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Normally, healthcare practitioners that see patients with flu-like symptoms in late fall, winter and how to get viagra online early spring assume the individual has influenza and treat them accordingly. This year is different. “Going into respiratory virus season, we’re going to have a much harder time knowing what is the cause of a person’s symptoms,” says Lisa Maragakis, the senior director of infection prevention at the Johns Hopkins Health System.Even with the potential for uncertainty, there are still some practices that physicians recommend everyone follows as the double-whammy draws near — especially if you start to develop symptoms.Take PrecautionsFor starters, get your flu shot, says Maragakis. These vaccines aren’t perfect — how to get viagra online according to the CDC, each yearly flu vaccine bounces between about 20 and 60 percent efficacy. Even though the injections don’t guarantee protection for everyone, they will work for some and can help rule out the possibility that any sniffles or body aches you develop stem from the flu.Speaking of those all-too-familiar aches and pains.

If you develop any respiratory how to get viagra online symptoms, a fever, headaches or gastrointestinal issues that are out of the ordinary, isolate yourself. Stay home from work, skip social gatherings, and if there are any high-risk people in your home — individuals with diabetes, for example — keep to yourself if possible, says Sankar Swaminathan, chief of the infectious diseases division at University of Utah Health.“It would be hard for me, with most people, to get at whether they have the flu or COVID-19 because the symptoms overlap to such a degree,” he adds. For the most part, only a test can parse whether or not you have the flu, a cold or COVID-19. So until you’re able to talk to a medical professional or get results back from the lab, it’s best to take precautions and behave as if you have a how to get viagra online COVID-19 diagnosis. Remember that symptoms that look like a cold might actually be COVID-19 related.

Colds will still be circulating among people during the fall and winter, and already Maragakis has heard from patients who chalked their runny nose and sore throat up as a typical cold. To combat those kinds of assumptions, “we’re asking people to have a high index of suspicion,” she says.Since the best way to diagnose someone how to get viagra online is to examine which (if any) virus is living in their body, SARS-CoV-2 testing needs to be widespread, accessible and fast. Right now, however, a majority of states fall short of daily testing goals. Recent surveys suggest that about 63 percent of people tested wait longer than one to two days for results, even though that is the how to get viagra online ideal turnaround window for contact tracing. The shortfall may stem from national coordination issues.

"As far as I have seen, it's not a lack of willingness to provide more tests — it comes down to ability," says Maragakis. Faltering supply chains mean the how to get viagra online essential tools needed to test and test fast are in short supply. "In my opinion, we need a much more coordinated national response to testing in order to solve those problems." What A Test Can DoSARS-CoV-2 tests do more than deliver peace of mind if, say, you feel congested and learn that it’s a regular cold. The results inform public health officials about the spread and containment of COVID-19 and help determine what kind of care you get.For example, many people getting a SARS-CoV-2 test will also get an influenza test (possibly with a new two-in-one technology). If someone has the regular flu, there are approved how to get viagra online medications to fight off the infection they can take.

In past flu seasons, healthcare practitioners administered influenza tests but often treated the individual as if they had the infection before getting results, Swaminathan says. The odds of their illness being the flu are high how to get viagra online enough to make that a reasonable choice. With much more uncertainty this year about what someone might have and what treatments could help them, the prescribe-before-results habit will likely be much less common. The prospects of not knowing what kind of illness you might have, or waiting a long time for official lab results, might sound gloomy. But there is a bright side how to get viagra online.

It's possible that our COVID-19 mitigation tactics, like wearing masks, social distancing and avoiding large gatherings, could reduce influenza spread as well. This scenario likely played out in the Southern Hemisphere earlier this year. That half of the globe sees an influenza season during the Northern Hemisphere's spring and summer, and how to get viagra online many countries reported very low non-COVID diagnoses. To keep influenza and COVID-19 cases low — and to keep you from playing the symptomatic guessing game with yourself — stick with those preventative health measures for the foreseeable future. "It’s not going to last forever," says Swaminathan, "but we have to be patient and we have to be vigilant.".

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But it’s not clear conservatives on the court will agree.With so much emphasis on the ACA’s insurance marketplace, the expansion of the Medicaid program for low-income people and protections for people with preexisting conditions, many consumers don’t realize that the law touches nearly all aspects of health care, including guarantees of preventive services, insurance practices and even requirements for calorie counts on restaurant menus.Ginsburg’s death could also influence efforts to undermine abortion rights. Two cases are already before the court, one involving the ability of doctors to remotely prescribe drugs that can end a pregnancy and a Mississippi ban on abortions after the 15th week of pregnancy.As the nation marks more than 200,000 deaths from the coronavirus, the “What the Health?. € panel looks at problems in viagra and high blood pressure the U.S. Effort to fight COVID-19, including flip-flops on the need for masks, inconsistent messaging from different parts of government and the politicization of science.The Centers for Disease Control and Prevention’s decision to remove guidance on the coronavirus’s ability to spread through the air created more concerns about the politicization of the federal government’s scientific studies. The controversy over the agency’s work is a stark change from the past, when the CDC was considered among the least politicized parts of the government.It may take years after these coronavirus controversies for the CDC to restore its credibility with the public, no matter who viagra and high blood pressure is elected president.Trump has touted his efforts to lower prescription drug prices, and last week The New York Times reported that the administration tried unsuccessfully to get drugmakers to send a $100 gift card to all seniors to help cover the costs of their medicines.

The companies objected because, among other reasons, they were worried the move could be seen as an effort to help the Trump campaign.This week, Rovner also interviews KHN’s Sarah Jane Tribble, whose new podcast, “Where It Hurts,” drops Sept. 29. The podcast chronicles what happens to a small rural community in Kansas after its local hospital closes.Plus, for extra credit, the panelists recommend their favorite health policy stories of the week they think you should read too:Julie Rovner. KHN’s “Battle Rages Inside Hospitals Over How COVID Strikes and Kills,” by Robert Lewis and Christina JewettAnna Edney. The New Yorker’s “A Young Kennedy, in Kushnerland, Turned Whistle-Blower,” by Jane MayerKimberly Leonard.

The Wall Street Journal’s “Medicare Wouldn’t Cover Costs of Administering Coronavirus Vaccine Approved Under Emergency-Use Authorization,” by Stephanie ArmourMary Ellen McIntire. The New York Times’ “Many Hospitals Charge More Than Twice What Medicare Pays for the Same Care,” by Reed AbelsonOther stories discussed by the panelists this week:The New York Times’ “A Deal on Drug Prices Undone by White House Insistence on ‘Trump Cards,’” by Jonathan Martin and Maggie HabermanThe Daily Beast’s “A Notorious COVID Troll Actually Works for Dr. Fauci’s Agency,” by Lachlan MarkayPolitico’s “Trump Administration Shakes Up HHS Personal Office After Tumultuous Hires,” by Dan DiamondThe Washington Post’s “Pentagon Used Taxpayer Money Meant for Masks and Swabs to Make Jet Engine Parts and Body Armor,” by Aaron Gregg and Yeganeh TorbatiTo hear all our podcasts, click here.And subscribe to What the Health?. on iTunes, Stitcher, Google Play, Spotify or Pocket Casts. Related Topics Courts Elections Health Care Costs Insurance Multimedia Pharmaceuticals The Health Law Abortion CDC COVID-19 Drug Costs HHS KHN's 'What The Health?.

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Can’t see how to get viagra online the audio player?. Click here to listen on SoundCloud. The death of Supreme Court Justice Ruth Bader Ginsburg — and the insistence of President how to get viagra online Donald Trump and the GOP-led Senate to fill that vacancy this year — could have major implications for health care. The high court will hear yet another case challenging the constitutionality of the Affordable Care Act the week after the November election, and a long list of cases involving women’s reproductive rights, including both abortion and birth control, are working their way through lower federal courts.Meanwhile, scandals at the Department of Health and Human Services continue to surface, such as the case of a media spokesperson for the National Institutes of Health who criticized his boss’s handling of the pandemic via a conservative website. And the Centers for Disease Control and Prevention continues to struggle with its credibility, after posting and then taking down another set of guidelines, this one concerning whether the COVID-19 virus is spread through aerosol particles.This week’s panelists are Julie Rovner of Kaiser Health News, Anna Edney of Bloomberg News, Kimberly Leonard of Business Insider and Mary Ellen McIntire of CQ Roll Call.Among the takeaways from this week’s podcast:The Supreme Court’s upcoming ACA case was brought by Republican how to get viagra online state officials seeking to invalidate the law based Congress’ elimination of the penalty for not having insurance, a provision that the court once used to uphold the law because it was considered part of Congress’ right to impose taxes.Many legal experts believe that even if the high court were to decide that the loss of the penalty invalidates the individual mandate to get insurance, other parts of the law should be able to stand.

