Low cost zithromax

On this page IntroductionEach year, Health low cost zithromax Canada receives thousands of reports of suspected adverse reactions (side effects) about drugs and natural health products and of suspected medical device incidents. These reports, captured through the Canada Vigilance Program, contribute to Health Canada’s post-market monitoring of health product safety.Manufacturers, importers, hospitals and other mandatory reporters are required to report to Health Canada on adverse reactions and incidents related to marketed health products. Health Canada also encourages health care professionals, patients, caregivers and consumers to low cost zithromax submit voluntary reports about serious adverse reactions or incidents concerning drugs, natural health products or medical devices. Data from both the Canada Vigilance Program and other sources, like recalls that are reported to Health Canada, provide critical information that helps improve patient safety.Building the Canada Vigilance Program Since the Canada Vigilance Program began, the number of reports submitted to Health Canada has increased every year. This increase is due to a number of factors, such as.

The rise in the overall number of marketed health products the implementation of mandatory reporting for all hospitals in Canada the expansion of the Canadian Medical Devices Sentinel Network (CMDSNet), Health Canada’s proactive surveillance program that encourages program participants to report medical device incidents the implementation of voluntary consumer reporting Health Canada’s efforts to promote simpler and easier ways to report a changing and aging Canadian population with changing low cost zithromax health needs an increase in patient safety programs by industry, which leads to an increase in targeted detection and reporting proactive information gathering efforts by Health Canada, which lead to the discovery of unreported adverse drug reactions and medical device incidents While the number of reports is increasing, we know that adverse drug reactions and medical device incidents continue to be under-reported in Canada and worldwide.Improving the Canada Vigilance ProgramHealth Canada continues to improve the quantity and quality of all incoming Canada Vigilance Program data by. Providing feedback to stakeholders on the quality of reports identifying and flagging duplicate reports in the Canada Vigilance database cleaning the data so it can be analyzed using automated data entry to reduce human error implementing mandatory reporting by hospitals of serious adverse drug reactions and medical device incidents (as of December 2019) About the 2019 dataThis page summarizes data on adverse reaction reports received by Health Canada during 2019 and key trends over the past 10 years. We present data on. Adverse reactions to drugs and natural health products incidents related to the use of medical devices recalls that occurred after low cost zithromax products were approved for sale in CanadaData on adverse drug reactions and medical device incidents are based on reports sent to Health Canada through the Canada Vigilance Program. Recall data are based on the work of the Regulatory Operations and Enforcement Branch.

The statistics on this page are based only on Canadian reports low cost zithromax and do not include data from other countries (foreign reports).Adverse reactions to drugs and natural health productsTotal number of reportsIn 2019, Health Canada received 96,559 domestic reports.Over the last 10 years. The number of Canadian reports has increased over 4-fold (from 22,211 reports in 2010 to 96,559 reports in 2019) Health Canada received an average of 8,000 Canadian reports per month in 2019 Source of reportsIn 2019. 90,350 (93.6%) of reports came from mandatory reporters Canada has a strong reporting system in place to ensure that industry is responsible for their products and that they submit reports in a timely manner 3,849 (4.0%) were voluntary reports from health professionals working outside of hospitals 956 (1.0%) were voluntary reports from the general population 1,248 (1.3%) were from hospitals, which, until December 16, 2019, submitted reports to Health Canada on a voluntary basis Going forward, Health Canada anticipates receiving a larger volume of reports from hospitals because of the new mandatory reporting regulations Over the last 10 years. 9 out of 10 low cost zithromax reports received at Health Canada were submitted by industryTypes of reported productsOne or more drugs or natural health products may be mentioned in a report because the reporter suspects they played a role in the adverse reaction.In 2019. A total of 208,383 drugs or natural health products were mentioned in the 96,559 reports sent to Health Canada pharmaceutical drug products were most often reported, at 68.1% biotechnological products were the second most frequently reported, at 28.1% within these product categories, the specific products most often reported were.

immunosuppressants (drugs that aim to reduce the activity of the body’s immune system) at 32.5% of all reported suspected products anti-neoplastic agents (drugs used to treat cancer) at 16.4% of all reported suspected products Over the last 10 years. The most common products reported each year in adverse drug reactions have been immunosuppressants and low cost zithromax anti-neoplastic agents these numbers reflect the. large number of anti-neoplastic agents approved for use in Canada known risks associated with these products large number of patient reporting programs in place for these products severity of the underlying disease in the population being treated each year, more drugs and natural health products are included in the adverse reactions reported to Health Canada from 25,668 reported products in 2010 to 208,383 reported products in 2019, an 8-fold increase this may be due to improved reporting mechanisms and increased general awareness of the risks involved in using multiple products with the reporting of more drugs and natural health products, we can look at product interactions seen in real-world situations involving Canadians with complex medical needs Adverse reactionsA report may mention more than one adverse reaction. In 2019 low cost zithromax. 420,120 adverse reactions were mentioned in the reports sent to Health Canada the top 4 reported adverse reactions included.

general disorders and administration site conditions, such as pain or weakness (96,640, or 23.0%) gastrointestinal disorders, such as vomiting or diarrhea (37,892, or 9.0%) investigations that include performing tests and physical examinations (33,651, or 8.0%) musculoskeletal and connective tissue disorders resulting in swelling or joint pain (33,531, or 8.0%) Over the last 10 years. Each year, more adverse reactions are included in the reports sent to Health Canada from low cost zithromax 79,249 adverse reactions in 2010 to 420,120 reported reactions in 2019, a 5-fold increase this may be due to improved reporting mechanisms if more reporters report similar details about adverse reactions, this will help to reinforce ongoing issues seen with certain products this may signal a potential public health issue for further review OutcomesIn 2019. 7 out of 10 (67,754, or 70.2%) adverse reactions reported to Health Canada were of a serious natureOver the last 10 years. The majority of adverse reaction reports were serious because. regulated parties are low cost zithromax legally obligated to report all serious reactions to Health Canada health professionals and consumers are more likely to report serious reactions that result in harm We make it a priority to review the most serious product safety issues affecting Canadians.

However, all reports are important. Together, they help to flag potential product low cost zithromax safety issues .In 2019. 6,119 (6.3%) reports mentioned a suspected link between a death that had occurred and the use of a drug or natural health product 18,852 (19.5%) reports mentioned hospitalization 2,483 (2.6%) reports mentioned the occurrence of a potentially life-threatening condition 193 (0.2%) reports mentioned a congenital anomaly (birth defect) 52,119 (54.0%) reports indicated that, without intervention, the reported adverse reaction could have resulted in a serious outcomeOutcomes are complex and may be the result of multiple factors, including existing medical conditions or the progression of an illness. A reported outcome may not be directly caused by the use of a drug or natural health product. Increasing the quantity and quality of reports submitted to low cost zithromax Health Canada can provide more robust evidence and help to determine if there is a link to specific products.

This in turn can keep Canadians safer from the harmful effects of certain health products. Medical device incidentsTotal number of incidentsIn 2019, Health Canada received information about 25,235 domestic incidents.Over the last 10 years. The number of Canadian incidents has increased almost 4-fold (from 6,326 incidents in 2010 to 24,726 low cost zithromax incidents in 2019) an average of 2,000 Canadian incidents were reported each month in 2019Source of reportsIn 2019. 22,809 (92.2%) incidents were reported by industry Canada has a strong reporting system in place where industry is held accountable for their products and must report incidents in a timely manner to Health Canada as per the Medical Devices Regulations 1,018 (4.1%) incidents were based on voluntary reports from the community Voluntary reports from consumers, health care professionals and others add to the quality and quantity of incoming data and help provide a comprehensive picture of medical device problems or issues 554 (2.2%) incidents were reported by health care institutions participating in CMDSNet CMDSNet is a proactive surveillance program that encourages the reporting of medical device problem reports from participating institutions CMDSNet provides a complementary data source for post-market safety evaluations Over the last 10 years. 9 out of 10 incidents were reported by industryWith the introduction of mandatory reporting for all hospitals in December 2019, we anticipate receiving a larger volume of incident reports from hospitals in the future.Types of reported productsA medical device incident may involve more than one medical device.

