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The Empire Justice Center published a report in May, 2013 exploring the where is better to buy cipro policies that guide immigrant access to health care and making recommendations for why not find out more improving immigrant access through New York's Health Insurance Exchange. New York's Exchange Portal. A Gateway to Coverage for Immigrants The report includes a new tool -- Immigrant Eligibility Crosswalk -- Eligibility by Immigration Status-- designed to help advocates and policymakers sort through the tangle of immigrant eligibility categories to determine who is eligible for which health care programs in 2014 and beyond. The report was made possible with support from the United Hospital Fund and benefited from the advice and input from many of our national partners in the effort to ensure maximum participation of immigrants in the nation's healthcare system as well as experts from the New York State Department of Health and the Centers for Medicare and Medicaid Services where is better to buy cipro.

SEE more about "PRUCOL" immigrant eligibility for Medicaid in this article. "Undocumented" immigrants are, with some exceptions for pregnant women and Child Health Plus, only eligible for "emergency Medicaid."NYS announced the 2020 Income and Resource levels in GIS 19 MA/12 – 2020 Medicaid Levels and Other Updates ) and levels based on the Federal Poverty Level are in GIS 20 MA/02 – 2020 Federal Poverty Levels Here is the 2020 HRA Income and Resources Level Chart Non-MAGI - 2020 Disabled, 65+ or Blind ("DAB" or SSI-Related) and have Medicare MAGI (2020) (<. 65, Does not have Medicare)(OR has Medicare where is better to buy cipro and has dependent child <. 18 or <.

19 in school) 138% FPL*** Children <. 5 and pregnant women have HIGHER LIMITS than shown ESSENTIAL PLAN For where is better to buy cipro MAGI-eligible people over MAGI income limit up to 200% FPL No long term care. See info here 1 2 1 2 3 1 2 Income $875 (up from $859 in 201) $1284 (up from $1,267 in 2019) $1,468 $1,983 $2,498 $2,127 $2,873 Resources $15,750 (up from $15,450 in 2019) $23,100 (up from $22,800 in 2019) NO LIMIT** NO LIMIT SOURCE for 2019 figures is GIS 18 MA/015 - 2019 Medicaid Levels and Other Updates (PDF). All of the attachments with the various levels are posted here.

NEED TO KNOW PAST MEDICAID where is better to buy cipro INCOME AND RESOURCE LEVELS?. Which household size applies?. The rules are complicated. See rules here where is better to buy cipro.

On the HRA Medicaid Levels chart - Boxes 1 and 2 are NON-MAGI Income and Resource levels -- Age 65+, Blind or Disabled and other adults who need to use "spend-down" because they are over the MAGI income levels. Box 10 on page 3 are the MAGI income levels -- The Affordable Care Act changed the rules for Medicaid income eligibility for many BUT NOT ALL New Yorkers. People in where is better to buy cipro the "MAGI" category - those NOT on Medicare -- have expanded eligibility up to 138% of the Federal Poverty Line, so may now qualify for Medicaid even if they were not eligible before, or may now be eligible for Medicaid without a "spend-down." They have NO resource limit. Box 3 on page 1 is Spousal Impoverishment levels for Managed Long Term Care &.

Nursing Homes and Box 8 has the Transfer Penalty rates for nursing home eligibility Box 4 has Medicaid Buy-In for Working People with Disabilities Under Age 65 (still 2017 levels til April 2018) Box 6 are Medicare Savings Program levels (will be updated in April 2018) MAGI INCOME LEVEL of 138% FPL applies to most adults who are not disabled and who do not have Medicare, AND can also apply to adults with Medicare if they have a dependent child/relative under age 18 or under 19 if in school. 42 where is better to buy cipro C.F.R. § 435.4. Certain populations have an even higher income limit - 224% FPL for pregnant women and babies <.

Age 1, 154% FPL for children age 1 - 19 where is better to buy cipro. CAUTION. What is counted as income may not be what you think. For the NON-MAGI Disabled/Aged 65+/Blind, income will still be determined by the same rules as before, explained in this outline and these charts where is better to buy cipro on income disregards.

However, for the MAGI population - which is virtually everyone under age 65 who is not on Medicare - their income will now be determined under new rules, based on federal income tax concepts - called "Modifed Adjusted Gross Income" (MAGI). There are good changes and bad changes. GOOD. Veteran's benefits, Workers compensation, and gifts from family or others no longer where is better to buy cipro count as income.

BAD. There is no more "spousal" or parental refusal for this population (but there still is for the Disabled/Aged/Blind.) and some other rules. For all of the where is better to buy cipro rules see. ALSO SEE 2018 Manual on Lump Sums and Impact on Public Benefits - with resource rules The income limits increase with the "household size." In other words, the income limit for a family of 5 may be higher than the income limit for a single person.

HOWEVER, Medicaid rules about how to calculate the household size are not intuitive or even logical. There are different where is better to buy cipro rules depending on the "category" of the person seeking Medicaid. Here are the 2 basic categories and the rules for calculating their household size. People who are Disabled, Aged 65+ or Blind - "DAB" or "SSI-Related" Category -- NON-MAGI - See this chart for their household size.

These same rules apply to the Medicare Savings where is better to buy cipro Program, with some exceptions explained in this article. Everyone else -- MAGI - All children and adults under age 65, including people with disabilities who are not yet on Medicare -- this is the new "MAGI" population. Their household size will be determined using federal income tax rules, which are very complicated. New rule is explained in State's directive 13 ADM-03 - where is better to buy cipro Medicaid Eligibility Changes under the Affordable Care Act (ACA) of 2010 (PDF) pp.

8-10 of the PDF, This PowerPoint by NYLAG on MAGI Budgeting attempts to explain the new MAGI budgeting, including how to determine the Household Size. See slides 28-49. Also seeLegal Aid Society and Empire Justice Center materials OLD RULE used until end of 2013 -- Count the person(s) applying for where is better to buy cipro Medicaid who live together, plus any of their legally responsible relatives who do not receive SNA, ADC, or SSI and reside with an applicant/recipient. Spouses or legally responsible for one another, and parents are legally responsible for their children under age 21 (though if the child is disabled, use the rule in the 1st "DAB" category.

Under this rule, a child may be excluded from the household if that child's income causes other family members to lose Medicaid eligibility. See 18 NYCRR 360-4.2, MRG p. 573, NYS GIS 2000 MA-007 CAUTION. Different people in the same household may be in different "categories" and hence have different household sizes AND Medicaid income and resource limits.

If a man is age 67 and has Medicare and his wife is age 62 and not disabled or blind, the husband's household size for Medicaid is determined under Category 1/ Non-MAGI above and his wife's is under Category 2/MAGI. The following programs were available prior to 2014, but are now discontinued because they are folded into MAGI Medicaid. Prenatal Care Assistance Program (PCAP) was Medicaid for pregnant women and children under age 19, with higher income limits for pregnant woman and infants under one year (200% FPL for pregnant women receiving perinatal coverage only not full Medicaid) than for children ages 1-18 (133% FPL). Medicaid for adults between ages 21-65 who are not disabled and without children under 21 in the household.

