if it's unconstitutional, can be easily severed from venden viagra en walmart the rest of the 974-page law. That reasoning is questionable because before the court can address severability, it must first decide whether the mandate is constitutional.She concurs that severing an unconstitutional provision from the rest of a statute is always a judge's "presumption" and stressed, "I am not here on a mission to destroy the Affordable Care Act. I'm here to apply the law and adhere to the rule of law." She also gave no commitments to the White House on how she would rule.

(A more complete analysis of the options for what the Supreme Court may do with Barrett on the bench is covered venden viagra en walmart here.)Despite Barrett's protestations to the contrary, it's unclear how unbiased she might be if she does get on the high court -- remember that Trump chose her. A more fundamental question lurks. Regardless of how cases are decided, is it ethical to take away a venden viagra en walmart law that has become a legislative embodiment of what many now consider to be their lifeline -- their right -- to healthcare?. The History of the Right to HealthcareBack in 2008 while Obama was on the campaign trail running against the late Sen. John McCain (R-Ariz.), he called healthcare a right venden viagra en walmart -- not a privilege or a responsibility.

That position has become the description du jour this election cycle by many running for office, but they were not the first. Various forms for providing healthcare besides the venden viagra en walmart ACA have been floated since, from a Medicare-for-All system, to reducing the age to become Medicare-eligible, to amending ACA with a public option, the latter supported by Biden. Opponents of government-run healthcare rail against government interference in their lives and call such systems "socialism," even as they hold tightly to their Medicare cards. And consider who paid for Trump's recent erectile dysfunction treatment hospital and venden viagra en walmart medical care at Walter Reed. It surely wasn't a private insurer.The idea of healthcare as a right has been around for decades, tracing its roots back to FDR in 1943 when he crafted his proposed "Second Bill of Rights." As more fully explained by authors Jean Carmalt and Sarah Zaidi, FDR declared "freedom from want" to be four essential liberties for human security, including "the right to adequate medical care and the opportunity to achieve and enjoy good health." Carmalt and Zaidi wrote, "The right to health was subsequently enshrined in the Universal Declaration of Human Rights, a 1948 United Nations document." We can even go back to the Declaration of Independence for our inalienable rights to life, liberty, and the pursuit of happiness as words connoting an ability to achieve, maintain, and regain our health.Of course, there is no "right" to healthcare in the Constitution.

Instead, it is considered a moral venden viagra en walmart imperative, a human right -- at least, that's how every other industrialized country views it except for the U.S., where it's considered a profit-making opportunity. True, other facets of life might also be considered "rights" -- equal treatment for LGBTQ persons, fair housing, civil rights, and the right to vote. And while each of those is surely a noble cause, healthcare is the only one that affects every one of us from birth to death (including the "right to die" for those terminally ill with a painful disease).Ethical Questions to PonderThe judiciary committee expects to approve Barrett's nomination along party lines later this week, and full Senate approval is expected soon thereafter. In the meantime, her nomination has become a symbol for assaulting the venden viagra en walmart ACA, a law that's a prime example of the right to healthcare.This assault on the healthcare law raises many ethical questions. Is it ethical, for example, to decide a seminal law in a way that allows destruction of a moral imperative that millions of Americans have counted on for a decade to preserve and protect health?.

That includes those venden viagra en walmart enrolled in its Medicaid expansion programs, children who are now allowed to remain on their parents' policies until age 26, and anyone benefitting from the law's ban on annual or lifetime coverage caps. Not to mention the more than 8 million people infected with erectile dysfunction treatment who will benefit from the ACA's ban on insurer discrimination against people with preexisting conditions.The justices will have to decide the ACA case using analyses within a legal framework and employing various legal doctrines, notably severability. But another dilemma, also of some ethical proportion, awaits their particular analysis venden viagra en walmart. If they find the entire act unconstitutional, there is currently nothing with which to replace it, nor is a replacement likely to appear any time soon. The court venden viagra en walmart may have to decide the case, but it can't simply throw Obamacare under the bus even as the justices know their newest member was chosen through a process that some are calling a sham.