This means that multiple devices may be described low cost zithromax in the reports sent to Health Canada.In 2019. A total of 25,519 suspected medical devices were mentioned in the incidents reported to Health Canada the most frequently reported devices were used in. general and plastic surgery (8,926, or 35.8%) general hospital settings (5,977, or 24.0%) cardiovascular care, like pacemakers, defibrillators and stents (2,478, low cost zithromax or 10.0%) Over the last 10 years prior to 2019. Devices for general hospital use (such as needles, catheters and syringes) were most often reported these incidents do not mean that these devices have more risk or cause more harm. Rather, they were.

reported more frequently to low cost zithromax Health Canada used more often more readily available when compared to other medical devices in more specialized categories In 2019. The category of general and plastic surgery (with devices such as electrodes, implants and surgical staplers) was the most reported this was due to the submission of a large number of reports related to breast implants this prompted Health Canada and its partners to. investigate the risks associated with some types of breast implants take some unsafe breast implant products off the market educate Canadians about breast implants Over the last 10 years. Each year, more suspected products are being reported in the medical device incidents sent to low cost zithromax Health Canada from 6,544 devices in 2010 to 25,519 devices in 2019, a 4-fold increase this may be due to improved reporting mechanisms and increased general awareness of the importance of reporting increased reporting gives us the ability to better understand what happens when people use more than one device at a time Device issuesMore than one issue or problem with a device may be mentioned in a medical device incident. In 2019.

28,124 issues related low cost zithromax to the use of medical devices were experienced material integrity problems (for example, material rupture, a burst container or vessel, or breaking) were mentioned 28.1% of the time mechanical problems (especially fluid leaks) were mentioned 21.1% of the time Over the last 10 years. The types of reported issues may vary from year to year more issues with medical devices are being included in the reports sent to Health Canada from 374 issues in 2010 to 28,124 issues in 2019 this is likely due to improved reporting practices, which are capturing more detail, and the increase in the number of incoming reports we are working on improving standardized reporting and categorization of information, which will increase the quality and usability of the dataHealth effectsMore than one health effect may be mentioned in a medical device incident.In 2019. 22,518 health effects were mentioned in incidents reported to Health Canada the top reported health effect was hyperglycemia (high blood sugar), which was reported in 1,896 (8.4%) incidents other reported health effects included. capsular contracture (when the capsule surrounding an implanted device distorts) (1,671, or 7.4%) injury (1,338, or 5.9%) pain (761, or low cost zithromax 3.4%) Over the last 10 years. Hyperglycemia has remained a top reported health effect this is not unexpected.

Devices that measure blood sugar, such as glucose meters and glucose monitoring systems, are some of the most frequently used medical devices in CanadaOutcomesIn 2019. 7,949 (34.5%) medical device incidents reported to Health Canada were low cost zithromax of a serious natureOver the last 10 years. The proportion of medical device incidents that were serious. varied between 10.3% and 19.6% from 2010 to 2018 jumped to over one-third of all incidents in 2019 this was due to the submission low cost zithromax of a large number of reports related to breast implants While priority is given to reports that are flagged as serious, all reports are important. Taken together, reports of medical device incidents may indicate a potential public health issue.

In 2019. 85 (0.4%) of all medical device incidents mentioned a possible link between a death that occurred and the use of a medical device however, the reported death may not have been directly caused by the suspected medical device incident surgery was the most common outcome reported in medical device incidents, with 3,365 incidents involving some form of surgery low cost zithromax 1,659 (49.3%) were revision surgeries (to fix an issue) 1,291 (38.4%) were explantations (removal of device) 1,274 (76.8%) of the reported revision surgeries and 1,079 (83.6%) of the explantations involved breast implants 3,791 (19.7%) incidents indicated that there was no reported patient involvement or consequences to a patient these incidents did not cause harm, but were reported to Health Canada because they were near misses under different circumstances or without intervention, serious harm may have occurred this information helps us work with industry to take action before an actual harm occurs Marketed health product recallsRecallsA drug or natural health product recall results in the correction of a distributed product or its removal from further sale or use.A medical device recall may result in. Removal of a product from further sale or use an on-site correction of the device an advisement to consumers of problems or potential problems with their device alternative labelling, which may include updates to instructions or manualsIn 2019, Health Canada received reports of. 162 pharmaceutical drug recalls 32 natural health product recalls 822 medical device recallsFor each report, the Department evaluates the recall strategy to ensure the appropriate corrective actions are taken and that the actions are effective. Identified health risksThere are 3 types of health low cost zithromax hazards.

Type I. Using or being exposed to a product will probably cause serious adverse health effects or death Type II. Using or being exposed to a product may cause temporary adverse health consequences or the possibility of serious adverse health effects is remote low cost zithromax Type III. Using or being exposed to a product is not likely to cause any adverse health effectsOf the 162 recalls of pharmaceutical drugs (prescription, non-prescription, radiopharmaceutical and active pharmaceutical ingredient). 52 were classified as type I 59 were low cost zithromax classified as type II 51 were classified as type IIIOf the 32 natural health product recalls.

16 were classified as type I 8 were classified as type II 8 were classified as type IIIOf the 822 medical device recalls. 37 were classified as type I 493 were classified as type II 292 were classified as type IIIRelated linksThe purpose of this notice is to advise stakeholders that Health Canada is proposing to. On this page Overview The low cost zithromax interim order (IO) introduced on May 23, 2020, provides another pathway to facilitate clinical trials for potential buy antibiotics drugs and medical devices, while upholding strong patient safety requirements and validity of trial data. The IO expires on May 23, 2021, at which time authorizations for clinical trials issued under the IO will end. In light of the ongoing buy antibiotics zithromax, there’s a need for sponsors of clinical trials for urgent drugs and devices used to diagnose, treat, mitigate or prevent buy antibiotics to continue their work.

Thus, Health Canada proposes low cost zithromax to maintain the flexibilities and regulatory oversight provided by the IO until at least the fall of 2021. We’re also proposing to bring forward regulatory amendments that would allow the flexibilities under the IO to continue after the fall of 2021. Sponsors will be able to continue conducting clinical trials authorized under low cost zithromax the IO as well as use this other pathway for new or later-phase buy antibiotics clinical trials. The proposed regulatory amendments will also. maintain patient safety while broadening access to these trials support the development of safe and effective therapies, yet through flexible measures will reduce the overall impact on the health care system contribute to ensuring further regulatory predictability to sponsors engaged in these important clinical trials The proposed regulatory amendments will have minimal changes in relation to the IO.

The only substantive change is to extend the records retention requirement beyond the duration of the IO low cost zithromax. For IO-authorized drug clinical trials, Health Canada is proposing to set most records retention requirements to 15 years. For medical devices, we’re proposing to align records requirements with those outlined in the Medical Devices Regulations. Neither the IO nor low cost zithromax these proposed transition regulations would apply to radiopharmaceutical drugs and Class I medical devices. Health Canada is also proposing to reduce most 25-year records retention requirements to 15 years for trials authorized through normal regulatory pathways.

This would apply low cost zithromax to drugs (excluding radiopharmaceuticals) as well as natural health products under the Food and Drug Regulations and Natural Health Products Regulations. Health Canada is considering certain exceptions to this proposal. Next steps Health Canada will consult with interested industry stakeholders, health system partners and other government departments on the proposed regulations. We will be holding a webinar and teleconference in low cost zithromax each official language in December 2020. Written comments are also welcome by January 25, 2021.

Once stakeholder input is considered, we will publish the transition regulations in the Canada Gazette and revised guidance. Contact us For more information or to provide comments about this notice, please email us at hc.policy.bureau.enquiries.sc@canada.ca. For more information on the proposed records retention requirements, please email us at hc.prsd-questionsdspr.sc@canada.ca. Related links.