But it’s not clear conservatives on the court will agree.With so much emphasis on the ACA’s insurance marketplace, the expansion of the Medicaid program for low-income people and protections for people with preexisting conditions, many consumers don’t realize that the law touches nearly all aspects of health care, including guarantees of preventive services, insurance practices and even requirements for calorie counts on restaurant menus.Ginsburg’s death could also influence efforts to undermine abortion rights. Two cases are already before the court, one involving the ability of doctors to remotely prescribe drugs that can end a pregnancy and a Mississippi ban on abortions after the 15th week of pregnancy.As the nation marks more than 200,000 deaths from the coronavirus, the “What the Health?. € panel looks how to get viagra online at problems in the U.S. Effort to fight COVID-19, including flip-flops on the need for masks, inconsistent messaging from different parts of government and the politicization of science.The Centers for Disease Control and Prevention’s decision to remove guidance on the coronavirus’s ability to spread through the air created more concerns about the politicization of the federal government’s scientific studies. The controversy over the how to get viagra online agency’s work is a stark change from the past, when the CDC was considered among the least politicized parts of the government.It may take years after these coronavirus controversies for the CDC to restore its credibility with the public, no matter who is elected president.Trump has touted his efforts to lower prescription drug prices, and last week The New York Times reported that the administration tried unsuccessfully to get drugmakers to send a $100 gift card to all seniors to help cover the costs of their medicines.

The companies objected because, among other reasons, they were worried the move could be seen as an effort to help the Trump campaign.This week, Rovner also interviews KHN’s Sarah Jane Tribble, whose new podcast, “Where It Hurts,” drops Sept. 29. The podcast chronicles what happens to a small rural community in Kansas after its local hospital closes.Plus, for extra credit, the panelists recommend their favorite health policy stories of the week they think you should read too:Julie Rovner. KHN’s “Battle Rages Inside Hospitals Over How COVID Strikes and Kills,” by Robert Lewis and Christina JewettAnna Edney. The New Yorker’s “A Young Kennedy, in Kushnerland, Turned Whistle-Blower,” by Jane MayerKimberly Leonard.

The Wall Street Journal’s “Medicare Wouldn’t Cover Costs of Administering Coronavirus Vaccine Approved Under Emergency-Use Authorization,” by Stephanie ArmourMary Ellen McIntire. The New York Times’ “Many Hospitals Charge More Than Twice What Medicare Pays for the Same Care,” by Reed AbelsonOther stories discussed by the panelists this week:The New York Times’ “A Deal on Drug Prices Undone by White House Insistence on ‘Trump Cards,’” by Jonathan Martin and Maggie HabermanThe Daily Beast’s “A Notorious COVID Troll Actually Works for Dr. Fauci’s Agency,” by Lachlan MarkayPolitico’s “Trump Administration Shakes Up HHS Personal Office After Tumultuous Hires,” by Dan DiamondThe Washington Post’s “Pentagon Used Taxpayer Money Meant for Masks and Swabs to Make Jet Engine Parts and Body Armor,” by Aaron Gregg and Yeganeh TorbatiTo hear all our podcasts, click here.And subscribe to What the Health?. on iTunes, Stitcher, Google Play, Spotify or Pocket Casts. Related Topics Courts Elections Health Care Costs Insurance Multimedia Pharmaceuticals The Health Law Abortion CDC COVID-19 Drug Costs HHS KHN's 'What The Health?.

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Start Preamble Health Resources and Services Administration (HRSA), Department of Health order viagra and Human Services. Notice. In compliance with the requirement for order viagra opportunity for public comment on proposed data collection projects of the Paperwork Reduction Act of 1995, HRSA announces plans to submit an Information Collection Request (ICR), described below, to the Office of Management and Budget (OMB).

Prior to submitting the ICR to OMB, HRSA seeks comments from the public regarding the burden estimate, below, or any other aspect of the ICR. Comments on this ICR should order viagra be received no later than December 15, 2020. Submit your comments to paperwork@hrsa.gov or mail the HRSA Information Collection Clearance Officer, Room 14N136B, 5600 Fishers Lane, Rockville, Maryland 20857.

Start Further Info To request more information on the proposed project or to obtain a copy of the data collection plans and draft instruments, email paperwork@hrsa.gov or call order viagra Lisa Wright-Solomon, the HRSA Information Collection Clearance Officer at (301) 443-1984. End Further Info End Preamble Start Supplemental Information When submitting comments or requesting Start Printed Page 65835information, please include the ICR title for reference. Information Collection Request Title.

National Practitioner Data Bank for Adverse Information on Physicians and Other Health Care Practitioners—45 CFR part 60 Regulations and Forms, order viagra OMB No. 0915-0126—Revision. Abstract order viagra.

This is a request for OMB's approval for a revision to the information collection contained in regulations found at 45 CFR part 60 governing the National Practitioner Data Bank (NPDB) and the forms to be used in registering with, reporting information to, and requesting information from the NPDB. Administrative forms are also included to order viagra aid in monitoring compliance with Federal reporting and querying requirements. Responsibility for NPDB implementation and operation resides in HRSA's Bureau of Health Workforce.

The intent of the NPDB is to improve the quality of health care by encouraging entities such as hospitals, State licensing boards, professional societies, and other eligible entities [] providing health care services to identify and discipline those who engage in unprofessional behavior, and to restrict the ability of incompetent health care practitioners, providers, or suppliers to move from state to state without disclosure or discovery of previous damaging or incompetent order viagra performance. It also serves as a fraud and abuse clearinghouse for the reporting and disclosing of certain final adverse actions (excluding settlements in which no findings of liability have been made) taken against health care practitioners, providers, or suppliers by health plans, Federal agencies, and State agencies. Users of the NPDB include reporters (entities that are required to submit reports) and queriers (entities and individuals that are authorized to request for information).

The reporting forms, request for information forms (query forms), and administrative forms (used to monitor order viagra compliance) are accessed, completed, and submitted to the NPDB electronically through the NPDB website at https://www.npdb.hrsa.gov/​. All reporting and querying is performed through the secure portal of this website. This revision proposes changes to improve order viagra overall data integrity.

In addition, this revision contains the four NPDB forms that were originally approved in the “National Practitioner Data Bank (NPDB) Attestation of Reports by Hospitals, Medical Malpractice Payers, Health Plans, and Certain Other Health Care Entities, OMB No. 0906-0028” which will be discontinued upon approval of order viagra this ICR. Need and Proposed Use of the Information.

The NPDB order viagra acts primarily as a flagging system. Its principal purpose is to facilitate comprehensive review of practitioners' professional credentials and background. Information is collected from, and disseminated to, eligible entities (entities that are entitled to query and/or report to the NPDB as authorized in Title 45 CFR part 60 of the Code of Federal Regulations) on the following.

(1) Medical malpractice payments, (2) licensure actions taken by Boards of Medical Examiners, (3) State licensure and certification order viagra actions, (4) Federal licensure and certification actions, (5) negative actions or findings taken by peer review organizations or private accreditation entities, (6) adverse actions taken against clinical privileges, (7) Federal or State criminal convictions related to the delivery of a health care item or service, (8) civil judgments related to the delivery of a health care item or service, (9) exclusions from participation in Federal or State health care programs, and (10) other adjudicated actions or decisions. It is intended that NPDB information should be considered with other relevant information in evaluating credentials of health care practitioners, providers, and suppliers. Likely Respondents order viagra.

Eligible entities or individuals that are entitled to query and/or report to the NPDB as authorized in regulations found at 45 CFR part 60. Burden Statement order viagra. Burden in this context means the time expended by persons to generate, maintain, retain, disclose, or provide the information requested.