It was sometimes known as "S/CC" category for Singles and Childless Couples. This category had lower income limits than DAB/ADC-related, but had no asset limits. It did not allow "spend down" of excess income.

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About This TrackerThis tracker provides the number of confirmed cases and deaths from novel antibiotics by country, the trend in confirmed case and death counts by country, and a where is better to buy cipro global map showing which countries have confirmed cases and deaths. The data are drawn from the Johns Hopkins University (JHU) antibiotics Resource Center’s buy antibiotics Map and the World Health Organization’s (WHO) antibiotics Disease (buy antibiotics-2019) situation reports.This tracker will be updated regularly, as new data are released.Related Content. About buy antibiotics antibioticsIn late 2019, a new antibiotics emerged in central China to cause disease in humans where is better to buy cipro.

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Experiencing first-hand the impact that truly compassionate nurses had on the care of her cipro joint pain brother, UC Davis Health’s Natalie Detwiler understands that it’s vitally important to involve and engage with a patient’s family and loved ones.Hear her describe, in her own words, some of the ways nurses reach out and make connections.In celebration of Florence Nightingale's 200th birthday, 2020 is the Year of the Nurse. Beginning on National Nurses Week (May 6-12) and continuing throughout the year, a special blog will feature the stories, memories and motivations of UC Davis Health nurses.Hear their words, and get to know why and how they invest such heart, cipro joint pain passion, expertise and commitment in their life-changing work..

Experiencing first-hand the impact that truly compassionate nurses had on the care of her brother, UC Davis Health’s Natalie Detwiler understands that it’s vitally important to involve and engage with a patient’s family and loved ones.Hear her describe, in her own words, some of the ways nurses reach out where is better to buy cipro and make connections.In celebration of Florence Nightingale's 200th birthday, 2020 is the Year of the Nurse. Beginning on National Nurses Week (May 6-12) and continuing throughout the year, a special blog will feature the stories, memories and motivations of UC Davis Health nurses.Hear their words, and get to where is better to buy cipro know why and how they invest such heart, passion, expertise and commitment in their life-changing work..

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This document is unpublished cipres mutuelle Continue. It is scheduled to be published on 07/23/2021. Once it is published it will cipres mutuelle be available on this page in an official form.

Until then, you can download the unpublished PDF version. Although we make a concerted effort to reproduce the original document in full on our Public Inspection pages, in some cases graphics may not be displayed, and non-substantive markup language may appear alongside substantive text. If you are using public inspection listings for legal research, you should cipres mutuelle verify the contents of documents against a final, official edition of the Federal Register.

Only official editions of the Federal Register provide legal notice to the public and judicial notice to the courts under 44 U.S.C. 1503 & cipres mutuelle. 1507.

Learn more here.The Centers for Medicare &. Medicaid Services (CMS) is proposing changes to address the widening gap in health cipres mutuelle equity highlighted by the buy antibiotics Public Health Emergency (PHE) and to expand patient access to comprehensive care, especially in underserved populations. In CMS’s annual Physician Fee Schedule (PFS) proposed rule, the agency is recommending steps that continue the Biden-Harris Administration’s commitment to strengthen and build upon Medicare by promoting health equity.

Expanding access to cipres mutuelle services furnished via telehealth and other telecommunications technologies for behavioral health care. Enhancing diabetes prevention programs. And further improving CMS’s quality programs to ensure quality care for Medicare beneficiaries and to create equal opportunities for physicians in both small and large clinical practices.“Over the past year, the public health emergency has highlighted the disparities in the U.S.

Health care system, while at the same cipres mutuelle time demonstrating the positive impact of innovative policies to reduce these disparities,” said CMS Administrator Chiquita Brooks-LaSure. €œCMS aims to take the lessons learned during this time and move forward toward a system where no patient is left out and everyone has access to comprehensive quality health services.” CMS Seeks Feedback on Health Equity Data Collection CMS is committed to addressing the significant and persistent inequities in health outcomes in the U.S. By improving data collection to better measure and analyze disparities across cipres mutuelle programs and policies.

In the proposed PFS rule, CMS is soliciting feedback on the collection of data, and on how the agency can advance health equity for people with Medicare (while protecting individual privacy), potentially through the creation of confidential reports that allow providers to look at patient impact through a variety of data points­­ ̶̶ including, but not limited to, LGBTQ+, race and ethnicity, dual-eligible beneficiaries, disability, and rural populations. Access to these data may enable a more comprehensive assessment of health equity and support initiatives to close the equity gap. In addition, hospitals and health care providers may be able to use the results from the disparity analyses to identify and cipres mutuelle develop strategies to promote health equity.

Expanding Telehealth and Other Telecommunications Technologies for Behavioral and Mental Health Care In the proposed rule, CMS is reinforcing its commitment to expanding access to behavioral health care and reducing barriers to treatment. CMS is proposing to implement recently enacted legislation that removes certain statutory restrictions to allow patients in any cipres mutuelle geographic location and in their homes access to telehealth services for diagnosis, evaluation, and treatment of mental health disorders. Along with this change, CMS is proposing to expand access to mental health services for rural and vulnerable populations by allowing, for the first time, Medicare to pay for mental health visits when they are provided by Rural Health Clinics (RHCs) and Federally Qualified Health Centers (FQHCs) to include visits furnished through interactive telecommunications technology.

This proposal would expand access to Medicare beneficiaries, especially those living in rural and other underserved areas. To further expand access to care, CMS is proposing to allow payment to eligible practitioners when they provide certain mental and cipres mutuelle behavioral health services to patients via audio-only telephone calls from their homes when certain conditions are met. This includes counseling and therapy services provided through Opioid Treatment Programs.

These changes would be particularly helpful for those in areas with poor broadband infrastructure and among people with Medicare who are not capable of, or do not consent to the use of, devices that permit a two-way, cipres mutuelle audio/video interaction for their health care visits. “The buy antibiotics cipro has put enormous strain on families and individuals, making access to behavioral health services more crucial than ever,” said Brooks-LaSure. €œThe changes we are proposing will enhance the availability of telehealth and similar options for behavioral health care to those in need, especially in traditionally underserved communities.” Boosting Participation in the Medicare Diabetes Prevention Program CMS is proposing a change to expand the reach of the Medicare Diabetes Prevention Program (MDPP) expanded model.

MDPP was cipres mutuelle developed to help people with Medicare with prediabetes from developing type 2 diabetes. The expanded model is implemented at the local level by MDPP suppliers. Organizations who provide structured, coach-led sessions in community and health care settings using a Centers for Disease Control and Prevention approved curriculum to provide training in dietary change, increased physical activity, and weight loss strategies.

Approximately one in three American adults (over 88 million) have prediabetes, and more cipres mutuelle than eight in 10 do not even know they have it. Many are at risk for developing type 2 diabetes within five years. Several underserved cipres mutuelle communities ̶̶ including African Americans, Hispanic/Latino Americans, American Indians, Pacific Islanders, and some Asian Americans ̶̶ are at particularly high risk for type 2 diabetes.

During the buy antibiotics PHE, CMS has been waiving the Medicare enrollment fee for new MDPP suppliers and has observed increased supplier enrollment. CMS is proposing to waive this fee for all organizations that submit an application to enroll in Medicare as an MDPP supplier on or after January 1, 2022. Additionally, CMS cipres mutuelle is proposing changes to make delivery of MDPP services more sustainable and to improve patient access by making it easier for local suppliers to participate and reach their communities by proposing to shorten the MDPP services period to one year instead of two years.