Zithromax for chlamydia and gonorrhea

	Zithromax	Vantin	Neggram	Sumycin	Ciloxan
Cheapest price	Ask your Doctor	Yes	Yes	Ask your Doctor	Ask your Doctor
How long does stay in your system	Nearby pharmacy	Indian Pharmacy	At walmart	Pharmacy	Pharmacy
Best way to use	1000mg 60 tablet $224.95	100mg 90 tablet $149.95	500mg 88 tablet $114.90	250mg 90 tablet $75.00	0.3% 5ml 1 solution $12.00
How fast does work	No	Yes	Online	Yes	No
Take with alcohol	Yes	Online	Yes	Yes	No
Where to buy	Ask your Doctor	100mg	Ask your Doctor	You need consultation	Ask your Doctor

A 2870 g male infant was born at 36+1 weeks’ can you buy zithromax over the counter in canada gestation by cesarean zithromax for chlamydia and gonorrhea section due to mild polyhydramnios and a non-reassuring cardiotocography. An uasound at 31 weeks demonstrated transient hyperechogenic fetal bowel (HFB).At birth, the Apgar scores were 9 and 10. The abdominal zithromax for chlamydia and gonorrhea examination was unremarkable.He spontaneously passed meconium. After 20 hours, he developed left hemiabdominal distension with visible dilated bowel loop sign (figure 1) and bile-stained vomiting.Figure 1 ‘Bowel loop sign’ on abdominal wall due to a segmental intestinal dilatation.Abdominal radiography ….

A 2870 g male infant was born at 36+1 weeks’ gestation by cesarean section due to mild polyhydramnios and a non-reassuring low cost zithromax cardiotocography. An uasound at 31 weeks demonstrated transient hyperechogenic fetal bowel (HFB).At birth, the Apgar scores were 9 and 10. The abdominal examination was low cost zithromax unremarkable.He spontaneously passed meconium. After 20 hours, he developed left hemiabdominal distension with visible dilated bowel loop sign (figure 1) and bile-stained vomiting.Figure 1 ‘Bowel loop sign’ on abdominal wall due to a segmental intestinal dilatation.Abdominal radiography ….

What side effects may I notice from Zithromax?

Side effects that you should report to your prescriber or health care professional as soon as possible:

• dark yellow or brown urine;
• difficulty breathing; severe or watery diarrhea;
• skin rash, itching;
• irregular heartbeat, palpitations, or chest pain;
• vomiting;
• yellowing of the eyes or skin

Side effects that usually do not require medical attention (report to your prescriber or health care professional if they continue or are bothersome):

• diarrhea;
• dizziness, drowsiness;
• hearing loss;
• headache;
• increased sensitivity to the sun;
• nausea;
• stomach pain or cramps;
• tiredness;
• vaginal irritation, itching or discharge

This list may not describe all possible side effects.

Amoxicillin vs zithromax for bronchitis

WASHINGTON, DC – The Departments of Labor and Homeland Security have published a joint temporary final rule making available an additional 22,000 H-2B temporary nonagricultural guest worker visas for amoxicillin vs zithromax for bronchitis fiscal year 2021 to employers who are likely to suffer irreparable harm without these additional workers. Of the supplemental visas, 6,000 are reserved for nationals of the Northern Triangle countries of Honduras, El Salvador and Guatemala.DHS first announced the planned supplemental increase of 22,000 visas for the H-2B Temporary Non-Agricultural Worker program on April 20, 2021. The supplemental H-2B visa allocation consists of 16,000 visas available only to returning H-2B workers from one of the last three fiscal years (FY 2018, 2019 or 2020), and 6,000 visas for Northern Triangle nationals, who are exempt from the amoxicillin vs zithromax for bronchitis returning worker requirement. €œToday’s joint rule helps American businesses and addresses the need for robust worker protections,” said Secretary of Homeland Security Alejandro N.

Mayorkas. €œFor the first time, we are setting aside supplemental visas for noncitizens from Northern Triangle countries, in furtherance of President Biden’s and Vice President Harris’ direction to expand legal pathways for protection and opportunity for individuals from those countries.” “The temporary final rule is designed to prevent permanent and severe financial loss to U.S. Employers by supplementing the congressionally mandated H-2B visa cap, takes into account feedback from American businesses, employer organizations, and labor representatives, and is one piece of the administration’s broader comprehensive framework for managing migration throughout North and Central America,” said USCIS Acting Director Tracy L. Renaud.

€œThis rule incorporates several key provisions to ensure adequate safeguards for U.S. Workers and H-2B workers. The rule requires that employers take additional steps to recruit U.S. Workers, and provides for “portability,” which allows H-2B workers already in the U.S.

To begin employment with a new H-2B employer or agent once USCIS receives a timely filed, non-frivolous H-2B petition, but before the petition is approved. Portability enables H-2B workers to change employers more quickly if they encounter unsafe or abusive working conditions. DHS and the Department of Labor will also conduct a significant number of post-adjudication reviews to ensure compliance with the program’s requirements.” Starting May 25, eligible employers who have already completed a test of the U.S. Labor market to verify that there are no U.S.

Workers who are willing, qualified and able to perform the seasonal nonagricultural work can file Form I-129, Petition for a Nonimmigrant Worker to seek additional H-2B workers. They must submit an attestation with their petition to demonstrate their business is likely to suffer irreparable harm without a supplemental workforce. Additional details on eligibility and filing requirements are available in the temporary final rule and the Temporary Increase in H-2B Nonimmigrant Visas for FY 2021 webpage. For more information on USCIS and its programs, please visit uscis.gov or follow us on Twitter, Instagram, YouTube, Facebook and LinkedIn.ALBUQUERQUE, NM - The U.S.

Department of Labor, in partnership with El Centro de Igualdad y Derechos and NM Comunidades En Acción Y De Fé(CAFé), the New Mexico Workforce Solutions and Somos Un Pueblo Unido will present a Spanish-language webinar on the U.S. Department of Labor Wage and Hour Division’s Essential Workers ‒ Essential Protections initiative on May 26 at 5 p.m. MT.Grocery, healthcare, delivery service, retail, agricultural and other workers in essential industries have risked their health and that of their families in pursuit of a needed paycheck. The Wage and Hour Division is committed to ensuring that these and all workers receive the workplace protections the law provides.

Rapid changes in the workplace have recently left workers, their advocates and employers with many questions about wages, hours worked and time off for workers or their family members dealing with serious illness. The Fair Labor Standards Act and the Family and Medical Leave Act provide protections for workers that may be more crucial now than ever before. To address these concerns, the division is offering Spanish-language training on these critical workplace protections through the Essential Workers ‒ Essential Protections initiative. Attendance is free, but participants must register for the seminar in advance.

For questions, please contact Patricia Chavez at the Wage and Hour Division’s office at (505) 248-2674 or email Chavez.patricia@dol.gov. Lea En Español.

WASHINGTON, DC – The Departments of Labor and Homeland Security have published low cost zithromax a joint temporary final rule making available an additional 22,000 H-2B temporary nonagricultural guest worker visas for fiscal year 2021 to employers who are likely to suffer irreparable harm without these additional workers. Of the supplemental visas, 6,000 are reserved for nationals of the Northern Triangle countries of Honduras, El Salvador and Guatemala.DHS first announced the planned supplemental increase of 22,000 visas for the H-2B Temporary Non-Agricultural Worker program on April 20, 2021. The supplemental H-2B visa allocation consists of 16,000 visas available only to returning H-2B workers from one of the last three fiscal years (FY 2018, 2019 or 2020), and 6,000 visas for Northern Triangle nationals, who low cost zithromax are exempt from the returning worker requirement.

€œToday’s joint rule helps American businesses and addresses the need for robust worker protections,” said Secretary of Homeland Security Alejandro N. Mayorkas. €œFor the first time, we are setting aside supplemental visas for noncitizens from Northern Triangle countries, in furtherance of President Biden’s and Vice President Harris’ direction to expand legal pathways for protection and opportunity for individuals from those countries.” “The temporary final rule is designed to prevent permanent and severe financial loss to U.S.