This includes the time needed to review order viagra instructions. To develop, acquire, install, and utilize technology and systems for the purpose of collecting, validating, and verifying information, processing and maintaining information, and disclosing and providing information. To train personnel and to be able to respond to a collection of information.

To search data sources order viagra. To complete and review the collection of information. And to transmit order viagra or otherwise disclose the information.

The total annual burden hours estimated for this ICR are summarized in the table below. Total Estimated Annualized Burden HoursRegulation citationForm nameNumber of respondentsNumber of responses per respondentTotal responsesAverage order viagra burden per response (in hours)Total burden hours (rounded up)§ 60.6. Reporting errors, omissions, revisions or whether an action is on appeal.Correction, Revision-to-Action, Void, Notice of Appeal (manual)11,918111,918.252,980 Correction, Revision-to-Action, Void, Notice of Appeal (automated)18,301118,301.00035§ 60.7.

Reporting medical malpractice paymentsMedical Malpractice Payment (manual)11,481111,481.758,611 Medical Malpractice Payment (automated)2961296.00031Start Printed Page 65836§ 60.8. Reporting licensure order viagra actions taken by Boards of Medical ExaminersState Licensure or Certification (manual)19,749119,749.7514,812§ 60.9. Reporting licensure and certification actions taken by StatesState Licensure or Certification (automated)17,189117,189.00035§ 60.10.

Reporting Federal order viagra licensure and certification actions.DEA/Federal Licensure6001600.75450§ 60.11. Reporting negative actions or findings taken by peer review organizations or private accreditation entitiesPeer Review Organization10110.758 Accreditation10110.758§ 60.12. Reporting adverse actions taken against clinical privilegesTitle IV Clinical order viagra Privileges Actions9781978.75734 Professional Society41141.7531§ 60.13.

Reporting Federal or State criminal convictions related to the delivery of a health care item or serviceCriminal Conviction (Guilty Plea or Trial) (manual)1,17411,174.75881 Criminal Conviction (Guilty Plea or Trial) (automated)6831683.00031 Deferred Conviction or Pre-Trial Diversion70170.7553 Nolo Contendere (no contest plea)1271127.7595 Injunction10110.758§ 60.14. Reporting civil judgments related to the order viagra delivery of a health care item or serviceCivil Judgment919.757§ 60.15. Reporting exclusions from participation in Federal or State health care programsExclusion or Debarment (manual)1,70711,707.751,280 Exclusion or Debarment (automated)2,50612,506.00031§ 60.16.

Reporting other adjudicated actions or decisionsGovernment Administrative (manual)1,75011,750.751,313 Government Administrative (automated)39139.00031 Health Plan Action4881488.75366§ 60.17 Information which hospitals must request from the National Practitioner Data BankOne-Time Query for an Individual (manual)1,958,17611,958,176.08156,654§ 60.18 Requesting Information from the NPDBOne-Time Query for an Individual (automated)3,349,77813,349,778.00031,005 One-Time Query for an Organization (manual)50,681150,681.084,054 One-Time Query for an Organization (automated)25,610125,610.00038 Self-Query on an Individual168,5571168,557.4270,794 Self-Query on an Organization1,05911,059.42445 Continuous Query (manual)806,9711806,971.0864,558Start Printed Page 65837 Continuous Query (automated)619,0011619,001.0003186§ 60.21. How to dispute the accuracy of NPDB order viagra informationSubject Statement and Dispute3,26413,264.752,448 Request for Dispute Resolution741748592AdministrativeEntity Registration (Initial)3,48413,48413,484 Entity Registration (Renewal &. Update)13,245113,245.253,311 State Licensing Board Data Request6016010.5630 State Licensing Board Attestation32513251325 Authorized Agent Attestation35013501350 Health Center Attestation72217221722 Hospital Attestation3,41613,41613,416 Medical Malpractice Payer, Peer Review Organization, or Private Accreditation Organization Attestation27412741274 Other Eligible Entity Attestation1,88411,88411,884 Corrective Action Plan (Entity)10110.081 Reconciling Missing Actions1,49111,491.08119 Agent Registration (Initial)44144144 Agent Registration (Renewal &.

Update)3041304.0824 Electronic Funds Transfer (EFT) Authorization6441644.0852 Authorized Agent Designation1831183.2546 Account Discrepancy85185.2521 New Administrator Request6001600.0848 Purchase Query Credits1,78611786.08143 Education Request40140.083 Account Balance Transfer10110.081 Missing Report From Query Form10110.081Total7,101,2747,101,274347,294 HRSA specifically requests comments on (1) the necessity and utility of the proposed information collection for the proper performance of the agency's functions, (2) the accuracy of the estimated burden, (3) ways to enhance the quality, utility, order viagra and clarity of the information to be collected, and (4) the use of automated collection techniques or other forms of information technology to minimize the information collection burden. Start Signature Maria G. Button, Director, order viagra Executive Secretariat.

End Signature End Supplemental Information [FR Doc. 2020-22953 Filed order viagra 10-15-20. 8:45 am]BILLING CODE 4165-15-PStart Preamble Health Resources and Services Administration (HRSA), Department of Health and Human Services.

Notice. In compliance with the requirement for opportunity for public comment on proposed data collection projects of the Paperwork Reduction order viagra Act of 1995, HRSA announces plans to submit an Information Collection Request (ICR), described below, to the Office of Management and Budget (OMB). Prior to submitting the ICR to OMB, HRSA seeks comments from the public regarding the burden estimate, below, or any other aspect of the ICR.

Comments on this ICR should be order viagra received no later than December 15, 2020. Submit your comments to paperwork@hrsa.gov or mail the HRSA Information Collection Clearance Officer, Room 14N136B, 5600 Fishers Lane, Rockville, MD 20857. Start Further Info To request more information on the proposed project or to obtain a copy of the data collection plans and draft instruments, order viagra email paperwork@hrsa.gov or call Lisa Wright-Solomon, the HRSA Information Collection Clearance Officer at (301) 443-1984.

End Further Info End Preamble Start Supplemental Information When submitting comments or requesting information, please include the Start Printed Page 65834information request collection title for reference. Information Collection Request Title order viagra. Survey of Eligible Users of the National Practitioner Data Bank, OMB No.

0915-0366—Reinstatement With Change. Abstract order viagra. HRSA plans to survey the users National Practitioner Data Bank (NPDB).

The purpose of this survey is to assess the overall satisfaction of the eligible users of the order viagra NPDB. This survey will evaluate the effectiveness of the NPDB as a flagging system, source of information, and its use in decision making. Furthermore, this survey will collect information from organizations and individuals who query the NPDB to understand and improve their user experience order viagra.

This survey is a reinstatement of the 2012 NPDB survey with some changes. Need and Proposed Use of the Information. The survey will collect information regarding the participants' experiences of querying and reporting to the NPDB, perceptions of health care practitioners with order viagra reports, impact of NPDB reports on organizations' decision-making, and satisfaction with various NPDB products and services.

The survey will also be administered to health care practitioners that use the self-query service provided by the NPDB. The self-queriers order viagra will be asked about their experiences of querying, the impact of having reports in the NPDB on their careers and health care organizations' perceptions, and their satisfaction with various NPDB products and services. Understanding self-queriers' satisfaction and their use of the information is an important component of the survey.

Proposed changes order viagra to this ICR include the following. 1. In the proposed entity survey, there are 37 modules and 258 questions.

From the previous 2012 survey, there are 15 deleted questions and 13 new questions in addition to proposed changes to 12 survey questions. 2. In the proposed self-query survey, there are 22 modules and 88 questions.

From the previous 2012 survey, there are 5 deleted questions and 5 new questions in addition to proposed changes to two survey questions. Likely Respondents. Eligible users of the NPDB will be asked to complete a web-based survey.

Data gathered from the survey will be compared with previous survey results. This survey will provide HRSA with the information necessary for research purposes and for improving the usability and effectiveness of the NPDB. Burden Statement.

Burden in this context means the time expended by persons to generate, maintain, retain, disclose or provide the information requested. This includes the time needed to review instructions, to develop, acquire, install and utilize technology and systems for the purpose of collecting, validating and verifying information, processing and maintaining information, and disclosing and providing information, to train personnel and to be able to respond to a collection of information, to search data sources, to complete and review the collection of information, and to transmit or otherwise disclose the information. The total annual burden hours estimated for this Information Collection Request are summarized in the table below.