Barrett's nomination has proceeded at warp speed while an election is ongoing, with millions of votes for the next president already cast.Not since the days of Abraham Lincoln -- in which a vacancy occurred 27 days before a presidential election -- has a justice been chosen in such haste and with utter disregard for what the people want. (Lincoln, unlike Trump, waited until immediately after the election to nominate a replacement -- both because the Senate wasn't in session when the vacancy occurred, and because he could use the opening to his advantage during the campaign.) Even Barrett's colleagues at venden viagra en walmart the University of Notre Dame, in an open letter, are calling on her to put the country ahead of the rush to get her confirmed.Whether she likes it or not, Amy Coney Barrett has become the poster child for whether or not the ACA will remain the sine qua non of healthcare as a right for all.Miles J. Zaremski, JD, has been a healthcare attorney and writer for 47 years. He has written and lectured extensively in the venden viagra en walmart healthcare law space, both nationally and abroad. He has written books and also contributed essays to the Huffington Post and to CNN's Michael Smerconish site.

He is past president of the American College of Legal Medicine and for 5 years served as chair of the American Bar Association's Standing Committee on Medical Professional Liability..

In her opening statement before the Senate Judiciary Committee last week, Judge Amy Coney Barrett, President Trump's nominee to the Supreme Court, opined that courts are not policymakers.This should not be surprising -- after all, she has also said that the courts' obligation is not to decide what legislators meant in the words used to write laws, only to seek out their clarity buy viagra online without a prescription. Barrett also criticized Supreme Court Chief Justice John Roberts' majority opinion in a 2012 case upholding the Affordable Care Act (ACA), saying that he failed to follow the clear language of the statute when he decided that the fine imposed under the law for not purchasing health insurance was a "tax" allowed under Congress' taxing authority and not a penalty disallowed by the Commerce Clause.In fact, Trump is before the Supreme Court right now, with a case being argued before the justices on Nov. 10 arguing that all of buy viagra online without a prescription Obamacare is unconstitutional.

Pundits have rightfully conjectured that he chose Barrett to do his bidding and vote to strike down the law. As Barrett's confirmation hearing began last week, Trump tweeted:"We will have Healthcare which is FAR BETTER than ObamaCare, at a FAR LOWER COST – big premium REDUCTION, PEOPLE WITH PRE EXISTING CONDITIONS WILL BE PROTECTED AT buy viagra online without a prescription AN EVEN HIGHER LEVEL THAN NOW. HIGHLY UNPOPULAR AND UNFAIR INDIVIDUAL MANDATE ALREADY TERMINATED.

YOU'RE WELCOME! buy viagra online without a prescription. "He has delivered such a message throughout his presidency, in this year alone starting with his State of the Union address, declaring support for Americans with pre-existing conditions and promising every so often that he will be introducing a spanking new healthcare plan to replace the ACA. Nothing has come buy viagra online without a prescription forth, nor will it.

It's pure bluster and deceit.Trump's Last Chance -- Possibly -- to Destroy the ACABut a struggle now comes to bear between Barrett's views on what courts are limited in doing, and Trump wanting her to be his messenger. Trump knows this may be his last chance to destroy Obama's most prizeworthy legislative achievement, one that has buy viagra online without a prescription survived 70 attempts by Republicans in Congress to kill it. Indeed, Democrats are characterizing Barrett's nomination as an attack on Americans' right to healthcare.Barrett told committee members that her prior published views disagreeing with the Supreme Court's two decisions upholding Obamacare (in another case in 2015, the Supreme Court also found the ACA constitutional) have no bearing on her thinking, because the case before the court in November deals with a different issue.

Whether the individual mandate, if it's unconstitutional, can be buy viagra online without a prescription easily severed from the rest of the 974-page law. That reasoning is questionable because before the court can address severability, it must first decide whether the mandate is constitutional.She concurs that severing an unconstitutional provision from the rest of a statute is always a judge's "presumption" and stressed, "I am not here on a mission to destroy the Affordable Care Act. I'm here to apply the law and adhere to the rule of law." She also gave no commitments to the White House on how she would rule.

(A more complete analysis of the options for what the Supreme Court may do with Barrett on the bench is covered here.)Despite Barrett's protestations to the contrary, it's unclear how unbiased she might be if she does get on buy viagra online without a prescription the high court -- remember that Trump chose her. A more fundamental question lurks. Regardless of how cases are decided, is it ethical to take away a law that has become a legislative embodiment of what many now consider to be their lifeline buy viagra online without a prescription -- their right -- to healthcare?.