Employers by supplementing the congressionally mandated H-2B visa cap, takes into account feedback from American businesses, employer organizations, and labor representatives, and is one piece of the administration’s broader comprehensive framework for managing migration throughout North and Central America,” said USCIS Acting Director Tracy L. Renaud. €œThis rule incorporates several key provisions to ensure adequate safeguards for U.S.

Workers and H-2B workers. The rule requires that employers take additional steps to recruit U.S. Workers, and provides for “portability,” which allows H-2B workers already in the U.S.

To begin employment with a new H-2B employer or agent once USCIS receives a timely filed, non-frivolous H-2B petition, but before the petition is approved. Portability enables H-2B workers to change employers more quickly if they encounter unsafe or abusive working conditions. DHS and the Department of Labor will also conduct a significant number of post-adjudication reviews to ensure compliance with the program’s requirements.” Starting May 25, eligible employers who have already completed a test of the U.S.

Labor market to verify that there are no U.S. Workers who are willing, qualified and able to perform the seasonal nonagricultural work can file Form I-129, Petition for a Nonimmigrant Worker to seek additional H-2B workers. They must submit an attestation with their petition to demonstrate their business is likely to suffer irreparable harm without a supplemental workforce.

Additional details on eligibility and filing requirements are available in the temporary final rule and the Temporary Increase in H-2B Nonimmigrant Visas for FY 2021 webpage. For more information on USCIS and its programs, please visit uscis.gov or follow us on Twitter, Instagram, YouTube, Facebook and LinkedIn.ALBUQUERQUE, NM - The U.S. Department of Labor, in partnership with El Centro de Igualdad y Derechos and NM Comunidades En Acción Y De Fé(CAFé), the New Mexico Workforce Solutions and Somos Un Pueblo Unido will present a Spanish-language webinar on the U.S.

Department of Labor Wage and Hour Division’s Essential Workers ‒ Essential Protections initiative on May 26 at 5 p.m. MT.Grocery, healthcare, delivery service, retail, agricultural and other workers in essential industries have risked their health and that of their families in pursuit of a needed paycheck. The Wage and Hour Division is committed to ensuring that these and all workers receive the workplace protections the law provides.

Rapid changes in the workplace have recently left workers, their advocates and employers with many questions about wages, hours worked and time off for workers or their family members dealing with serious illness. The Fair Labor Standards Act and the Family and Medical Leave Act provide protections for workers that may be more crucial now than ever before. To address these concerns, the division is offering Spanish-language training on these critical workplace protections through the Essential Workers ‒ Essential Protections initiative.

Attendance is free, but participants must register for the seminar in advance. For questions, please contact Patricia Chavez at the Wage and Hour Division’s office at (505) 248-2674 or email Chavez.patricia@dol.gov. Lea En Español.

How to get prescribed zithromax

Elon Musk on Friday unveiled a coin-sized prototype of a how to get prescribed zithromax brain implant developed by his startup Neuralink to enable people who are paralyzed to operate smartphones and robotic limbs with their thoughts — and said the company had worked to “dramatically simplify” the device since presenting an earlier version last summer.In an event live-streamed on YouTube to more than 150,000 viewers at one point, the company staged a demonstration in which Related Site it trotted out a pig named Gertrude that was said to have had the company’s device implanted in its head two months ago. The live stream showed what Musk claimed to be Gertrude’s real-time brain activity as it sniffed around a pen. At no point, though, did he provide evidence that the signals — rendered in beeps and bright blue wave patterns on screen — were, in fact, how to get prescribed zithromax emanating from the pig’s brain.A pig presented at a Neuralink demonstration was said to have one of the company’s brain implants in its head. YouTube screenshot“This is obviously sounding increasingly like a Black Mirror episode,” Musk said at one point during the event as he responded affirmatively to a question about whether the company’s implant could eventually be used to save and replay memories.

€œThe future’s going to be weird.”advertisement Musk said that in July Neuralink received a breakthrough device designation from the Food and Drug Administration — a regulatory pathway that could allow the company how to get prescribed zithromax to soon start a clinical trial in people with paraplegia and tetraplegia. The big reveal came after four former Neuralink employees told STAT that the company’s leaders have long fostered an internal culture characterized by rushed timelines and the “move fast and break things” ethos of a tech company — a pace sometimes at odds with the slow and incremental pace that’s typical of medical device development. Advertisement Friday’s event began, 40 minutes late, with a glossy video about the company’s work — and then how to get prescribed zithromax panned to Musk, standing in front of a blue curtain beside a gleaming new version of the company’s surgical “sewing machine” robot that could easily have been mistaken for a giant Apple device. Musk described the event as a “product demo” and said its primary purpose was to recruit potential new employees.

It was unclear whether the demonstration was taking how to get prescribed zithromax place at the company’s Fremont, Calif., headquarters or elsewhere. Musk proceeded to reveal the new version of Neuralink’s brain implant, which he said was designed to fit snugly into the top of the skull. Neuralink’s technological design has how to get prescribed zithromax changed significantly since its last big update in July 2019. At that time, the company’s brain implant system involved a credit-card sized device designed to be positioned behind the back of a person’s ear, with several wires stretching to the top of the skull.

After demonstrating the pig’s brain activity at Friday’s event, Musk showed video how to get prescribed zithromax footage of a pig walking on a treadmill and said Neuralink’s device could be used to “predict the position of limbs with high accuracy.” That capability would be critical to allowing someone using the device to do something like controlling a prosthetic limb, for example.Neuralink for months has signaled that it initially plans to develop its device for people who are paralyzed. It said at its July 2019 event that it wanted to start human testing by the end of 2020. Receiving the breakthrough device designation from the FDA — designed to how to get prescribed zithromax speed up the lengthy regulatory process — is a step forward, but it by no means guarantees that a device will receive a green light, either in a short or longer-term time frame. After Musk’s presentation, a handful of the company’s employees — all wearing masks, but seated only inches apart — joined him to take questions submitted on Twitter or from the small audience in the room.In typical fashion for a man who in 2018 sent a Tesla Roadster into space, Musk didn’t hesitate to use the event to cross-promote his electric car company.

Asked whether the Neuralink chip would allow people to summon their how to get prescribed zithromax Tesla telepathically, Musk responded. €œDefinitely — of course.”Matthew MacDougall, the company’s head neurosurgeon, appearing in scrubs, said the company had so far only implanted its technology into the brain’s cortical surface, the coaster-width layer enveloping the brain, but added that it hoped to go deeper in the future. Still, Musk how to get prescribed zithromax said. €œYou could solve blindness, you could solve paralysis, you could solve hearing — you can solve a lot just by interfacing with the cortex.”Musk and MacDougall said they hoped to eventually implant Neuralink’s devices — which they referred to on stage simply as “links” — in the deeper structures of the brain, such as in the hypothalamus, which is believed to play a critical role in mental illnesses including depression, anxiety, and PTSD.There were no updates at the event of Neuralink’s research in monkeys, which the company has been conducting in partnership with the University of California, Davis since 2017.

At last July’s event, Musk said — without providing evidence — that a monkey had controlled a computer with its brain.At that same July 2019 event, Neuralink released a preprint paper — published a few months later — that claimed to show that a series of Neuralink how to get prescribed zithromax electrodes implanted in the brains of rats could record neural signals. Critically, the work did not show where in the brain the implanted electrodes were recording from, for how long they were recording, or whether the recordings could be linked to any of the rats’ bodily movements.In touting Friday’s event — and Neuralink’s technological capabilities — on Twitter in recent weeks, Musk spoke of “AI symbiosis while u wait” and referenced the “matrix in the matrix” — a science-fiction reference about revealing the true nature of reality. The progress the company reported on how to get prescribed zithromax Friday fell far short of that. Neuralink’s prototype is ambitious, but it has yet to show evidence that it can match up to the brain-machine interfaces developed by academic labs and other companies.