Total Estimated Annualized Burden HoursForm nameNumber of respondentsNumber of responses per respondentTotal responsesAverage burden per response (in hours)Total burden hoursNPDB Users Entities Respondents15,000115,0000.253,750NPDB Self-Query Respondents2,00012,0000.10200Total17,00017,0003,950 HRSA specifically requests comments on (1) the necessity and utility of the proposed information collection for the proper performance of the agency's functions, (2) the accuracy of the estimated burden, (3) ways to enhance the quality, utility, and clarity of the information to be collected, and (4) the use of automated collection techniques or other forms of information technology to minimize the information collection burden. Start Signature Maria G. Button, Director, Executive Secretariat.

End Signature End Supplemental Information [FR Doc. 2020-22964 Filed 10-15-20. 8:45 am]BILLING CODE 4165-15-P.

Start Preamble Health Resources and Services how to get viagra online Administration (HRSA), Department of Health and Human Services. Notice. In compliance with the requirement for opportunity for public comment on proposed data collection projects of the Paperwork Reduction Act how to get viagra online of 1995, HRSA announces plans to submit an Information Collection Request (ICR), described below, to the Office of Management and Budget (OMB).

Prior to submitting the ICR to OMB, HRSA seeks comments from the public regarding the burden estimate, below, or any other aspect of the ICR. Comments on this ICR how to get viagra online should be received no later than December 15, 2020. Submit your comments to paperwork@hrsa.gov or mail the HRSA Information Collection Clearance Officer, Room 14N136B, 5600 Fishers Lane, Rockville, Maryland 20857.

Start Further Info To request more information on the proposed project or to obtain a copy of the data collection plans and draft instruments, email paperwork@hrsa.gov or call Lisa Wright-Solomon, the HRSA Information Collection Clearance how to get viagra online Officer at (301) 443-1984. End Further Info End Preamble Start Supplemental Information When submitting comments or requesting Start Printed Page 65835information, please include the ICR title for reference. Information Collection Request Title.

National Practitioner Data Bank for Adverse Information on Physicians how to get viagra online and Other Health Care Practitioners—45 CFR part 60 Regulations and Forms, OMB No. 0915-0126—Revision. Abstract how to get viagra online.

This is a request for OMB's approval for a revision to the information collection contained in regulations found at 45 CFR part 60 governing the National Practitioner Data Bank (NPDB) and the forms to be used in registering with, reporting information to, and requesting information from the NPDB. Administrative forms are also included to aid in monitoring compliance with Federal reporting how to get viagra online and querying requirements. Responsibility for NPDB implementation and operation resides in HRSA's Bureau of Health Workforce.

The intent of the NPDB is to improve the quality of health care by encouraging entities such as hospitals, State licensing boards, professional societies, and other eligible entities [] providing health care services to identify and discipline those who engage in unprofessional behavior, and to restrict the ability of incompetent health care practitioners, providers, or suppliers to move from state to state without disclosure or discovery of previous how to get viagra online damaging or incompetent performance. It also serves as a fraud and abuse clearinghouse for the reporting and disclosing of certain final adverse actions (excluding settlements in which no findings of liability have been made) taken against health care practitioners, providers, or suppliers by health plans, Federal agencies, and State agencies. Users of the NPDB include reporters (entities that are required to submit reports) and queriers (entities and individuals that are authorized to request for information).

The reporting forms, request for information forms (query forms), and administrative forms (used to monitor compliance) are accessed, completed, and submitted to the NPDB electronically through the NPDB website how to get viagra online at https://www.npdb.hrsa.gov/​. All reporting and querying is performed through the secure portal of this website. This revision proposes changes to improve overall data integrity how to get viagra online.

In addition, this revision contains the four NPDB forms that were originally approved in the “National Practitioner Data Bank (NPDB) Attestation of Reports by Hospitals, Medical Malpractice Payers, Health Plans, and Certain Other Health Care Entities, OMB No. 0906-0028” which will be discontinued upon approval how to get viagra online of this ICR. Need and Proposed Use of the Information.

The NPDB acts primarily as a how to get viagra online flagging system. Its principal purpose is to facilitate comprehensive review of practitioners' professional credentials and background. Information is collected from, and disseminated to, eligible entities (entities that are entitled to query and/or report to the NPDB as authorized in Title 45 CFR part 60 of the Code of Federal Regulations) on the following.

(1) Medical malpractice payments, (2) licensure actions taken by Boards of Medical Examiners, (3) State licensure and certification actions, (4) Federal licensure and certification actions, (5) negative actions or findings taken by peer review organizations or private accreditation entities, (6) adverse actions taken against clinical privileges, (7) Federal or State criminal convictions related to the delivery of a health care how to get viagra online item or service, (8) civil judgments related to the delivery of a health care item or service, (9) exclusions from participation in Federal or State health care programs, and (10) other adjudicated actions or decisions. It is intended that NPDB information should be considered with other relevant information in evaluating credentials of health care practitioners, providers, and suppliers. Likely Respondents how to get viagra online.

Eligible entities or individuals that are entitled to query and/or report to the NPDB as authorized in regulations found at 45 CFR part 60. Burden Statement how to get viagra online. Burden in this context means the time expended by persons to generate, maintain, retain, disclose, or provide the information requested.

This includes how to get viagra online the time needed to review instructions. To develop, acquire, install, and utilize technology and systems for the purpose of collecting, validating, and verifying information, processing and maintaining information, and disclosing and providing information. To train personnel and to be able to respond to a collection of information.

To search data sources how to get viagra online. To complete and review the collection of information. And to how to get viagra online transmit or otherwise disclose the information.

The total annual burden hours estimated for this ICR are summarized in the table below. Total Estimated how to get viagra online Annualized Burden HoursRegulation citationForm nameNumber of respondentsNumber of responses per respondentTotal responsesAverage burden per response (in hours)Total burden hours (rounded up)§ 60.6. Reporting errors, omissions, revisions or whether an action is on appeal.Correction, Revision-to-Action, Void, Notice of Appeal (manual)11,918111,918.252,980 Correction, Revision-to-Action, Void, Notice of Appeal (automated)18,301118,301.00035§ 60.7.

Reporting medical malpractice paymentsMedical Malpractice Payment (manual)11,481111,481.758,611 Medical Malpractice Payment (automated)2961296.00031Start Printed Page 65836§ 60.8. Reporting licensure actions taken by Boards of Medical how to get viagra online ExaminersState Licensure or Certification (manual)19,749119,749.7514,812§ 60.9. Reporting licensure and certification actions taken by StatesState Licensure or Certification (automated)17,189117,189.00035§ 60.10.

Reporting Federal licensure how to get viagra online and certification actions.DEA/Federal Licensure6001600.75450§ 60.11. Reporting negative actions or findings taken by peer review organizations or private accreditation entitiesPeer Review Organization10110.758 Accreditation10110.758§ 60.12. Reporting adverse actions taken against clinical privilegesTitle IV Clinical Privileges Actions9781978.75734 Professional how to get viagra online Society41141.7531§ 60.13.

Reporting Federal or State criminal convictions related to the delivery of a health care item or serviceCriminal Conviction (Guilty Plea or Trial) (manual)1,17411,174.75881 Criminal Conviction (Guilty Plea or Trial) (automated)6831683.00031 Deferred Conviction or Pre-Trial Diversion70170.7553 Nolo Contendere (no contest plea)1271127.7595 Injunction10110.758§ 60.14. Reporting civil judgments related to the delivery of a health how to get viagra online care item or serviceCivil Judgment919.757§ 60.15. Reporting exclusions from participation in Federal or State health care programsExclusion or Debarment (manual)1,70711,707.751,280 Exclusion or Debarment (automated)2,50612,506.00031§ 60.16.