This proposal would reduce the administrative burden and costs to suppliers. CMS is also proposing to restructure payments so MDPP suppliers receive larger payments for participants cipres mutuelle who reach milestones for attendance and weight loss. Advancing the Quality Payment Program CMS is taking further steps to improve the quality of care for people with Medicare through changes to the agency’s Quality Payment Program (QPP), a value-based payment program that promotes the delivery of high-value care by clinicians through a combination of financial incentives and disincentives.

CMS is proposing to require clinicians to meet a higher performance threshold to be eligible for incentives. This new threshold aligns with cipres mutuelle the requirements established for the QPP’s Merit-based Incentive Payment System (MIPS) under the Medicare Access and CHIP Reauthorization Act of 2015. To ensure more meaningful participation for clinicians and improved outcomes for patients, CMS is moving forward with the next evolution of QPP and proposing its first seven MIPS Value Pathways (MVPs) ̶ subsets of connected and complementary measures and activities, established through rulemaking, used to meet MIPS reporting requirements.

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Medicare payments to physicians and mass immunizers for administering flu, pneumonia, and hepatitis B treatments have decreased by around 30% over the last seven years. In the PFS proposed rule, CMS is requesting feedback to help update payment rates for administration of preventive treatments covered under Part cipres mutuelle B. In addition to seeking information on the types of health care providers who furnish treatments and their associated costs, CMS is looking for feedback on its recently adopted payment add-on of $35 for immunizers who vaccinate certain underserved patients in the patient’s home.

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Under the proposed change, beginning January 1, 2022, the amount of coinsurance patients will pay for such additional services would be reduced over time, so that by January 1, 2030, it would be down to zero. For a fact sheet on the CY 2022 Physician Fee Schedule proposed rule, please visit. https://www.cms.gov/newsroom/fact-sheets/calendar-year-cy-2022-medicare-physician-fee-schedule-proposed-rule For a fact sheet on the CY 2022 Quality Payment Program proposed changes, please visit.

Https://qpp-cm-prod-content.s3.amazonaws.com/uploads/1517/2022%20QPP%20Proposed%20Rule%20Overview%20Fact%20Sheet.pdf For a fact sheet on the proposed Medicare Diabetes Prevention Program changes, please visit. https://www.cms.gov/newsroom/fact-sheets/proposed-policies-medicare-diabetes-prevention-program-mdpp-expanded-model-calendar-year-2022 To view the CY 2022 Physician Fee Schedule and Quality Payment Program proposed rule, please visit. Https://www.federalregister.gov/public-inspection/current #### Get CMS news at cms.gov/newsroom, sign up for CMS news via email and follow CMS on Twitter @CMSgov.

This document is where is better to buy cipro where can i buy cipro unpublished. It is scheduled to be published on 07/23/2021. Once it is published it will be where is better to buy cipro available on this page in an official form. Until then, you can download the unpublished PDF version.

Although we make a concerted effort to reproduce the original document in full on our Public Inspection pages, in some cases graphics may not be displayed, and non-substantive markup language may appear alongside substantive text. If you are using public inspection listings for legal research, you should verify the contents of documents against a final, official edition of where is better to buy cipro the Federal Register. Only official editions of the Federal Register provide legal notice to the public and judicial notice to the courts under 44 U.S.C. 1503 & where is better to buy cipro.

1507. Learn more here.The Centers for Medicare &. Medicaid Services (CMS) is proposing changes to address the widening gap in health equity highlighted by where is better to buy cipro the buy antibiotics Public Health Emergency (PHE) and to expand patient access to comprehensive care, especially in underserved populations. In CMS’s annual Physician Fee Schedule (PFS) proposed rule, the agency is recommending steps that continue the Biden-Harris Administration’s commitment to strengthen and build upon Medicare by promoting health equity.

Expanding access to services furnished via telehealth and other telecommunications technologies for behavioral health care where is better to buy cipro. Enhancing diabetes prevention programs. And further improving CMS’s quality programs to ensure quality care for Medicare beneficiaries and to create equal opportunities for physicians in both small and large clinical practices.“Over the past year, the public health emergency has highlighted the disparities in the U.S. Health care system, while at where is better to buy cipro the same time demonstrating the positive impact of innovative policies to reduce these disparities,” said CMS Administrator Chiquita Brooks-LaSure.

€œCMS aims to take the lessons learned during this time and move forward toward a system where no patient is left out and everyone has access to comprehensive quality health services.” CMS Seeks Feedback on Health Equity Data Collection CMS is committed to addressing the significant and persistent inequities in health outcomes in the U.S. By improving data collection to better measure and analyze disparities across programs where is better to buy cipro and policies. In the proposed PFS rule, CMS is soliciting feedback on the collection of data, and on how the agency can advance health equity for people with Medicare (while protecting individual privacy), potentially through the creation of confidential reports that allow providers to look at patient impact through a variety of data points­­ ̶̶ including, but not limited to, LGBTQ+, race and ethnicity, dual-eligible beneficiaries, disability, and rural populations. Access to these data may enable a more comprehensive assessment of health equity and support initiatives to close the equity gap.

In addition, hospitals and health where is better to buy cipro care providers may be able to use the results from the disparity analyses to identify and develop strategies to promote health equity. Expanding Telehealth and Other Telecommunications Technologies for Behavioral and Mental Health Care In the proposed rule, CMS is reinforcing its commitment to expanding access to behavioral health care and reducing barriers to treatment. CMS is proposing to implement recently enacted legislation that removes certain statutory restrictions to where is better to buy cipro allow patients in any geographic location and in their homes access to telehealth services for diagnosis, evaluation, and treatment of mental health disorders. Along with this change, CMS is proposing to expand access to mental health services for rural and vulnerable populations by allowing, for the first time, Medicare to pay for mental health visits when they are provided by Rural Health Clinics (RHCs) and Federally Qualified Health Centers (FQHCs) to include visits furnished through interactive telecommunications technology.

This proposal would expand access to Medicare beneficiaries, especially those living in rural and other underserved areas. To further expand access to care, CMS is proposing to where is better to buy cipro allow payment to eligible practitioners when they provide certain mental and behavioral health services to patients via audio-only telephone calls from their homes when certain conditions are met. This includes counseling and therapy services provided through Opioid Treatment Programs. These changes would be particularly helpful for those in areas with poor broadband infrastructure and among people with Medicare who are not capable of, where is better to buy cipro or do not consent to the use of, devices that permit a two-way, audio/video interaction for their health care visits.

“The buy antibiotics cipro has put enormous strain on families and individuals, making access to behavioral health services more crucial than ever,” said Brooks-LaSure. €œThe changes we are proposing will enhance the availability of telehealth and similar options for behavioral health care to those in need, especially in traditionally underserved communities.” Boosting Participation in the Medicare Diabetes Prevention Program CMS is proposing a change to expand the reach of the Medicare Diabetes Prevention Program (MDPP) expanded model. MDPP was where is better to buy cipro developed to help people with Medicare with prediabetes from developing type 2 diabetes. The expanded model is implemented at the local level by MDPP suppliers.