Other groups have shown that they can listen in on neural activity and allow primates and people how to get prescribed zithromax to control a computer cursor with their brain — so-called “read-out” technology — and have also shown that they can use electrical stimulation to input information, such as a command or the heat of a hot cup of coffee, using “write-in” technology. Neuralink said on Friday that its technology would have both read-out and write-in capabilities.Musk acknowledged that Neuralink still has a long way to go. In closing the event after more how to get prescribed zithromax than 70 minutes, Musk said. €œThere’s a tremendous amount of work to be done to go from here to a device that is widely available and affordable and reliable.”Following the news this week of what appears to have been the first confirmed case of a buy antibiotics re, other researchers have been coming forward with their own reports.

One in Belgium, another in the Netherlands. And now, one in Nevada.What caught experts’ attention about the case of the 25-year-old Reno man was not that he appears to have contracted antibiotics (the name of the zithromax that causes buy antibiotics) a second time how to get prescribed zithromax. Rather, it’s that his second bout was more serious than his first.Immunologists had expected that if the immune response generated after an initial could not prevent a second case, then it should at least stave off more severe illness. That’s what occurred with the first known re case, in a 33-year-old Hong how to get prescribed zithromax Kong man.advertisement Still, despite what happened to the man in Nevada, researchers are stressing this is not a sky-is-falling situation or one that should result in firm conclusions.

They always presumed people would become vulnerable to buy antibiotics again some time after recovering from an initial case, based on how our immune systems respond to other respiratory zithromaxes, including other antibioticses. It’s possible that these early cases of re are outliers and have features that won’t apply to the tens of millions of other people who have already shaken off buy antibiotics.“There are millions and millions of cases,” said Michael Mina, how to get prescribed zithromax an epidemiologist at Harvard’s T.H. Chan School of Public Health. The real question that should get the most focus, Mina said, is, how to get prescribed zithromax “What happens to most people?.

€advertisement But with more re reports likely to make it into the scientific literature soon, and from there into the mainstream press, here are some things to look for in assessing them.What’s the deal with the Nevada case?. The Reno resident in question first tested positive for antibiotics in April after coming down with a sore throat, cough, and headache, as well as nausea and how to get prescribed zithromax diarrhea. He got better over time and later tested negative twice. But then, some 48 days how to get prescribed zithromax later, the man started experiencing headaches, cough, and other symptoms again.

Eventually, he became so sick that he had to be hospitalized and was found to have pneumonia.Researchers sequenced zithromax samples from both of his s and found they were different, providing evidence that this was a new distinct from the first. What happens when we how to get prescribed zithromax get buy antibiotics in the first case?. Researchers are finding that, generally, people who get buy antibiotics develop a healthy immune response replete with both antibodies (molecules that can block pathogens from infecting cells) and T cells (which help wipe out the zithromax). This is what happens after other viral s.In addition to fending off the zithromax the first how to get prescribed zithromax time, that immune response also creates memories of the zithromax, should it try to invade a second time.

It’s thought, then, that people who recover from buy antibiotics will typically be protected from another case for some amount of time. With other antibioticses, protection is thought to last for perhaps a little less than a year to about three years.But researchers can’t tell how to get prescribed zithromax how long immunity will last with a new pathogen (like antibiotics) until people start getting reinfected. They also don’t know exactly what mechanisms provide protection against buy antibiotics, nor do they know what levels of antibodies or T cells are required to signal that someone is protected through a blood test. (These are called the “correlates how to get prescribed zithromax of protection.”) Why do experts expect second cases to be milder?.

With other zithromaxes, protective immunity doesn’t just vanish one day. Instead, it wanes over time how to get prescribed zithromax. Researchers have then hypothesized that with antibiotics, perhaps our immune systems might not always be able to prevent it from getting a toehold in our cells — to halt entirely — but that it could still put up enough of a fight to guard us from getting really sick. Again, this is what happens with other respiratory pathogens.And it’s why some researchers actually looked at the how to get prescribed zithromax Hong Kong case with relief.

The man had mild to moderate buy antibiotics symptoms during the first case, but was asymptomatic the second time. It was a demonstration, experts said, of what you how to get prescribed zithromax would want your immune system to do. (The case was only detected because the man’s sample was taken at the airport when he arrived back in Hong Kong after traveling in Europe.)“The fact that somebody may get reinfected is not surprising,” Malik Peiris, a virologist at the University of Hong Kong, told STAT earlier this week about the first re. €œBut the re didn’t cause disease, so that’s the first point.”The Nevada case, then, provides a counterexample to that.

What kind of immune response did the person who was how to get prescribed zithromax reinfected generate initially?. Earlier, we described the robust immune response that most people who have buy antibiotics seem to mount. But that was a generalization how to get prescribed zithromax. s and the immune responses they induce in different people are “heterogeneous,” said Sarah Cobey, an epidemiologist and evolutionary biologist at the University of Chicago.Older people often generate weaker immune responses than younger people.

Some studies have also indicated that milder how to get prescribed zithromax cases of buy antibiotics induce tamer immune responses that might not provide as lasting or as thorough of a defense as stronger immune responses. The man in Hong Kong, for example, did not generate antibodies to the zithromax after his first , at least to the level that could be detected by blood tests. Perhaps that explains why he contracted the zithromax again just about 4 1/2 months after recovering from his initial .In the Nevada case, researchers did not test what kind of immune response the man generated after the how to get prescribed zithromax first case.“ is not some binary event,” Cobey said. And with re, “there’s going to be some viral replication, but the question is how much is the immune system getting engaged?.

€What might be broadly meaningful is when people who mounted robust immune responses start getting reinfected, how to get prescribed zithromax and how severe their second cases are. Are people who have buy antibiotics a second time infectious?. As discussed, immune memory can prevent how to get prescribed zithromax re. If it can’t, it might stave off serious illness.

But there’s a third aspect of this, too.“The most important question for re, with the most serious implications for controlling the zithromax, is whether reinfected people can transmit the zithromax to others,” Columbia how to get prescribed zithromax University virologist Angela Rasmussen wrote in Slate this week.Unfortunately, neither the Hong Kong nor the Reno studies looked at this question. But if most people who get reinfected don’t spread the zithromax, that’s obviously good news. What happens when how to get prescribed zithromax people broadly become susceptible again?. Whether it’s six months after the first or nine months or a year or longer, at some point, protection for most people who recover from buy antibiotics is expected to wane.

And without the arrival of a treatment and broad uptake of it, that could change the dynamics of local outbreaks.In how to get prescribed zithromax some communities, it’s thought that more than 20% of residents have experienced an initial buy antibiotics case, and are thus theoretically protected from another case for some time. That is still below the point of herd immunity — when enough people are immune that transmission doesn’t occur — but still, the fewer vulnerable people there are, the less likely spread is to occur.On the flip side though, if more people become susceptible to the zithromax again, that could increase the risk of transmission. Modelers are starting to how to get prescribed zithromax factor that possibility into their forecasts.A crucial question for which there is not an answer yet is whether what happened to the man in Reno, where the second case was more severe than the first, remains a rare occurrence, as researchers expect and hope. As the Nevada researchers wrote, “the generalizability of this finding is unknown.”An advocacy group has asked the Department of Defense to investigate what it called “an apparent failure” by Moderna (MRNA) to disclose millions of dollars in awards received from the Defense Advanced Research Projects Agency in patent applications the company filed for treatments.In a letter to the agency, Knowledge Ecology International explained that a review of dozens of patent applications found the company received approximately $20 million from the federal government in grants several years ago and the funds “likely” led to the creation of its treatment technology.

This was used to develop treatments to combat different zithromaxes, such as Zika and, later, the zithromax that causes buy antibiotics.In arguing for an investigation, the advocacy group maintained Moderna is obligated under federal law to disclose the grants how to get prescribed zithromax that led to nearly a dozen specific patent applications and explained the financial support means the U.S. Government would have certain rights over the patents. In other how to get prescribed zithromax words, U.S. Taxpayers would have an ownership stake in treatments developed by the company.advertisement “This clarifies the public’s right in the inventions,” said Jamie Love, who heads Knowledge Ecology International, a nonprofit that tracks patents and access to medicines issues.