Reporting other adjudicated actions or decisionsGovernment Administrative (manual)1,75011,750.751,313 Government Administrative (automated)39139.00031 Health Plan Action4881488.75366§ 60.17 Information which hospitals must request from the National Practitioner Data BankOne-Time Query for an Individual (manual)1,958,17611,958,176.08156,654§ 60.18 Requesting Information from the NPDBOne-Time Query for an Individual (automated)3,349,77813,349,778.00031,005 One-Time Query for an Organization (manual)50,681150,681.084,054 One-Time Query for an Organization (automated)25,610125,610.00038 Self-Query on an Individual168,5571168,557.4270,794 Self-Query on an Organization1,05911,059.42445 Continuous Query (manual)806,9711806,971.0864,558Start Printed Page 65837 Continuous Query (automated)619,0011619,001.0003186§ 60.21. How to dispute the accuracy of NPDB informationSubject Statement and Dispute3,26413,264.752,448 Request for how to get viagra online Dispute Resolution741748592AdministrativeEntity Registration (Initial)3,48413,48413,484 Entity Registration (Renewal &. Update)13,245113,245.253,311 State Licensing Board Data Request6016010.5630 State Licensing Board Attestation32513251325 Authorized Agent Attestation35013501350 Health Center Attestation72217221722 Hospital Attestation3,41613,41613,416 Medical Malpractice Payer, Peer Review Organization, or Private Accreditation Organization Attestation27412741274 Other Eligible Entity Attestation1,88411,88411,884 Corrective Action Plan (Entity)10110.081 Reconciling Missing Actions1,49111,491.08119 Agent Registration (Initial)44144144 Agent Registration (Renewal &.

Update)3041304.0824 Electronic Funds Transfer (EFT) Authorization6441644.0852 Authorized Agent Designation1831183.2546 Account Discrepancy85185.2521 New Administrator Request6001600.0848 Purchase Query Credits1,78611786.08143 Education Request40140.083 Account Balance Transfer10110.081 Missing Report From Query Form10110.081Total7,101,2747,101,274347,294 HRSA specifically requests comments on (1) the necessity and utility of the proposed information collection for the proper performance of the agency's functions, (2) the accuracy of the estimated burden, (3) ways to enhance the quality, utility, and clarity of the information to be collected, and (4) how to get viagra online the use of automated collection techniques or other forms of information technology to minimize the information collection burden. Start Signature Maria G. Button, Director, Executive how to get viagra online Secretariat.

End Signature End Supplemental Information [FR Doc. 2020-22953 Filed how to get viagra online 10-15-20. 8:45 am]BILLING CODE 4165-15-PStart Preamble Health Resources and Services Administration (HRSA), Department of Health and Human Services.

Notice. In compliance with the requirement how to get viagra online for opportunity for public comment on proposed data collection projects of the Paperwork Reduction Act of 1995, HRSA announces plans to submit an Information Collection Request (ICR), described below, to the Office of Management and Budget (OMB). Prior to submitting the ICR to OMB, HRSA seeks comments from the public regarding the burden estimate, below, or any other aspect of the ICR.

Comments on this ICR should be received how to get viagra online no later than December 15, 2020. Submit your comments to paperwork@hrsa.gov or mail the HRSA Information Collection Clearance Officer, Room 14N136B, 5600 Fishers Lane, Rockville, MD 20857. Start Further Info To request more information on the proposed project or to obtain a copy of the data collection plans and draft instruments, email paperwork@hrsa.gov or call Lisa how to get viagra online Wright-Solomon, the HRSA Information Collection Clearance Officer at (301) 443-1984.

End Further Info End Preamble Start Supplemental Information When submitting comments or requesting information, please include the Start Printed Page 65834information request collection title for reference. Information Collection Request how to get viagra online Title. Survey of Eligible Users of the National Practitioner Data Bank, OMB No.

0915-0366—Reinstatement With Change. Abstract how to get viagra online. HRSA plans to survey the users National Practitioner Data Bank (NPDB).

The purpose of this survey is to assess the overall satisfaction of the eligible users of how to get viagra online the NPDB. This survey will evaluate the effectiveness of the NPDB as a flagging system, source of information, and its use in decision making. Furthermore, this survey will collect information from organizations and individuals who query the NPDB to understand and improve their user experience how to get viagra online.

This survey is a reinstatement of the 2012 NPDB survey with some changes. Need and Proposed Use of the Information. The survey will collect information regarding the participants' experiences of querying and reporting to how to get viagra online the NPDB, perceptions of health care practitioners with reports, impact of NPDB reports on organizations' decision-making, and satisfaction with various NPDB products and services.

The survey will also be administered to health care practitioners that use the self-query service provided by the NPDB. The self-queriers will be asked about their experiences of querying, the impact of having reports in the NPDB how to get viagra online on their careers and health care organizations' perceptions, and their satisfaction with various NPDB products and services. Understanding self-queriers' satisfaction and their use of the information is an important component of the survey.

Proposed changes to this ICR include the following how to get viagra online. 1. In the how to get viagra online proposed entity survey, there are 37 modules and 258 questions.

From the previous 2012 survey, there are 15 deleted questions and 13 new questions in addition to proposed changes to 12 survey questions. 2. In the how to get viagra online proposed self-query survey, there are 22 modules and 88 questions.

From the previous 2012 survey, there are 5 deleted questions and 5 new questions in addition to proposed changes to two survey questions. Likely how to get viagra online Respondents. Eligible users of the NPDB will be asked to complete a web-based survey.

Data gathered how to get viagra online from the survey will be compared with previous survey results. This survey will provide HRSA with the information necessary for research purposes and for improving the usability and effectiveness of the NPDB. Burden Statement how to get viagra online.

Burden in this context means the time expended by persons to generate, maintain, retain, disclose or provide the information requested. This includes the time needed to review instructions, to develop, acquire, install and utilize technology and systems for the purpose of collecting, validating and verifying information, processing and maintaining information, and disclosing and providing information, to train personnel and to be able to respond to a collection of information, to search data sources, to complete and review the collection of information, and to transmit or otherwise disclose the information. The total annual burden hours estimated for this Information Collection Request are summarized in how to get viagra online the table below.

Total Estimated Annualized Burden HoursForm nameNumber of respondentsNumber of responses per respondentTotal responsesAverage burden per response (in hours)Total burden hoursNPDB Users Entities Respondents15,000115,0000.253,750NPDB Self-Query Respondents2,00012,0000.10200Total17,00017,0003,950 HRSA specifically requests comments on (1) the necessity and utility of the proposed information collection for the proper performance of the agency's functions, (2) the accuracy of the estimated burden, (3) ways to enhance the quality, utility, and clarity of the information to be collected, and (4) the use of automated collection techniques or other forms of information technology to minimize the information collection burden. Start Signature Maria G. Button, Director, Executive Secretariat.

End Signature End Supplemental Information [FR Doc. 2020-22964 Filed 10-15-20. 8:45 am]BILLING CODE 4165-15-P.

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About This TrackerThis tracker provides the number of confirmed cases and deaths from novel coronavirus by country, the trend in confirmed case and death counts does walmart sell viagra by country, and a global map showing which countries have confirmed cases and deaths. The data does walmart sell viagra are drawn from the Johns Hopkins University (JHU) Coronavirus Resource Center’s COVID-19 Map and the World Health Organization’s (WHO) Coronavirus Disease (COVID-2019) situation reports.This tracker will be updated regularly, as new data are released.Related Content. About COVID-19 CoronavirusIn late 2019, a new coronavirus emerged in central China to cause disease in humans.

Cases of this does walmart sell viagra disease, known as COVID-19, have since been reported across around the globe. On January 30, 2020, the World Health Organization (WHO) declared the virus represents a public health emergency of international concern, and on January 31, 2020, the U.S. Department of Health and Human Services declared it to be a health emergency for the United States.With schools nationwide preparing for fall and the federal government encouraging in-person classes, key concerns for school officials, teachers and parents include the risks that coronavirus poses to children and their role in transmission of does walmart sell viagra the disease.A new KFF brief examines the latest available data and evidence about the issues around COVID-19 and children and what they suggest about the risks posed for reopening classrooms.

The review concludes that while children does walmart sell viagra are much less likely than adults to become severely ill, they can transmit the virus. Key findings include:Disease severity is significantly less in children, though rarely some do get very sick. Children under age 18 account for 22% of the population but account for just 7% of the more than 4 million COVID-19 cases and less than 1% of deaths.The does walmart sell viagra evidence is mixed about whether children are less likely than adults to become infected when exposed.