Organizations who provide structured, coach-led sessions in community and health care settings using a Centers for Disease Control and Prevention approved curriculum to provide training in dietary change, increased physical activity, and weight loss strategies. Approximately one in three American adults (over 88 visit their website million) have prediabetes, and more than eight in 10 do not even know where is better to buy cipro they have it. Many are at risk for developing type 2 diabetes within five years. Several underserved communities ̶̶ including African Americans, Hispanic/Latino Americans, American Indians, Pacific Islanders, and some Asian Americans ̶̶ are at particularly high risk where is better to buy cipro for type 2 diabetes.

During the buy antibiotics PHE, CMS has been waiving the Medicare enrollment fee for new MDPP suppliers and has observed increased supplier enrollment. CMS is proposing to waive this fee for all organizations that submit an application to enroll in Medicare as an MDPP supplier on or after January 1, 2022. Additionally, CMS is proposing changes to make delivery of MDPP services more sustainable and to improve patient access by making it easier for local suppliers to participate and reach their communities by proposing to shorten the MDPP services period to one year instead of two years where is better to buy cipro. This proposal would reduce the administrative burden and costs to suppliers.

CMS is also proposing to restructure payments so MDPP suppliers receive larger payments for participants where is better to buy cipro who reach milestones for attendance and weight loss. Advancing the Quality Payment Program CMS is taking further steps to improve the quality of care for people with Medicare through changes to the agency’s Quality Payment Program (QPP), a value-based payment program that promotes the delivery of high-value care by clinicians through a combination of financial incentives and disincentives. CMS is proposing to require clinicians to meet a higher performance threshold to be eligible for incentives. This new threshold aligns with the requirements established for the QPP’s Merit-based Incentive Payment where is better to buy cipro System (MIPS) under the Medicare Access and CHIP Reauthorization Act of 2015.

To ensure more meaningful participation for clinicians and improved outcomes for patients, CMS is moving forward with the next evolution of QPP and proposing its first seven MIPS Value Pathways (MVPs) ̶ subsets of connected and complementary measures and activities, established through rulemaking, used to meet MIPS reporting requirements. The initial set where is better to buy cipro of proposed MVP clinical areas include. Rheumatology, stroke care and prevention, heart disease, chronic disease management, lower extremity joint repair (e.g., knee replacement), emergency medicine, and anesthesia. MVPs will more effectively measure and compare performance across clinician types and provide clinicians more meaningful feedback.

CMS is also proposing to revise the current where is better to buy cipro eligible clinician definition to include clinical social workers and certified nurse-midwives, as these professionals are often on the front lines serving communities with acute health care needs. Additionally, CMS is proposing to implement a recent statutory change that authorizes Medicare to make direct Medicare payments to Physician Assistants (PAs) for professional services they furnish under Part B. Beginning January 1, 2022, for the first time, physician assistants would be able to bill Medicare directly, thus expanding access to care and reducing the administrative where is better to buy cipro burden that currently requires a PA’s employer or independent contractor to bill Medicare for a PA’s professional services. Updating treatment Payment Rates The buy antibiotics cipro has highlighted the importance of access to treatments.

The Biden-Harris Administration has taken steps to increase American’s access to buy antibiotics vaccinations and is committed to meeting people where they are and making it as easy as possible for all Americans to get vaccinated. That commitment where is better to buy cipro extends to other, more common vaccinations. Medicare payments to physicians and mass immunizers for administering flu, pneumonia, and hepatitis B treatments have decreased by around 30% over the last seven years. In the PFS proposed rule, CMS is requesting feedback to help where is better to buy cipro update payment rates for administration of preventive treatments covered under Part B.

In addition to seeking information on the types of health care providers who furnish treatments and their associated costs, CMS is looking for feedback on its recently adopted payment add-on of $35 for immunizers who vaccinate certain underserved patients in the patient’s home. CMS is also seeking comments on the treatment of buy antibiotics monoclonal antibody products as treatments, and whether those products should be treated like other monoclonal antibody products after the buy antibiotics PHE. Proposal to Phase Out Coinsurance for Colorectal Screening Additional Services CMS is also proposing to implement a recent statutory change to provide a special coinsurance rule for procedures that are planned as colorectal cancer screening tests but become diagnostic tests when the practitioner identifies the need for additional services where is better to buy cipro (e.g., removal of polyps). Currently, the addition of any procedure beyond the planned colorectal screening (for which there is no coinsurance) results in a patient having to pay coinsurance.

Under the proposed change, beginning January 1, 2022, the where is better to buy cipro amount of coinsurance patients will pay for such additional services would be reduced over time, so that by January 1, 2030, it would be down to zero. For a fact sheet on the CY 2022 Physician Fee Schedule proposed rule, please visit. https://www.cms.gov/newsroom/fact-sheets/calendar-year-cy-2022-medicare-physician-fee-schedule-proposed-rule For a fact sheet on the CY 2022 Quality Payment Program proposed changes, please visit. Https://qpp-cm-prod-content.s3.amazonaws.com/uploads/1517/2022%20QPP%20Proposed%20Rule%20Overview%20Fact%20Sheet.pdf For a fact sheet on the proposed Medicare Diabetes Prevention Program changes, please visit where is better to buy cipro.

https://www.cms.gov/newsroom/fact-sheets/proposed-policies-medicare-diabetes-prevention-program-mdpp-expanded-model-calendar-year-2022 To view the CY 2022 Physician Fee Schedule and Quality Payment Program proposed rule, please visit. Https://www.federalregister.gov/public-inspection/current #### Get CMS news at cms.gov/newsroom, sign up for CMS news via email and follow CMS on Twitter @CMSgov.

Is cipro good for bronchitis

MDEL Bulletin, June 24 2021, from the Medical Devices Compliance Program On this page Fees for Medical Device Establishment Licences (MDELs) We is cipro good for bronchitis issue Medical Device Establishment Licences (MDELs) to. class I manufacturers importers or distributors of all device classes for human use in Canada The MDEL fee is a flat fee, regardless of when we receive your initial application. The same is cipro good for bronchitis fee applies to applications for. a new MDEL the reinstatement of a suspended MDEL the annual licence review (ALR) of an MDEL If you submit any of these applications, you must pay the MDEL fee when you receive an invoice. See Part 3, Division 2 of the Fees in Respect of Drugs and Medical Devices Order.

Normally, we collect is cipro good for bronchitis the MDEL fee before we review an application. However, to help meet the demand for medical devices during the buy antibiotics cipro, we have been reviewing and processing MDEL applications before collecting the fees. As a result, some MDEL holders still haven't paid the fees for their 2020 initial MDEL application, despite multiple reminders. Authority to withhold services in case of non-payment As stated in the Food and Drug Act, Health Canada has the authority to withhold services, is cipro good for bronchitis approvals, rights and/or privileges, if the fee for an MDEL application is not paid. Non-payment of fees 30.64.