€œThe disclosure (also) changes the narrative about who has financed the inventive activity, often how to get prescribed zithromax the most risky part of development.” One particular patent assigned to Moderna concerns methods and compositions that can be used specifically against antibioticses, including buy antibiotics. The patent names a Moderna scientist and a former Moderna scientist as inventors, both of which acknowledged performing work under the DARPA awards in two academic papers, according to the report by the advocacy group.advertisement The group examined the 126 patents assigned to Moderna or ModernaTx as well as 154 patent applications. €œDespite the evidence that multiple inventions were conceived in the course of research supported by the DARPA awards, not a single one of the patents or applications assigned to Moderna disclose U.S. Federal government how to get prescribed zithromax funding,” the report stated.[UPDATE.

A DARPA spokesman sent us this over the weekend. €œIt appears that all past and present DARPA awards to Moderna include the requirement to how to get prescribed zithromax report the role of government funding for related inventions. Further, DARPA is actively researching agency awards to Moderna to identify which patents and pending patents, if any at all, may be associated with DARPA support. This effort is ongoing.”]We asked Moderna for comment and will update you accordingly.The missive to the Department of Defense follows a recent analysis by Public Citizen, another advocacy group, indicating the National how to get prescribed zithromax Institutes of Health may own mRNA-1273, the Moderna treatment candidate for buy antibiotics.

The advocacy group noted the federal government filed multiple patents covering the treatment and two patent applications, in particular, list federal scientists as co-inventors.The analyses are part of a larger campaign among advocacy groups and others in the U.S. And elsewhere to how to get prescribed zithromax ensure that buy antibiotics medical products are available to poor populations around the world. The concern reflects the unprecedented global demand for therapies and treatments, and a race among wealthy nations to snap up supplies from treatment makers. In the U.S., the effort has focused on the extent to which the federal government has provided taxpayer dollars to different companies to help how to get prescribed zithromax fund their discoveries.

In some cases, advocates argue that federal funding matters because it clarifies the rights that the U.S. Government has to ensure a therapy or treatment is available to Americans on reasonable terms.One example has been how to get prescribed zithromax remdesivir, the Gilead Sciences (GILD) treatment being given to hospitalized buy antibiotics patients. The role played by the U.S. Government in developing remdesivir to combat antibioticses involved contributions from government personnel at such agencies how to get prescribed zithromax as the U.S.

Army Medical Research Institute of Infectious Diseases.As for the Moderna treatment, earlier this month, the company was awarded a $1.525 billion contract by the Department of Defense and the Department of Health and Human Services to manufacture and deliver 100 million doses of its buy antibiotics treatment. The agreement also includes an option to purchase another 400 million doses, although the terms how to get prescribed zithromax were not disclosed. In announcing the agreement, the government said it would ensure Americans receive the buy antibiotics treatment at no cost, although they may be charged by health care providers for administering a shot.In this instance, however, Love said the “letter is not about price or profits. It’s about (Moderna) not owning up to how to get prescribed zithromax DARPA funding inventions.

If the U.S. Wants to pay for all of the development of Moderna’s treatment, as Moderna now acknowledges, and throw in a few more billion now, and an option to spend billions more, it’s not unreasonable to have some transparency over who paid for their inventions.”This is not the first time how to get prescribed zithromax Moderna has been accused of insufficient disclosure. Earlier this month, Knowledge Ecology International and Public Citizen maintained the company failed to disclose development costs in a $955 million contract awarded by BARDA for its buy antibiotics treatment. In all, the federal government has awarded the company approximately $2.5 billion to develop the how to get prescribed zithromax treatment.The coming few weeks represent a crucial moment for an ambitious plan to try to secure buy antibiotics treatments for roughly 170 countries around the world without the deep pockets to compete for what will be scarce initial supplies.Under the plan, countries that want to pool resources to buy treatments must notify the World Health Organization and other organizers — Gavi, the treatment Alliance, as well as the Coalition for Epidemic Preparedness Innovations — of their intentions by Monday.

That means it’s fish-or-cut-bait time for the so-called COVAX facility.Already, wealthy countries — the United States, the United Kingdom, Japan, Canada, and Australia, among others, as well as the European Union — have opted to buy their own treatment, signing bilateral contracts with manufacturers that have secured billions of doses of treatment already. That raises how to get prescribed zithromax the possibility that less wealthy countries will be boxed out of supplies.advertisement And yet Richard Hatchett, the CEO of CEPI, insists there is a path to billions of doses of treatment for the rest of the world in 2021. STAT spoke with Hatchett this week. A transcript of the how to get prescribed zithromax conversation, lightly edited for clarity and length, follows.

You said this is a critical time for CEPI. Can you explain what needs to happen between now and mid-September for this joint purchasing approach to be a success?. Advertisement The critical moment is now for countries to commit to the COVAX facility, because that will enable us to secure ample quantities of treatment and then to be able to convey when that treatment is likely to become available based on current information.What how to get prescribed zithromax we’re now here asking countries to do is to indicate their intent to participate by Aug. 31, and to make a binding commitment by Sept.

18. And to provide funds in support of that binding commitment by early October. Our negotiations with companies are already taking place and it will be important for us from a planning purpose that countries indicate their intent to participate.Those binding commitments we think will be sufficient to allow us to then secure the advance purchase agreements, particularly with those companies that don’t have a prior contractual obligation to COVAX. And then obviously, we need the funds to live up to those advance purchase agreements.Is it possible this thing could still fall apart?.

There appears to be some concern COVAX has been boxed out by rich countries. There was always a possibility that there wouldn’t be sufficient uptake. But I think we’re very encouraged at this point by the level of commitment, both from countries that would be beneficiaries of the advance market commitment — that’s the lower-income, lower-middle-income countries — as well as the self-financing countries. To have over 170 countries expressing interest in participating — they see the value.We’re much more encouraged now that it’s not going to fall apart.

We still need to bring it off to maximize its value. And we’re right at the crunch moment where countries are going to have to make these commitments. So, the next month is really absolutely critical to the facility. I am confident at this point that the world recognizes the value and wants it to work.I’ve been keeping tabs on advance purchase agreements that have been announced.

And at this point, a small number of rich countries have nailed down a lot of treatment — more than 3 billion doses. How hard does that make your job?. The fact that they’re doing it creates anxiety among other countries. And that in itself can accelerate the pace.

So, I’m not going to say that we’re not watching that with concern.I will say that for COVAX and the facility, this is absolutely critical moment. I think we still have a window of opportunity between now and mid-September — when we’re asking that the self-financing countries to make their commitments — to make the facility real and to make it work. Between doses that are committed to COVAX through the access agreements and other agreements — these are discussions with partners that CEPI has funded as well as partners that CEPI has not funded — we still see a pathway for COVAX to well over 3 billion doses in 2021.I think it’s really important to bear in mind is that there are at least a few countries — and I think the U.S. And the U.K.

Most publicly — that may be in a situation of significant oversupply. I believe the U.S. And U.K. Numbers, if you add them together, would result in enough treatment for 600 million people to receive two doses of treatment each.

And, you know, there is no possible way that the U.S. Or the U.K. Can use that much treatment.So, there may be a lot of extra supply that looks like it’s been tied up sloshing around later. I don’t think that the bilateral deals that have been struck are going to prevent COVAX from achieving its goals.But if so much treatment has been pre-ordered by rich countries, can countries in the COVAX pool get enough for their needs?.

One of the things that we’ve argued through COVAX is that to control the zithromax or to end the acute phase of the zithromax to allow normalcy to start to reassert itself, you don’t have to vaccinate 100% of your population.You need to vaccinate those at greatest risk for bad outcomes and you need to vaccinate certain critical workers, particularly your health care workforce. And if you can achieve that goal, which for most countries means vaccinating between 20% and maybe 30% of the population, then you can transform the zithromax into something that is much more manageable. Then you can buy yourself time to vaccinate everybody who wants to be vaccinated.We’ve argued the COVAX facility really offers the world the best shot at doing that globally in the fastest possible way, as well as providing for equitable access. This is a case where doing the equitable thing is also doing the efficient thing.CEPI has provided funding to nine treatments.