While one prominent study estimates children and teenagers are half as likely as adults over age 20 to catch the virus, other studies find children and adults are about equally likely to have antibodies that develop after a COVID-19 infection.While children do transmit to others, more evidence is needed on the frequency and extent of that transmission. A number of studies find children are less likely than adults to be the source of infections in households and other settings, though this could occur because of differences in testing, the does walmart sell viagra severity of the disease, and the impact of earlier school closures.Most countries that have reopened schools have not experienced outbreaks, but almost all had significantly lower rates of community transmission. Some countries, including Canada, Chile, France, and Israel did experience school-based outbreaks, sometimes significant ones, that required schools to close a second time.The analysis concludes that there is a risk of spread associated with reopening schools, particularly in states and communities where there is already widespread community transmission, that should be weighed carefully against the benefits of in-person education..

About This TrackerThis tracker provides the number of confirmed cases and deaths from novel coronavirus by country, the trend in confirmed case and death counts by country, how to get viagra online and a global map showing which countries have confirmed cases and deaths. The data are drawn from the Johns how to get viagra online Hopkins University (JHU) Coronavirus Resource Center’s COVID-19 Map and the World Health Organization’s (WHO) Coronavirus Disease (COVID-2019) situation reports.This tracker will be updated regularly, as new data are released.Related Content. About COVID-19 CoronavirusIn late 2019, a new coronavirus emerged in central China to cause disease in humans.

Cases of how to get viagra online this disease, known as COVID-19, have since been reported across around the globe. On January 30, 2020, the World Health Organization (WHO) declared the virus represents a public health emergency of international concern, and on January 31, 2020, the U.S. Department of Health and Human Services declared it to be a health emergency for the United States.With schools nationwide preparing for fall and the federal government encouraging in-person classes, key concerns for school officials, teachers and parents include the risks that coronavirus poses to children and their role in transmission of the disease.A new KFF brief examines the latest available data how to get viagra online and evidence about the issues around COVID-19 and children and what they suggest about the risks posed for reopening classrooms.

The review concludes that while children are much less likely than adults to become severely ill, they how to get viagra online can transmit the virus. Key findings include:Disease severity is significantly less in children, though rarely some do get very sick. Children under age 18 account for 22% of the population but account for just how to get viagra online 7% of the more than 4 million COVID-19 cases and less than 1% of deaths.The evidence is mixed about whether children are less likely than adults to become infected when exposed.

While one prominent study estimates children and teenagers are half as likely as adults over age 20 to catch the virus, other studies find children and adults are about equally likely to have antibodies that develop after a COVID-19 infection.While children do transmit to others, more evidence is needed on the frequency and extent of that transmission. A number of studies find children are less likely than adults to be the source of infections in households and other settings, though this could occur because of differences in testing, the severity of the disease, and the impact of earlier school closures.Most countries that have reopened schools have not experienced outbreaks, but almost all had significantly lower rates of community transmission how to get viagra online. Some countries, including Canada, Chile, France, and Israel did experience school-based outbreaks, sometimes significant ones, that required schools to close a second time.The analysis concludes that there is a risk of spread associated with reopening schools, particularly in states and communities where there is already widespread community transmission, that should be weighed carefully against the benefits of in-person education..

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Dr. Hill reports fees and grant support from Abbott Vascular, Boston Scientific, Abiomed, Shockwave Medical and is a stockholder in Shockwave Medical. Dr. Kereiakes is a consultant for SINO Medical Sciences Technologies, Inc., Boston Scientific, Elixir Medical, Svelte Medical Systems, Inc., Caliber Therapeutics/Orchestra Biomed, Shockwave Medical and is a stockholder in Ablative Solutions, Inc.

Dr. Shlofmitz is a speaker for Shockwave Medical, Inc. Dr. Klein reports no relationships with industry.

Dr. Riley reports honoraria from Boston Scientific, Asahi Intecc, and Medtronic. Dr. Price reports personal fees from ACIST Medical, AstraZeneca, Abbott Vascular, Boston Scientific, Chiesi USA, Medtronic, and W.L.

Gore. Dr. Herrmann reports research funding from Abbott, Boston Scientific, Medtronic, Shockwave Medical and is a consultant for Abbott, Medtronic, and Shockwave. Dr.

Bachinsky reports consultant, speakers bureau and research grant support from Abbott Vascular, Boston Scientific, BD Bard Vascular, Medtronic, Shockwave Medical. Dr. Waksman is on the Advisory Board of Amgen, Boston Scientific, Cardioset, Cardiovascular Systems Inc., Medtronic, Philips, Pi-Cardia Ltd. Is a consultant for Amgen, Biotronik, Boston Scientific, Cardioset, Cardiovascular Systems Inc., Medtronic, Philips, Pi-Cardia Ltd..

Has received grant support from AstraZeneca, Biotronik, Boston Scientific, Chiesi. Is a speaker for AstraZeneca, Chiesi. And is a stockholder in MedAlliance. Dr.

Stone is a speaker for Cook Medical. Is a consultant for Valfix Medical, TherOx, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Miracor, Neovasc, V-Wave, Abiomed, Ancora, MAIA Pharmaceuticals, Vectorious, Reva, Cardiomech. And has equity/options from Ancora, Qool Therapeutics, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, and Valfix.Twitter summary. Disrupt CAD III demonstrates safety and efficacy of intravascular lithotripsy to optimize stent expansion in severely calcified coronary artery disease.

Dr. Hill reports fees and grant support from Abbott Vascular, Boston Scientific, Abiomed, Shockwave Medical and is a stockholder in Shockwave Medical. Dr. Kereiakes is a consultant for SINO Medical Sciences Technologies, Inc., Boston Scientific, Elixir Medical, Svelte Medical Systems, Inc., Caliber Therapeutics/Orchestra Biomed, Shockwave Medical and is a stockholder in Ablative Solutions, Inc. Dr.

Shlofmitz is a speaker for Shockwave Medical, Inc. Dr. Klein reports no relationships with industry. Dr. Riley reports honoraria from Boston Scientific, Asahi Intecc, and Medtronic.

Dr. Price reports personal fees from ACIST Medical, AstraZeneca, Abbott Vascular, Boston Scientific, Chiesi USA, Medtronic, and W.L. Gore. Dr. Herrmann reports research funding from Abbott, Boston Scientific, Medtronic, Shockwave Medical and is a consultant for Abbott, Medtronic, and Shockwave.

Dr. Bachinsky reports consultant, speakers bureau and research grant support from Abbott Vascular, Boston Scientific, BD Bard Vascular, Medtronic, Shockwave Medical. Dr. Waksman is on the Advisory Board of Amgen, Boston Scientific, Cardioset, Cardiovascular Systems Inc., Medtronic, Philips, Pi-Cardia Ltd. Is a consultant for Amgen, Biotronik, Boston Scientific, Cardioset, Cardiovascular Systems Inc., Medtronic, Philips, Pi-Cardia Ltd..

Has received grant support from AstraZeneca, Biotronik, Boston Scientific, Chiesi. Is a speaker for AstraZeneca, Chiesi. And is a stockholder in MedAlliance. Dr. Stone is a speaker for Cook Medical.

Is a consultant for Valfix Medical, TherOx, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Miracor, Neovasc, V-Wave, Abiomed, Ancora, MAIA Pharmaceuticals, Vectorious, Reva, Cardiomech. And has equity/options from Ancora, Qool Therapeutics, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, and Valfix.Twitter summary. Disrupt CAD III demonstrates safety and efficacy of intravascular lithotripsy to optimize stent expansion in severely calcified coronary artery disease.