The Minister may withdraw or withhold a service, the use of a facility, a regulatory process or approval or a product, right or privilege under this Act from any person who fails to pay the fee fixed for it under subsection 30.61(1). For more information, please refer is cipro good for bronchitis to. Cancellation of existing MDELs We will cancel MDELs for existing MDEL holders with outstanding fees for. initial applications or annual licence review applications If your establishment licence is cancelled, you are no longer authorized to conduct licensable activities (such as manufacturing, distributing or importing medical devices). You must stop licensable activities as soon as you receive is cipro good for bronchitis your cancellation notice.

Resuming activities after MDEL cancellation To resume licensable activities, you must re-apply for a new establishment licence and pay the MDEL fee. See section 45 of the Medical Device is cipro good for bronchitis Regulations. To find out how to re-apply for a MDEL, please refer to our Guidance on medical device establishment licensing (GUI-0016). In line with the Compliance and Enforcement Policy (POL-0001), Health Canada monitors activities for compliance. If your MDEL has been cancelled, you may be subject to compliance and enforcement is cipro good for bronchitis actions if you conduct non-compliant activities.

If you have questions about a MDEL or the application process, please contact the Medical Device Establishment Licensing Unit at hc.mdel.questions.leim.sc@canada.ca. If you have questions about invoicing and fees for an MDEL application, please contact the Cost Recovery Invoicing Unit at hc.criu-ufrc.sc@canada.ca. Related linksResponse to the Expert Panel is cipro good for bronchitis Report on “Priority strategies to optimize testing and quarantine at Canada’s borders” The Industry Advisory Roundtable on buy antibiotics Testing, Screening, Tracing and Data Management is pleased to release its third report. This report reiterates the importance of balancing public health measures to reduce the importation of buy antibiotics with the need to ensure the free flow of people and goods across the Canadian border and support economic recovery. On this page Executive summary Soon after buy antibiotics was declared a global cipro in March 2020, international borders around the world closed in an effort to limit the spread of the cipro.

To ensure the health and safety of individuals, the movement of people and goods was is cipro good for bronchitis restricted. Yet, it was important to maintain access to essential goods and services and sustain trade-based economic sectors. Canada responded in step with other countries. The government implemented is cipro good for bronchitis public health measures such as mandatory testing and quarantine when crossing international borders. Restrictions are necessary to curb the spread of the cipro.

Yet, in a complex environment such as international borders, it’s crucial to implement and clearly communicate public health measures effectively and clearly. Border measures such as testing regimes and other public health measures must be is cipro good for bronchitis based on the most recent science-based public health evidence. Such measures must also leverage advances in testing options, consider vaccination rates and balance the needs of industries operating across borders. Furthermore, plans must be easy to implement is cipro good for bronchitis consistently across several entry modes. They should also be communicated broadly and include a roadmap for easing or increasing border restrictions based on objective criteria and benchmarks.

As we enter the second year of the cipro, the Roundtable is offering insights and recommendations to adjust current border measures. We have is cipro good for bronchitis based our recommendations on evidence collected from international scans and observations from industries that move goods and people across borders. The Roundtable recognizes the effort required to implement plans for easing border restrictions, given rapidly evolving public health circumstances and emerging variants of concern. Prompt action is needed to design and implement a border measures plan that reduces the risk of the cipro spreading while proactively moving towards economic recovery. Current border environment In March 2020, the ability of is cipro good for bronchitis people to move across the Canadian border was restricted.

Since then, several measures were taken to reduce the importation of buy antibiotics and limit the spread of the cipro. As circumstances changed over the following weeks and months, border measures became more restrictive. In early 2021, more stringent public is cipro good for bronchitis health measures were introduced for non-essential travellers at air and land borders. This was done to reduce the importation rate of buy antibiotics and its variants of concern. Measures included the following.

mandatory pre-departure buy antibiotics molecular test contact/quarantine plan using the ArriveCAN application on-arrival and post-arrival testing for travellers arriving by air, mandatory 3-day quarantine in government-authorized hotels followed by is cipro good for bronchitis quarantine or isolation at an approved location such as the traveller’s home The Government of Canada and the aviation industry also worked together on a plan to suspend Canadian air carrier flights to and from Mexico and Caribbean countries from January 31 to April 30, 2021. Then on February 3, 2021, all incoming international commercial passenger flights to Canada were restricted to the 4 largest airports. Montreal, Toronto, Calgary and Vancouver. In order to prevent importation of variants of concern, the Government of Canada took additional is cipro good for bronchitis measures that included suspension of flights from certain countries. Canada suspended all commercial and passenger flights from the United Kingdom between December 20, 2020 and January 6, 2021.

Additionally, on April 22, 2021, all commercial and private passenger flights from India and is cipro good for bronchitis Pakistan were suspended in response to a high number of cases detected among individuals travelling on flights originating from the two countries. These measures are in place until at least June 21, 2021. Internal data from the Public Health Agency of Canada indicates the following positivity rates for the seven days up to and including May 27, 2021, for air and land travel combined. the 7-day average positivity rate for testing on arrival was 0.2% the 7-day average positivity rate for second tests was is cipro good for bronchitis 0.3% As well, all positive tests undergo genomic sequencing to identify variants of concern. Cross-border travel volumes decreased significantly from December 2019 to December 2020.

Statistics Canada data show that the. number of travellers to Canada was down 93% total number of international travellers to and from Canada declined from 96.8 million in 2019 to 25.9 million in 2020 Air travel has experienced the most dramatic shifts, as travellers arriving by is cipro good for bronchitis air are mostly non-exempt from border measures. In comparison, travellers exempt from border measures make up the vast majority of land border traffic. Essential travel continued largely unimpeded, as governments recognized the importance of preserving vital supply chains to ensure that food, fuel and life-saving medicines continue to reach people. A shifting landscape As of May 28, 2021, variants of concern account for an estimated 70% of reported cases in is cipro good for bronchitis recent weeks.

Any border measures must account for this new reality. At the same time, individuals and organizations within and outside of Canada are increasingly looking for. a concrete roadmap to the economic reopening is cipro good for bronchitis of the country clear guidelines for restarting cross-border travel Plans and guidelines should clearly spell out the public health criteria for adjusting border measures. They should also outline when and how restrictions should be eased in the short and longer term. Guidelines must take into consideration the risk of importing new variants of concern in the move towards a safe restart is cipro good for bronchitis of the trade and tourism industries that operate internationally.

As scientists learn more about how the cipro spreads, as travellers are tested regularly and as vaccination efforts increase, it will be easier to manage the risk of importing buy antibiotics and its variants. Nevertheless, while the international border is open, there’s always the risk of importation. For a safe reopening, we need a risk framework that takes into account is cipro good for bronchitis public health measures and socio-economic factors. To bring the risk to an acceptable level, detection and surveillance options should be part of any robust border testing strategy. Evidence concerning restrictive border measures, including lengthy quarantines, shows that the effectiveness of these measures declines over time.

Non-compliance increases when is cipro good for bronchitis measures are too tough and/or not communicated well. This can counter efforts to reduce the spread of the cipro and break the chains of transmission. As more and more people in Canada and abroad are vaccinated, it will be necessary to update Canada’s strategy to allow the movement of vaccinated travellers, based on emerging scientific evidence and while respecting public health measures. Complex border measures may present significant implementation challenges, which can lead is cipro good for bronchitis to disparities in how the various rules, regulations and guidelines are applied at ports of entry. This may have a negative impact on people crossing the Canadian border and those industries engaged in cross-border and transnational business.