Is it true that all those manufacturers aren’t required to provide the COVAX facility with treatment?. That is correct. One of the things that we did, and I think it was an important role that CEPI played early on, was that we moved money very, very quickly, in small increments. You know, some of the early contracts were only $5 million or $10 million, to get programs up and running while we potentially put in place much larger-scale, longer-term contracts.If you were doing it over again, would you have given money without strings attached?.

Yes, I think I would have. I think that was critically important to initiating programs.Our contract with Moderna was established in about 48 hours. And that provided critical funding to them to manufacture doses that got them into clinical trials within nine weeks of the genetic sequences [of the antibiotics zithromax] being released.And if you look at the nine programs that we’ve invested in, seven are in clinical trials. Two — the AstraZeneca program now and the Moderna program — are among the handful in Phase 3 clinical trials.

And, I think the number of projects that that we funded initially, which started in kind of a biotech or academic phase that have now been picked up by large multinational corporations, there’s at least four. The Themis program being picked up by Merck, Oxford University by AstraZeneca, the University of Queensland by CSL, and Clover being in partnership with GSK, I think that speaks to the quality of the programs that we selected.So, I think that combination of rapid review, speed of funding, getting those programs started, getting them oriented in the right direction, I think all of that is critical to where we are now.Companies that got money from CEPI to build out production capacity — that money came with strings attached, right?. Yes, exactly. So, where CEPI has made investments that create manufacturing, or secure manufacturing capacity, the commitment has been that the capacity that is attributable to the CEPI investment is committed — at least right of first refusal — to the global procurement facility.WASHINGTON — The Trump administration removed a top Food and Drug Administration communications official from her post on Friday in the wake of several controversial agency misstatements, a senior administration official confirmed to STAT.The spokeswoman, Emily Miller, had played a lead role in defending the FDA commissioner, Stephen Hahn, after he misrepresented data regarding the use of blood plasma from recovered buy antibiotics patients.

The New York Times first reported Miller’s ouster. Miller’s tenure at as the top FDA spokeswoman lasted only 11 days. Her appointment was viewed with alarm by agency officials who felt her presence at the agency was emblematic of broader political pressure from the Trump administration, STAT first reported earlier this week.advertisement Before joining the FDA, Miller had no experience in health or medicine. Her former role as assistant commissioner for media affairs is typically not an appointment filled by political appointees.

The FDA’s communications arm typically maintains a neutral, nonpolitical tone.Miller’s appointment particularly alarmed FDA staff and outside scientists given her history in right-wing political advocacy and conservatism journalism. Her résumé included a stint as a Washington Times columnist, where she penned columns with titles that include “New Obamacare ads make young women look like sluts,” and a 2013 book on gun rights titled “Emily Gets Her Gun. But Obama Wants to Take Yours.”advertisement She also worked as a reporter for One America News Network, a right-wing cable channel that frequently espouses conspiracy theories and has declared an open alliance with President Trump.Miller quickly made her presence known at the FDA. In the wake of Hahn’s misstatements on blood plasma, she aggressively defended the commissioner, falsely claiming in a tweet that the therapy “has shown to be beneficial for 35% of patients.” An FDA press release on blood plasma, issued less than a week after her appointment, similarly alarmed agency insiders by trumpeting the emergency authorization as “Another Achievement in Administration’s Fight Against [the] zithromax.”.

Elon Musk on Friday unveiled a coin-sized prototype of a brain implant developed by his startup Neuralink to enable people who are paralyzed to operate smartphones and robotic limbs with their thoughts — and said the company had worked to low cost zithromax “dramatically simplify” the device since presenting an earlier version last summer.In an event live-streamed on YouTube to more than 150,000 viewers at one point, the company staged a demonstration http://thetrunkseries.com/?p=179 in which it trotted out a pig named Gertrude that was said to have had the company’s device implanted in its head two months ago. The live stream showed what Musk claimed to be Gertrude’s real-time brain activity as it sniffed around a pen. At no point, though, did he low cost zithromax provide evidence that the signals — rendered in beeps and bright blue wave patterns on screen — were, in fact, emanating from the pig’s brain.A pig presented at a Neuralink demonstration was said to have one of the company’s brain implants in its head. YouTube screenshot“This is obviously sounding increasingly like a Black Mirror episode,” Musk said at one point during the event as he responded affirmatively to a question about whether the company’s implant could eventually be used to save and replay memories.

€œThe future’s going to be weird.”advertisement Musk said that in July Neuralink received a breakthrough device designation from the Food and Drug Administration — a regulatory pathway that could allow the company to soon start a clinical trial in people with paraplegia low cost zithromax and tetraplegia. The big reveal came after four former Neuralink employees told STAT that the company’s leaders have long fostered an internal culture characterized by rushed timelines and the “move fast and break things” ethos of a tech company — a pace sometimes at odds with the slow and incremental pace that’s typical of medical device development. Advertisement Friday’s event began, 40 minutes late, with a glossy video about the company’s work — and then panned to Musk, standing in front of a blue curtain beside a gleaming low cost zithromax new version of the company’s surgical “sewing machine” robot that could easily have been mistaken for a giant Apple device. Musk described the event as a “product demo” and said its primary purpose was to recruit potential new employees.

It was unclear whether the demonstration was taking low cost zithromax place at the company’s Fremont, Calif., headquarters or elsewhere. Musk proceeded to reveal the new version of Neuralink’s brain implant, which he said was designed to fit snugly into the top of the skull. Neuralink’s technological design has changed significantly since its last big update in July low cost zithromax 2019. At that time, the company’s brain implant system involved a credit-card sized device designed to be positioned behind the back of a person’s ear, with several wires stretching to the top of the skull.

After demonstrating the pig’s brain activity at Friday’s event, Musk showed video footage of a pig walking on a treadmill and said Neuralink’s device could be used low cost zithromax to “predict the position of limbs with high accuracy.” That capability would be critical to allowing someone using the device to do something like controlling a prosthetic limb, for example.Neuralink for months has signaled that it initially plans to develop its device for people who are paralyzed. It said at its July 2019 event that it wanted to start human testing by the end of 2020. Receiving the breakthrough device designation from the FDA — designed to speed up the lengthy regulatory process — is a step forward, but it by no means guarantees that low cost zithromax a device will receive a green light, either in a short or longer-term time frame. After Musk’s presentation, a handful of the company’s employees — all wearing masks, but seated only inches apart — joined him to take questions submitted on Twitter or from the small audience in the room.In typical fashion for a man who in 2018 sent a Tesla Roadster into space, Musk didn’t hesitate to use the event to cross-promote his electric car company.

Asked whether the Neuralink chip would allow people to summon their low cost zithromax Tesla telepathically, Musk responded. €œDefinitely — of course.”Matthew MacDougall, the company’s head neurosurgeon, appearing in scrubs, said the company had so far only implanted its technology into the brain’s cortical surface, the coaster-width layer enveloping the brain, but added that it hoped to go deeper in the future. Still, Musk said low cost zithromax. €œYou could solve blindness, you could solve paralysis, you could solve hearing — you can solve a lot just by interfacing with the cortex.”Musk and MacDougall said they hoped to eventually implant Neuralink’s devices — which they referred to on stage simply as “links” — in the deeper structures of the brain, such as in the hypothalamus, which is believed to play a critical role in mental illnesses including depression, anxiety, and PTSD.There were no updates at the event of Neuralink’s research in monkeys, which the company has been conducting in partnership with the University of California, Davis since 2017.

At last July’s event, Musk said — without providing evidence — that a monkey had controlled a computer with its brain.At that same July 2019 event, Neuralink released a preprint paper — published a few months later — that claimed to show that a series of low cost zithromax Neuralink electrodes implanted in the brains of rats could record neural signals. Critically, the work did not show where in the brain the implanted electrodes were recording from, for how long they were recording, or whether the recordings could be linked to any of the rats’ bodily movements.In touting Friday’s event — and Neuralink’s technological capabilities — on Twitter in recent weeks, Musk spoke of “AI symbiosis while u wait” and referenced the “matrix in the matrix” — a science-fiction reference about revealing the true nature of reality. The progress low cost zithromax the company reported on Friday fell far short of that. Neuralink’s prototype is ambitious, but it has yet to show evidence that it can match up to the brain-machine interfaces developed by academic labs and other companies.