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A recent announcement by the Australian government means that female viagra walmart from October 9th the number of psychologist appointments covered by Medicare will double, from 10 to 20. One of the less evident effects of the coronavirus pandemic is without doubt the mental health impact that not only the disease itself, but the effect that lockdowns, social restrictions and the economic fallout female viagra walmart have had on Australians.What is the 'shadow pandemic'?. This has been referred to as the 'shadow female viagra walmart pandemic,' with many mental health professionals issuing grave warnings about the flow-on effects that they say we will see for months, if not years, following the arrival of COVID-19 on the global agenda. Sky News reports that up to one million Australians have sought mental health support since the beginning of the pandemic, and upwards of 351,000 Victorians - who have suffered through some of the longest lockdowns globally - sought help from GPs, psychologists and counselling services in September and October - representing a 31 per cent increase since 2019.Similarly, the Kids Helpline saw a 61 per cent increase in young people over the past four weeks, taking about 3700 calls from those needing help.Mental health care plans have been doubledIn response to this, the Australian government has doubled the number of mental health therapy sessions Australians can access for free under the Medical Benefits female viagra walmart Scheme - an initiative they're calling Better Access Scheme - from 10 appointments per calendar year to 20. Thank you, female viagra walmart Medicare.Like what you see?.

Sign up to our bodyandsoul.com.au newsletter for more stories like this.How has female viagra walmart this changed?. The key difference between this and what was available before (which was based on if your state or territory was under lockdown restrictions), is that the scheme is now open to all Australians whose mental health may have been affected by COVID, and the timeframe to access these free sessions has been extended until 30 June, 2022 for in-person appointments, and until 31 March, 2021 for Telehealth or phone appointments.The Department of Health published the following last week. "From 9 October 2020 until 30 June 2022, 10 additional individual psychological therapy sessions, previously available only female viagra walmart to people whose movement was restricted by a state or territory public health order, are now available each calendar year to all eligible patients under the existing Better Access to Psychiatrists, Psychologists and General Practitioners through the MBS (Better Access) initiative." This comes at a reported cost of $101 million.Are there any drawbacks?. However, the Royal Australian College of General Practitioners believes there could be a downside to the increased access to free female viagra walmart mental health appointments, stating that "The college believes appropriate safeguards and measures are needed to prevent any unintended negative consequences when increasing the number of Medicare Benefits Schedule (MBS)-related psychological therapy sessions. Inappropriately increasing the maximum number of sessions could drive up the number of patients who do not obtain any meaningful benefit from these referrals and potentially decreasing access for other people.If female viagra walmart you feel like your mental health is suffering, or you need to talk to someone, make an appointment with your GP and ask about getting a mental health care plan.In an emergency please call 000.If you or someone you know needs help, phone Lifeline on 13 11 14 or the 24-hour Suicide Call Back Service 1300 659 467.Mental health professionals are available 24/7 at the beyondblue Support Service – 1300 22 46 36 or via beyondblue.org.au/get-support for online chat (3pm-12am AEST) or email response.http://mbsonline.gov.au/internet/mbsonline/publishing.nsf/content/240DC3AF97EEAF79CA2585BC00827909/$File/Factsheet-Practitioners-Mental-Health-Services-COVID-19.pdfEarly detection is the key to survival, but young Australian women are almost twice as likely to have advanced breast cancer because mammograms aren’t as effective for women under 50.

It’s why checking yourself female viagra walmart regularly and knowing what’s ‘normal’ is so important. For Breast Cancer female viagra walmart Awareness month, Vered Keisar shares her story.Vered Keisar had never had a cyst before. Her mum had just passed away and a week after the funeral, she felt a lump in her breast. The next day, Vered visited her GP who said female viagra walmart the lump was “probably a cyst” and that she should come back next month if it was still there. She was 35, after all, fit and healthy.Not satisfied with her doctor’s response, Vered asked to be referred to a breast cancer clinic where a consultant, too, hypothesised the lump was just a cyst but Vered asked for a biopsy anyway, just in case.A few days female viagra walmart later came a call Vered was not expecting.

A nurse would like her to come back female viagra walmart to review the biopsy results.“I had a bad feeling and certain that they got my test mixed up with someone else’s result,” Vered tells Body+Soul.“[But] The nurse insisted I should come back the next day.”Like what you see?. Sign up to our bodyandsoul.com.au newsletter for more stories like this.The initial biopsy showed abnormal cells, the second, after a “long wait” revealed Stage 3, invasive ductal carcinoma, hormone-receptor-positive breast cancer.“It was aggressive and I should have my whole breast removed as soon female viagra walmart as possible,” Vered recalls being told. €œI was afraid I would die and that nothing would be the same again.”It was Friday and Vered was booked in for surgery the following Tuesday.“I could not stop crying that afternoon and wished my mother was there to tell me it will be alright,” she says.With a supportive group of friends and boyfriend (now husband), Vered says it was helpful to hear survivors’ success stories, drawing inspiration from Kylie Minogue’s diagnosis and even seeing the pop icon live in one of her first shows after her recovery.After surgeryVered’s first shower after her female viagra walmart mastectomy was “very sad”, she recalls.“I remember taking off my shirt and seeing some pale skin over the ribs where I used to have a breast. It was very sad. I felt a loss of an important feminine part.”She was also required to undergo chemotherapy, and while hair loss is a common experience, Vered was assured a scalp freezing treatment would prevent that from occurring.“But two weeks after the first female viagra walmart treatment I woke up one morning to discover that large chunks of my hair were left on the pillow,” she says.“I went to the bathroom and saw a bald patch on one side of my head.

As I leaned to the sink to brush female viagra walmart my teeth, my hair just dropped all over the room. As I did not think I would lose my hair, I was not emotionally ready to deal with the loss.”Vered was adamant she “didn’t want to look like a cancer patient,” so she built a small collection female viagra walmart of wigs, make-up, and false eyelashes. She managed to hide her female viagra walmart condition from strangers so well, another woman at chemo was surprised Vered was there for treatment herself.As well as making you feel ill, impacting your energy, mood, and sleep patterns, chemotherapy can also affect fertility, and because Vered wanted to be a mother, she underwent IVF in an effort to preserve that future.Recovery and awarenessThis October, coinciding with Breast Cancer Awareness Month, Vered is celebrating 10 years in remission. She counts herself among the lucky ones, but Vered is also aware that without funding for research, there will be others out there who won’t be so lucky.The National Breast female viagra walmart Cancer Foundation recently revealed that without adequate funding, 30,000 lives could be lost to breast cancer over the next 10 years. Over half of which are predicted to be women who do not reach the five-year milestone after their diagnosis.Young Australian women like Vered are almost twice as likely to have advanced breast cancer, rather than localised disease, at diagnosis, partially due to the fact that breast cancer in women under 50 is more difficult to detect via mammogram due to increased tissue density.Vered’s advice to young women, therefore is to “conduct a breast self-test at least once a month and a GP test once a year as early detection is the key to survival.”.

A recent announcement by how to get viagra online the Australian government means that from October 9th the number of psychologist appointments covered by Medicare will double, from 10 to 20. One of the less evident effects of the coronavirus pandemic is how to get viagra online without doubt the mental health impact that not only the disease itself, but the effect that lockdowns, social restrictions and the economic fallout have had on Australians.What is the 'shadow pandemic'?. This has been referred to as the 'shadow pandemic,' with many mental health professionals issuing grave warnings about the flow-on how to get viagra online effects that they say we will see for months, if not years, following the arrival of COVID-19 on the global agenda. Sky News reports that up to one million Australians have sought mental health support since the beginning of the pandemic, and upwards of 351,000 Victorians - who have suffered through some of the longest lockdowns globally - sought help from GPs, psychologists and counselling services in September and October - representing a 31 per cent increase since 2019.Similarly, the Kids Helpline saw a 61 per cent increase in young people over the past four weeks, taking about 3700 calls from those needing help.Mental health care plans have been doubledIn response to this, the Australian government has doubled how to get viagra online the number of mental health therapy sessions Australians can access for free under the Medical Benefits Scheme - an initiative they're calling Better Access Scheme - from 10 appointments per calendar year to 20.

Thank you, Medicare.Like how to get viagra online what you see?. Sign up to our bodyandsoul.com.au newsletter for how to get viagra online more stories like this.How has this changed?. The key difference between this and what was available before (which was based on if your state or territory was under lockdown restrictions), is that the scheme is now open to all Australians whose mental health may have been affected by COVID, and the timeframe to access these free sessions has been extended until 30 June, 2022 for in-person appointments, and until 31 March, 2021 for Telehealth or phone appointments.The Department of Health published the following last week. "From 9 October 2020 until 30 June 2022, 10 additional individual psychological therapy sessions, previously available only to people whose movement was restricted by a state or territory public health order, are now available each calendar year to all eligible patients how to get viagra online under the existing Better Access to Psychiatrists, Psychologists and General Practitioners through the MBS (Better Access) initiative." This comes at a reported cost of $101 million.Are there any drawbacks?.