Small and medium companies may be especially impacted. Although essential workers have largely been exempt from border measures, the Roundtable is aware of the challenges they face when rules are applied is cipro good for bronchitis inconsistently. For example, several Canadian companies have reported incidences where some engineers, technicians and other specialists have faced challenges crossing the Canada-US border and meeting their contractual obligations to provide skilled services. Some business executives and professional services providers with cross-border responsibilities are constrained in their ability to manage their operations effectively. As well, disruptions to the cross-border travel of these workers could expose businesses to legal recourse is cipro good for bronchitis from clients for failure to meet commitments.

Many countries, including Canada, are aggressively rolling out vaccination regimes and partially permitting the movement of people (with restrictions). Canada is now is cipro good for bronchitis the top country in the G7, G20 and OECD for vaccination rates of first doses. As the campaign shifts to second doses, Canada must continue to reach vulnerable populations to ensure treatment equity and broad-based coverage to facilitate re-opening the economy and growth. Canada’s biggest trading partner also shares its largest border. Efforts should be made to align public health and economic recovery goals is cipro good for bronchitis between Canada and the United States.

Prioritizing the Canada-US border would be consistent with the commitments made by both countries in the Roadmap for a Renewed U.S.-Canada Partnership. This roadmap recommends a coordinated and science-based approach to ease border restrictions in the future. Countries around the world are also exploring cooperative arrangements with other countries and looking at piloting innovative technology and information-sharing platforms designed to facilitate safe travel, such as treatment is cipro good for bronchitis certification. Implementing significant changes requires wide support and cooperation, as highlighted in the Industry Strategy Council’s Restart, recover, and reimagine prosperity for all Canadians report. The report proposes a three-phase action plan – restart, recover, and reimagine – focused on investment and growth, and embodies values and principles of action and shared responsibility to mobilize all sectors to propel Canada forward.

The phases are anchored in five recommendations to safely restore confidence and commerce, stabilize the hardest-hit sectors, reignite growth by doubling down on a future-oriented investment plan, develop an ambitious industrial strategy, and establish renewed public-private sector partnerships and investments anchored in a sound and rigorous fiscal framework is cipro good for bronchitis. At the same time, we must recognize we live in times of uncertainty and contend with a rapidly shifting landscape. Plans should be flexible in order to balance public health concerns with the desire to ease restrictions. We must work with public health experts to establish and clearly communicate criteria and benchmarks to help travellers and businesses understand how and when border restrictions will be eased is cipro good for bronchitis or increased in the coming months. Provinces and territories have outlined their reopening plans, with an important strength being the use of benchmarks to move between several steps of restrictions.

Communicating a clear path with well-defined criteria will provide a much-needed level of predictability for reopening to industry and travellers alike. Recommendations The Industry Roundtable recommends an approach to border measures that include both short- and is cipro good for bronchitis longer-term recommendations. Short-term recommendations Provide clear definitions of cross-border essential travellers and apply these in a consistent manner at all ports of entry. Recognize that companies are well positioned to identify essential travellers within their organization, enabling them to leverage existing domestic testing regimes for employees to is cipro good for bronchitis demonstrate that public health requirements are met. Accepting employer-issued proof of testing would shift the onus away from the border and alleviate traveller flow pressures.

Explicitly state the conditions for testing travellers and the criteria for shortening or removing quarantine measures. Connect the pace of vaccination rollout with public health measures and the gradual lifting of travel restrictions, and include clear procedures is cipro good for bronchitis for vaccinated, partially vaccinated and unvaccinated travellers. This may need to adjust as new variants of concern emerge. Enable industry to take an active role in meeting vaccination targets in Canada by supporting priority vaccination of cross-border essential workers. Aggressive vaccination targets for these workers would help companies contribute to the safe reopening of the economy in a timely manner is cipro good for bronchitis.

Apply measures consistently at air and land borders, whenever possible. Provide clear, straightforward messaging for every person and company involved in the cross-border movement of people and goods. Clear communication leads to effective, is cipro good for bronchitis consistent implementation of any border measure and subsequent updates. Longer-term recommendations Take into account evolving scientific evidence and adopt emerging findings. For example, evidence suggests that rapid antigen testing can be effective as a screening tool and adds another layer of defence when used as part of surveillance testing.

Ensure that processes, information systems and infrastructure needed to implement modified border measures are in place and can manage is cipro good for bronchitis increased travel volumes effectively. Re-position Canada as a competitive participant in the tourism and global trade sectors through enabling border measures that facilitate the movement of people and goods across international borders. In collaboration with the private sector, the government should develop an enhanced framework to better prepare for and respond to future cipros..

MDEL Bulletin, June 24 2021, from the Medical Devices Compliance Program On this page where is better to buy cipro Fees for Medical Device Establishment Licences (MDELs) We issue Medical Device Establishment Licences (MDELs) to. class I manufacturers importers or distributors of all device classes for human use in Canada The MDEL fee is a flat fee, regardless of when we receive your initial application. The same fee applies to applications where is better to buy cipro for. a new MDEL the reinstatement of a suspended MDEL the annual licence review (ALR) of an MDEL If you submit any of these applications, you must pay the MDEL fee when you receive an invoice.

See Part 3, Division 2 of the Fees in Respect of Drugs and Medical Devices Order. Normally, we collect the where is better to buy cipro MDEL fee before we review an application. However, to help meet the demand for medical devices during the buy antibiotics cipro, we have been reviewing and processing MDEL applications before collecting the fees. As a result, some MDEL holders still haven't paid the fees for their 2020 initial MDEL application, despite multiple reminders.

Authority to withhold services in case of non-payment As stated in the Food and Drug Act, Health Canada has the authority to withhold services, approvals, rights and/or privileges, if the fee for an MDEL application is not paid where is better to buy cipro. Non-payment of fees 30.64. The Minister may withdraw or withhold a service, the use of a facility, a regulatory process or approval or a product, right or privilege under this Act from any person who fails to pay the fee fixed for it under subsection 30.61(1). For more information, please refer where is better to buy cipro to.

Cancellation of existing MDELs We will cancel MDELs for existing MDEL holders with outstanding fees for. initial applications or annual licence review applications If your establishment licence is cancelled, you are no longer authorized to conduct licensable activities (such as manufacturing, distributing or importing medical devices). You must stop licensable activities as soon where is better to buy cipro as you receive your cancellation notice. Resuming activities after MDEL cancellation To resume licensable activities, you must re-apply for a new establishment licence and pay the MDEL fee.

See section 45 of where is better to buy cipro the Medical Device Regulations. To find out how to re-apply for a MDEL, please refer to our Guidance on medical device establishment licensing (GUI-0016). In line with the Compliance and Enforcement Policy (POL-0001), Health Canada monitors activities for compliance. If your where is better to buy cipro MDEL has been cancelled, you may be subject to compliance and enforcement actions if you conduct non-compliant activities.