The History of the Right to HealthcareBack in 2008 while Obama was on the campaign trail running against the late Sen. John McCain buy viagra online without a prescription (R-Ariz.), he called healthcare a right -- not a privilege or a responsibility. That position has become the description du jour this election cycle by many running for office, but they were not the first.

Various forms for providing healthcare besides the ACA have been floated since, from a Medicare-for-All system, to reducing the age to become Medicare-eligible, to amending ACA with a public option, the latter supported by Biden buy viagra online without a prescription. Opponents of government-run healthcare rail against government interference in their lives and call such systems "socialism," even as they hold tightly to their Medicare cards. And consider who buy viagra online without a prescription paid for Trump's recent erectile dysfunction treatment hospital and medical care at Walter Reed.

It surely wasn't a private insurer.The idea of healthcare as a right has been around for decades, tracing its roots back to FDR in 1943 when he crafted his proposed "Second Bill of Rights." As more fully explained by authors Jean Carmalt and Sarah Zaidi, FDR declared "freedom from want" to be four essential liberties for human security, including "the right to adequate medical care and the opportunity to achieve and enjoy good health." Carmalt and Zaidi wrote, "The right to health was subsequently enshrined in the Universal Declaration of Human Rights, a 1948 United Nations document." We can even go back to the Declaration of Independence for our inalienable rights to life, liberty, and the pursuit of happiness as words connoting an ability to achieve, maintain, and regain our health.Of course, there is no "right" to healthcare in the Constitution. Instead, it is considered a moral imperative, buy viagra online without a prescription a human right -- at least, that's how every other industrialized country views it except for the U.S., where it's considered a profit-making opportunity. True, other facets of life might also be considered "rights" -- equal treatment for LGBTQ persons, fair housing, civil rights, and the right to vote.

And while each of those is surely a noble cause, healthcare is the only one that affects every one of us from birth to death (including the "right to die" for those terminally ill with a painful disease).Ethical Questions to PonderThe judiciary committee expects to approve Barrett's nomination along party lines later this week, and full Senate approval is expected soon thereafter. In the meantime, her nomination has become a symbol for assaulting the ACA, a law that's a prime example of the right to healthcare.This assault on the healthcare law raises buy viagra online without a prescription many ethical questions. Is it ethical, for example, to decide a seminal law in a way that allows destruction of a moral imperative that millions of Americans have counted on for a decade to preserve and protect health?.

That includes those enrolled in its Medicaid buy viagra online without a prescription expansion programs, children who are now allowed to remain on their parents' policies until age 26, and anyone benefitting from the law's ban on annual or lifetime coverage caps. Not to mention the more than 8 million people infected with erectile dysfunction treatment who will benefit from the ACA's ban on insurer discrimination against people with preexisting conditions.The justices will have to decide the ACA case using analyses within a legal framework and employing various legal doctrines, notably severability. But another dilemma, also of some ethical proportion, buy viagra online without a prescription awaits their particular analysis.

If they find the entire act unconstitutional, there is currently nothing with which to replace it, nor is a replacement likely to appear any time soon. The court may have to decide the case, but it can't simply throw Obamacare under buy viagra online without a prescription the bus even as the justices know their newest member was chosen through a process that some are calling a sham. Barrett's nomination has proceeded at warp speed while an election is ongoing, with millions of votes for the next president already cast.Not since the days of Abraham Lincoln -- in which a vacancy occurred 27 days before a presidential election -- has a justice been chosen in such haste and with utter disregard for what the people want.

(Lincoln, unlike Trump, waited until immediately after the election to nominate a replacement -- both because the Senate wasn't in session when the vacancy occurred, and because he could use the opening to his advantage during the campaign.) Even Barrett's colleagues at the University of Notre Dame, in an open letter, are calling on her to put the country ahead of the rush to get her confirmed.Whether she likes it or not, Amy buy viagra online without a prescription Coney Barrett has become the poster child for whether or not the ACA will remain the sine qua non of healthcare as a right for all.Miles J. Zaremski, JD, has been a healthcare attorney and writer for 47 years. He has written and lectured extensively in the healthcare law space, both nationally and buy viagra online without a prescription abroad.

He has written books and also contributed essays to the Huffington Post and to CNN's Michael Smerconish site. He is past president of the American College of Legal Medicine and for 5 years served as chair of the American Bar Association's Standing Committee on Medical Professional Liability..