However, the Royal Australian College of General Practitioners believes there could be a downside to the increased access to free mental health appointments, stating that "The college believes appropriate safeguards and measures are how to get viagra online needed to prevent any unintended negative consequences when increasing the number of Medicare Benefits Schedule (MBS)-related psychological therapy sessions. Inappropriately increasing the maximum number of sessions could drive up the number of patients who do not obtain any meaningful benefit from these referrals and potentially decreasing access for other people.If you feel like your mental health is suffering, or you need to talk to someone, make an how to get viagra online appointment with your GP and ask about getting a mental health care plan.In an emergency please call 000.If you or someone you know needs help, phone Lifeline on 13 11 14 or the 24-hour Suicide Call Back Service 1300 659 467.Mental health professionals are available 24/7 at the beyondblue Support Service – 1300 22 46 36 or via beyondblue.org.au/get-support for online chat (3pm-12am AEST) or email response.http://mbsonline.gov.au/internet/mbsonline/publishing.nsf/content/240DC3AF97EEAF79CA2585BC00827909/$File/Factsheet-Practitioners-Mental-Health-Services-COVID-19.pdfEarly detection is the key to survival, but young Australian women are almost twice as likely to have advanced breast cancer because mammograms aren’t as effective for women under 50. It’s why checking yourself regularly how to get viagra online and knowing what’s ‘normal’ is so important. For Breast Cancer how to get viagra online Awareness month, Vered Keisar shares her story.Vered Keisar had never had a cyst before.

Her mum had just passed away and a week after the funeral, she felt a lump in her breast. The next day, Vered visited her GP who said the lump was “probably a cyst” and that she should come back how to get viagra online next month if it was still there. She was 35, after all, fit and healthy.Not satisfied with her doctor’s how to get viagra online response, Vered asked to be referred to a breast cancer clinic where a consultant, too, hypothesised the lump was just a cyst but Vered asked for a biopsy anyway, just in case.A few days later came a call Vered was not expecting. A nurse would like her to come back to review the how to get viagra online biopsy results.“I had a bad feeling and certain that they got my test mixed up with someone else’s result,” Vered tells Body+Soul.“[But] The nurse insisted I should come back the next day.”Like what you see?.

Sign up to our bodyandsoul.com.au newsletter for more stories like this.The initial biopsy showed abnormal how to get viagra online cells, the second, after a “long wait” revealed Stage 3, invasive ductal carcinoma, hormone-receptor-positive breast cancer.“It was aggressive and I should have my whole breast removed as soon as possible,” Vered recalls being told. €œI was afraid I would die and that nothing would be the same again.”It was Friday and Vered was booked in for surgery the following Tuesday.“I could not stop crying that afternoon and wished my mother was there to tell me it will be alright,” she says.With a supportive group of friends and boyfriend (now husband), Vered says it was helpful to hear survivors’ success stories, drawing inspiration from Kylie how to get viagra online Minogue’s diagnosis and even seeing the pop icon live in one of her first shows after her recovery.After surgeryVered’s first shower after her mastectomy was “very sad”, she recalls.“I remember taking off my shirt and seeing some pale skin over the ribs where I used to have a breast. It was very sad. I felt a loss of an important feminine part.”She was also required to undergo chemotherapy, and while hair loss is a common experience, Vered was assured a scalp freezing treatment would prevent that from occurring.“But two weeks after the first treatment I woke up one morning to discover that large chunks of my hair were how to get viagra online left on the pillow,” she says.“I went to the bathroom and saw a bald patch on one side of my head.

As I leaned to the sink to how to get viagra online brush my teeth, my hair just dropped all over the room. As I did not think I would lose my hair, I was not emotionally ready to deal with the how to get viagra online loss.”Vered was adamant she “didn’t want to look like a cancer patient,” so she built a small collection of wigs, make-up, and false eyelashes. She managed to hide her condition from strangers so well, another woman at chemo was surprised Vered was there for treatment herself.As well as making you feel ill, impacting your energy, mood, and sleep patterns, chemotherapy can also affect fertility, how to get viagra online and because Vered wanted to be a mother, she underwent IVF in an effort to preserve that future.Recovery and awarenessThis October, coinciding with Breast Cancer Awareness Month, Vered is celebrating 10 years in remission. She counts herself among the lucky ones, but Vered is also aware that without funding for research, there will be others out there who won’t be so lucky.The National Breast Cancer Foundation recently how to get viagra online revealed that without adequate funding, 30,000 lives could be lost to breast cancer over the next 10 years.

Over half of which are predicted to be women who do not reach the five-year milestone after their diagnosis.Young Australian women like Vered are almost twice as likely to have advanced breast cancer, rather than localised disease, at diagnosis, partially due to the fact that breast cancer in women under 50 is more difficult to detect via mammogram due to increased tissue density.Vered’s advice to young women, therefore is to “conduct a breast self-test at least once a month and a GP test once a year as early detection is the key to survival.”.

How long does female viagra last

IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a how long does female viagra last 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 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 how long does female viagra last achieve European agreement on harmonisation of clinical management and laboratory practices.15–17 Another such initiative involved an update of the 2006 DSD consensus document by an international group of professionals and patient representatives.18 These initiatives have highlighted how cultural and financial aspects and 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 produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with how long does female viagra last 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 how long does female viagra last embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature 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 how long does female viagra last 23 Therefore, a section of the Dutch-Flemish guideline was written for these healthcare providers. Moreover, this enables DSD specialists to refer to the guideline when advising a referral. Transition from the prenatal to the postnatal team and from the paediatric to the adult team requires optimal how long does female viagra last 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 how long does female viagra last 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 how long does female viagra last 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 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 how long does female viagra last 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 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 how long does female viagra last 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, how long does female viagra last 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, the final version was presented to the paediatric and genetic associations for how long does female viagra last 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 the genotypic how long does female viagra last 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 how long does female viagra last 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 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 always included in NIPT analysis and reports how long does female viagra last. 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 how long does female viagra last aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team.

After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on the ultrasound how long does female viagra last 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 how long does female viagra last 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 need to be how long does female viagra last available to allow parents to make a well-informed decision about whether or not to continue the pregnancy. Termination of pregnancy can how long does female viagra last be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting parents may also consider termination of pregnancy, which, although considered controversial by some, is legal in Belgium and the 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 how long does female viagra last cannot be avoided completely. Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images.

In our experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a contact person before birth.After expert prenatal counselling, a significant number of pregnant couples decline prenatal testing (personal experience how long does female viagra last IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist. The terminology used in communication with parents should be carefully chosen,22 23 and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising how long does female viagra last 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 how long does female viagra last 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 how long does female viagra last 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 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 how to get viagra online 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 and the availability of resources differ significantly how to get viagra online 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 how to get viagra online (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with similarly structured healthcare systems and similar resources.

Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues. International networks such as the European Reference Network for rare endocrine conditions (EndoERN), in which DSD is embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion how to get viagra online points in the Dutch-Flemish 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 how to get viagra online 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 these healthcare providers.

Moreover, this enables DSD specialists to refer to the guideline when advising a referral. Transition from the prenatal to how to get viagra online 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 how to get viagra online 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 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 methods, for example, gene how to get viagra online 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 how to get viagra online 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 care).

Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports how to get viagra online 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 and, after having obtained agreement how to get viagra online 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, the final version was presented to the paediatric and genetic associations for how to get viagra online 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 how to get viagra online 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 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 how to get viagra online 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 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 always included in NIPT analysis and reports how to get viagra online.

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 how to get viagra online later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team. After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on how to get viagra online the ultrasound 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 how to get viagra online 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 need to be available to allow parents how to get viagra online 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 considered how to get viagra online 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 how to get viagra online and prognosis cannot be avoided completely. Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images.

In our experience, parents appreciate having already spoken to how to get viagra online 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 (personal experience IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist. The terminology used in communication with parents should be carefully chosen,22 23 and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is how to get viagra online 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 how to get viagra online 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 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 how to get viagra online cases there is no tight time limit, and 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..

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