If you have questions about a MDEL or the application process, please contact the Medical Device Establishment Licensing Unit at hc.mdel.questions.leim.sc@canada.ca. If you have questions about invoicing and fees for an MDEL application, please contact the Cost Recovery Invoicing Unit at hc.criu-ufrc.sc@canada.ca. Related linksResponse to the Expert Panel Report on “Priority strategies to optimize testing and quarantine at Canada’s borders” where is better to buy cipro The Industry Advisory Roundtable on buy antibiotics Testing, Screening, Tracing and Data Management is pleased to release its third report. This report reiterates the importance of balancing public health measures to reduce the importation of buy antibiotics with the need to ensure the free flow of people and goods across the Canadian border and support economic recovery.

On this page Executive summary Soon after buy antibiotics was declared a global cipro in March 2020, international borders around the world closed in an effort to limit the spread of the cipro. To ensure where is better to buy cipro the health and safety of individuals, the movement of people and goods was restricted. Yet, it was important to maintain access to essential goods and services and sustain trade-based economic sectors. Canada responded in step with other countries.

The government implemented public health measures such as where is better to buy cipro mandatory testing and quarantine when crossing international borders. Restrictions are necessary to curb the spread of the cipro. Yet, in a complex environment such as international borders, it’s crucial to implement and clearly communicate public health measures effectively and clearly. Border measures such as testing regimes and other public health where is better to buy cipro measures must be based on the most recent science-based public health evidence.

Such measures must also leverage advances in testing options, consider vaccination rates and balance the needs of industries operating across borders. Furthermore, plans must where is better to buy cipro be easy to implement consistently across several entry modes. They should also be communicated broadly and include a roadmap for easing or increasing border restrictions based on objective criteria and benchmarks. As we enter the second year of the cipro, the Roundtable is offering insights and recommendations to adjust current border measures.

We have based our recommendations on where is better to buy cipro evidence collected from international scans and observations from industries that move goods and people across borders. The Roundtable recognizes the effort required to implement plans for easing border restrictions, given rapidly evolving public health circumstances and emerging variants of concern. Prompt action is needed to design and implement a border measures plan that reduces the risk of the cipro spreading while proactively moving towards economic recovery. Current border environment In March 2020, the ability of people to move where is better to buy cipro across the Canadian border was restricted.

Since then, several measures were taken to reduce the importation of buy antibiotics and limit the spread of the cipro. As circumstances changed over the following weeks and months, border measures became more restrictive. In where is better to buy cipro early 2021, more stringent public health measures were introduced for non-essential travellers at air and land borders. This was done to reduce the importation rate of buy antibiotics and its variants of concern.

Measures included the following. mandatory pre-departure buy antibiotics molecular test contact/quarantine plan using the ArriveCAN application on-arrival and post-arrival testing for travellers arriving by air, mandatory 3-day quarantine in government-authorized hotels followed by quarantine or isolation at an approved location such as the traveller’s home The Government of Canada and the aviation industry also worked together on where is better to buy cipro a plan to suspend Canadian air carrier flights to and from Mexico and Caribbean countries from January 31 to April 30, 2021. Then on February 3, 2021, all incoming international commercial passenger flights to Canada were restricted to the 4 largest airports. Montreal, Toronto, Calgary and Vancouver.

In order to prevent importation of variants of concern, the Government of Canada where is better to buy cipro took additional measures that included suspension of flights from certain countries. Canada suspended all commercial and passenger flights from the United Kingdom between December 20, 2020 and January 6, 2021. Additionally, on April 22, 2021, all commercial and private passenger flights from India and Pakistan were suspended in response to a high number of cases detected among individuals travelling on flights originating from the two countries where is better to buy cipro. These measures are in place until at least June 21, 2021.

Internal data from the Public Health Agency of Canada indicates the following positivity rates for the seven days up to and including May 27, 2021, for air and land travel combined. the 7-day average positivity rate for testing on arrival was where is better to buy cipro 0.2% the 7-day average positivity rate for second tests was 0.3% As well, all positive tests undergo genomic sequencing to identify variants of concern. Cross-border travel volumes decreased significantly from December 2019 to December 2020. Statistics Canada data show that the.

number of travellers to Canada was down 93% total number of international travellers to and from Canada declined from 96.8 million in 2019 to where is better to buy cipro 25.9 million in 2020 Air travel has experienced the most dramatic shifts, as travellers arriving by air are mostly non-exempt from border measures. In comparison, travellers exempt from border measures make up the vast majority of land border traffic. Essential travel continued largely unimpeded, as governments recognized the importance of preserving vital supply chains to ensure that food, fuel and life-saving medicines continue to reach people. A shifting landscape As of May 28, 2021, variants of concern account for an estimated 70% of reported where is better to buy cipro cases in recent weeks.

Any border measures must account for this new reality. At the same time, individuals and organizations within and outside of Canada are increasingly looking for. a concrete roadmap to the economic reopening of the country clear guidelines for restarting cross-border travel Plans and guidelines should clearly spell out where is better to buy cipro the public health criteria for adjusting border measures. They should also outline when and how restrictions should be eased in the short and longer term.

Guidelines must take into consideration the risk of where is better to buy cipro importing new variants of concern in the move towards a safe restart of the trade and tourism industries that operate internationally. As scientists learn more about how the cipro spreads, as travellers are tested regularly and as vaccination efforts increase, it will be easier to manage the risk of importing buy antibiotics and its variants. Nevertheless, while the international border is open, there’s always the risk of importation. For a safe reopening, we need where is better to buy cipro a risk framework that takes into account public health measures and socio-economic factors.

To bring the risk to an acceptable level, detection and surveillance options should be part of any robust border testing strategy. Evidence concerning restrictive border measures, including lengthy quarantines, shows that the effectiveness of these measures declines over time. Non-compliance increases when where is better to buy cipro measures are too tough and/or not communicated well. This can counter efforts to reduce the spread of the cipro and break the chains of transmission.

As more and more people in Canada and abroad are vaccinated, it will be necessary to update Canada’s strategy to allow the movement of vaccinated travellers, based on emerging scientific evidence and while respecting public health measures. Complex border measures may present significant implementation challenges, where is better to buy cipro which can lead to disparities in how the various rules, regulations and guidelines are applied at ports of entry. This may have a negative impact on people crossing the Canadian border and those industries engaged in cross-border and transnational business. Small and medium companies may be especially impacted.

Although essential workers have largely been exempt from border measures, the Roundtable is aware of the where is better to buy cipro challenges they face when rules are applied inconsistently. For example, several Canadian companies have reported incidences where some engineers, technicians and other specialists have faced challenges crossing the Canada-US border and meeting their contractual obligations to provide skilled services. Some business executives and professional services providers with cross-border responsibilities are constrained in their ability to manage their operations effectively. As well, disruptions to the cross-border where is better to buy cipro travel of these workers could expose businesses to legal recourse from clients for failure to meet commitments.

Many countries, including Canada, are aggressively rolling out vaccination regimes and partially permitting the movement of people (with restrictions). Canada is now the top country in the G7, G20 and OECD for vaccination rates where is better to buy cipro of first doses. As the campaign shifts to second doses, Canada must continue to reach vulnerable populations to ensure treatment equity and broad-based coverage to facilitate re-opening the economy and growth. Canada’s biggest trading partner also shares its largest border.

Efforts should be made to align public health and economic recovery goals between Canada and where is better to buy cipro the United States. Prioritizing the Canada-US border would be consistent with the commitments made by both countries in the Roadmap for a Renewed U.S.-Canada Partnership. This roadmap recommends a coordinated and science-based approach to ease border restrictions in the future. Countries around the world are also exploring cooperative arrangements with other countries where is better to buy cipro and looking at piloting innovative technology and information-sharing platforms designed to facilitate safe travel, such as treatment certification.

Implementing significant changes requires wide support and cooperation, as highlighted in the Industry Strategy Council’s Restart, recover, and reimagine prosperity for all Canadians report. The report proposes a three-phase action plan – restart, recover, and reimagine – focused on investment and growth, and embodies values and principles of action and shared responsibility to mobilize all sectors to propel Canada forward. The phases are anchored in five recommendations to safely restore confidence and commerce, stabilize the hardest-hit sectors, reignite growth by doubling down on a future-oriented investment plan, develop an ambitious industrial strategy, and establish renewed public-private sector partnerships and where is better to buy cipro investments anchored in a sound and rigorous fiscal framework. At the same time, we must recognize we live in times of uncertainty and contend with a rapidly shifting landscape.

Plans should be flexible in order to balance public health concerns with the desire to ease restrictions. We must work with public health experts to establish and clearly communicate where is better to buy cipro criteria and benchmarks to help travellers and businesses understand how and when border restrictions will be eased or increased in the coming months. Provinces and territories have outlined their reopening plans, with an important strength being the use of benchmarks to move between several steps of restrictions. Communicating a clear path with well-defined criteria will provide a much-needed level of predictability for reopening to industry and travellers alike.

Recommendations The where is better to buy cipro Industry Roundtable recommends an approach to border measures that include both short- and longer-term recommendations. Short-term recommendations Provide clear definitions of cross-border essential travellers and apply these in a consistent manner at all ports of entry. Recognize that companies are well positioned to identify essential travellers within their organization, enabling them to leverage existing domestic testing regimes for where is better to buy cipro employees to demonstrate that public health requirements are met. Accepting employer-issued proof of testing would shift the onus away from the border and alleviate traveller flow pressures.

Explicitly state the conditions for testing travellers and the criteria for shortening or removing quarantine measures. Connect the pace of vaccination rollout with public health measures and the gradual lifting of travel restrictions, and include clear procedures for where is better to buy cipro vaccinated, partially vaccinated and unvaccinated travellers. This may need to adjust as new variants of concern emerge. Enable industry to take an active role in meeting vaccination targets in Canada by supporting priority vaccination of cross-border essential workers.

Aggressive vaccination targets for these workers would help companies contribute to the where is better to buy cipro safe reopening of the economy in a timely manner. Apply measures consistently at air and land borders, whenever possible. Provide clear, straightforward messaging for every person and company involved in the cross-border movement of people and goods. Clear communication where is better to buy cipro leads to effective, consistent implementation of any border measure and subsequent updates.

Longer-term recommendations Take into account evolving scientific evidence and adopt emerging findings. For example, evidence suggests that rapid antigen testing can be effective as a screening tool and adds another layer of defence when used as part of surveillance testing. Ensure that processes, information systems and infrastructure needed to implement modified border measures are in place and can manage increased travel volumes effectively where is better to buy cipro. Re-position Canada as a competitive participant in the tourism and global trade sectors through enabling border measures that facilitate the movement of people and goods across international borders.

In collaboration with the private sector, the government should develop an enhanced framework to better prepare for and respond to future cipros..

Cipro pseudomonas

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 in the composition of the multidisciplinary teams cipro pseudomonas that provide http://2017.swissbiotechday.ch/best-place-to-buy-propecia-online/ care for patients who 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 cipro pseudomonas and patient representatives.18 These initiatives have highlighted how cultural and financial aspects and 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 the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to cipro pseudomonas 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 cipro pseudomonas guideline that have been insufficiently addressed in the literature 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 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 cipro pseudomonas these healthcare providers.

Moreover, this enables DSD specialists to refer to the guideline when advising a referral. Transition from the prenatal to the postnatal team and from the paediatric to the cipro pseudomonas 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 the guideline revision, an interdisciplinary multicentre group was formed with all members responsible for updating the literature for a specific part cipro pseudomonas 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 cipro pseudomonas with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is 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, cipro pseudomonas 46,XX DSD, 46,XY DSD, 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 or retrievable cipro pseudomonas 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, revised into a final draft cipro pseudomonas.

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 input, the final version was cipro pseudomonas 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 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 cipro pseudomonas 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 form of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic sex revealed by non-invasive prenatal testing cipro pseudomonas (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 restrictions and/or ethical considerations, the X and Y chromosomes are not cipro pseudomonas 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 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 cipro pseudomonas 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 cipro pseudomonas findings and the limitations of 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 cipro pseudomonas 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 cipro pseudomonas 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 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 cipro pseudomonas considered controversial by some, is legal in Belgium and the 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 of not knowing exactly what the child’s genitalia will look like and uncertainty about the diagnosis, treatment and prognosis cannot be cipro pseudomonas 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 the DSD team during pregnancy and having a contact person before birth.After expert prenatal counselling, a significant number cipro pseudomonas 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 cipro pseudomonas 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 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 syndrome or carry cipro pseudomonas 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 cipro pseudomonas we propose completing the analysis well before the expected delivery.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." 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..

IntroductionIn recent years, many studies have where is better to buy cipro 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 Best place to buy propecia online that services and institutions still differ in the composition of the multidisciplinary teams that provide care for patients who 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 where is better to buy cipro and 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 the Netherlands and Flanders (the Dutch-speaking Northern part where is better to buy cipro 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 where is better to buy cipro that have been insufficiently addressed in the literature 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 a specialised team may be challenging, especially for professionals with limited experience in DSD.22 23 Therefore, a section of the where is better to buy cipro 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 where is better to buy cipro prenatal to 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 the guideline revision, an interdisciplinary multicentre group was formed with where is better to buy cipro 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 often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing where is better to buy cipro 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, guideline, multidisciplinary where is better to buy cipro care). Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports where is better to buy cipro were excluded, as were articles that were not open access 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 where is better to buy cipro and, after having obtained agreement on remaining points of discussion, 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 input, where is better to buy cipro 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 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 where is better to buy cipro 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 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 where is better to buy cipro later ultrasound findings. NIPT screens for CNVs in the fetus.

However, depending on where is better to buy cipro legal 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 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 where is better to buy cipro 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 where is better to buy cipro limitations of this technique. The procedure(s) that can be followed, including the risks associated with an amniocentesis.

And the type where is better to buy cipro of information genetic testing can and 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 where is better to buy cipro need to be available to allow parents to make a well-informed decision about whether or not to continue the pregnancy.

Termination of pregnancy can be considered, for instance, in a syndromic form where is better to buy cipro 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 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 of not knowing exactly what the child’s genitalia will look like and uncertainty about the diagnosis, treatment and prognosis cannot where is better to buy cipro 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 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 where is better to buy cipro (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 where is better to buy cipro 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 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 where is better to buy cipro 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 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 sex development where is better to buy cipro (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..