Other groups have shown that they can listen in on neural activity and allow primates and people to control a computer low cost zithromax cursor with their brain — so-called “read-out” technology — and have also shown that they can use electrical stimulation to input information, such as a command or the heat of a hot cup of coffee, using “write-in” technology. Neuralink said on Friday that its technology would have both read-out and write-in capabilities.Musk acknowledged that Neuralink still has a long way to go. In closing the event after more than 70 low cost zithromax minutes, Musk said. €œThere’s a tremendous amount of work to be done to go from here to a device that is widely available and affordable and reliable.”Following the news this week of what appears to have been the first confirmed case of a buy antibiotics re, other researchers have been coming forward with their own reports.

One in Belgium, another in the Netherlands. And now, one low cost zithromax in Nevada.What caught experts’ attention about the case of the 25-year-old Reno man was not that he appears to have contracted antibiotics (the name of the zithromax that causes buy antibiotics) a second time. Rather, it’s that his second bout was more serious than his first.Immunologists had expected that if the immune response generated after an initial could not prevent a second case, then it should at least stave off more severe illness. That’s what occurred with the first known re case, low cost zithromax in a 33-year-old Hong Kong man.advertisement Still, despite what happened to the man in Nevada, researchers are stressing this is not a sky-is-falling situation or one that should result in firm conclusions.

They always presumed people would become vulnerable to buy antibiotics again some time after recovering from an initial case, based on how our immune systems respond to other respiratory zithromaxes, including other antibioticses. It’s possible low cost zithromax that these early cases of re are outliers and have features that won’t apply to the tens of millions of other people who have already shaken off buy antibiotics.“There are millions and millions of cases,” said Michael Mina, an epidemiologist at Harvard’s T.H. Chan School of Public Health. The real question that should get the most focus, Mina said, low cost zithromax is, “What happens to most people?.

€advertisement But with more re reports likely to make it into the scientific literature soon, and from there into the mainstream press, here are some things to look for in assessing them.What’s the deal with the Nevada case?. The Reno resident in question low cost zithromax first tested positive for antibiotics in April after coming down with a sore throat, cough, and headache, as well as nausea and diarrhea. He got better over time and later tested negative twice. But then, some 48 days later, the man started experiencing headaches, cough, and other low cost zithromax symptoms again.

Eventually, he became so sick that he had to be hospitalized and was found to have pneumonia.Researchers sequenced zithromax samples from both of his s and found they were different, providing evidence that this was a new distinct from the first. What happens when we get buy antibiotics in the first case? low cost zithromax. Researchers are finding that, generally, people who get buy antibiotics develop a healthy immune response replete with both antibodies (molecules that can block pathogens from infecting cells) and T cells (which help wipe out the zithromax). This is what happens after other viral s.In addition to fending off the zithromax the first time, that immune response also creates memories of the zithromax, should it try to invade a second low cost zithromax time.

It’s thought, then, that people who recover from buy antibiotics will typically be protected from another case for some amount of time. With other antibioticses, protection is thought to last for perhaps a little less than a year to about three years.But researchers can’t tell how long immunity will last with a new pathogen (like antibiotics) low cost zithromax until people start getting reinfected. They also don’t know exactly what mechanisms provide protection against buy antibiotics, nor do they know what levels of antibodies or T cells are required to signal that someone is protected through a blood test. (These are called the “correlates of protection.”) Why do low cost zithromax experts expect second cases to be milder?.

With other zithromaxes, protective immunity doesn’t just vanish one day. Instead, it wanes over low cost zithromax time. Researchers have then hypothesized that with antibiotics, perhaps our immune systems might not always be able to prevent it from getting a toehold in our cells — to halt entirely — but that it could still put up enough of a fight to guard us from getting really sick. Again, this is what happens with other respiratory pathogens.And it’s why some researchers low cost zithromax actually looked at the Hong Kong case with relief.

The man had mild to moderate buy antibiotics symptoms during the first case, but was asymptomatic the second time. It was a demonstration, experts said, of low cost zithromax what you would want your immune system to do. (The case was only detected because the man’s sample was taken at the airport when he arrived back in Hong Kong after traveling in Europe.)“The fact that somebody may get reinfected is not surprising,” Malik Peiris, a virologist at the University of Hong Kong, told STAT earlier this week about the first re. €œBut the re didn’t cause disease, so that’s the first point.”The Nevada case, then, provides a counterexample to that.

What kind of immune response low cost zithromax did the person who was reinfected generate initially?. Earlier, we described the robust immune response that most people who have buy antibiotics seem to mount. But that low cost zithromax was a generalization. s and the immune responses they induce in different people are “heterogeneous,” said Sarah Cobey, an epidemiologist and evolutionary biologist at the University of Chicago.Older people often generate weaker immune responses than younger people.

Some studies have also indicated that milder cases of buy antibiotics induce tamer immune responses that might not provide as lasting or as thorough of low cost zithromax a defense as stronger immune responses. The man in Hong Kong, for example, did not generate antibodies to the zithromax after his first , at least to the level that could be detected by blood tests. Perhaps that explains why he contracted the zithromax again just about 4 1/2 months after recovering from his initial .In the Nevada case, researchers did not test what kind of immune response the man generated after the first case.“ is low cost zithromax not some binary event,” Cobey said. And with re, “there’s going to be some viral replication, but the question is how much is the immune system getting engaged?.

€What might low cost zithromax be broadly meaningful is when people who mounted robust immune responses start getting reinfected, and how severe their second cases are. Are people who have buy antibiotics a second time infectious?. As discussed, immune memory can prevent low cost zithromax re. If it can’t, it might stave off serious illness.

But there’s a third aspect of this, too.“The most important question for re, with the most serious implications for controlling the zithromax, is whether reinfected people can transmit the zithromax to others,” Columbia University virologist Angela Rasmussen wrote in Slate this week.Unfortunately, neither the Hong Kong nor the low cost zithromax Reno studies looked at this question. But if most people who get reinfected don’t spread the zithromax, that’s obviously good news. What happens low cost zithromax when people broadly become susceptible again?. Whether it’s six months after the first or nine months or a year or longer, at some point, protection for most people who recover from buy antibiotics is expected to wane.

And without the arrival of a treatment and broad uptake of it, that could change the dynamics of low cost zithromax local outbreaks.In some communities, it’s thought that more than 20% of residents have experienced an initial buy antibiotics case, and are thus theoretically protected from another case for some time. That is still below the point of herd immunity — when enough people are immune that transmission doesn’t occur — but still, the fewer vulnerable people there are, the less likely spread is to occur.On the flip side though, if more people become susceptible to the zithromax again, that could increase the risk of transmission. Modelers are starting to factor that possibility into their forecasts.A crucial question for which there is not an answer yet is whether what happened to low cost zithromax the man in Reno, where the second case was more severe than the first, remains a rare occurrence, as researchers expect and hope. As the Nevada researchers wrote, “the generalizability of this finding is unknown.”An advocacy group has asked the Department of Defense to investigate what it called “an apparent failure” by Moderna (MRNA) to disclose millions of dollars in awards received from the Defense Advanced Research Projects Agency in patent applications the company filed for treatments.In a letter to the agency, Knowledge Ecology International explained that a review of dozens of patent applications found the company received approximately $20 million from the federal government in grants several years ago and the funds “likely” led to the creation of its treatment technology.

This was used to develop treatments to combat different zithromaxes, such as Zika and, later, the zithromax that causes buy antibiotics.In arguing for an investigation, low cost zithromax the advocacy group maintained Moderna is obligated under federal law to disclose the grants that led to nearly a dozen specific patent applications and explained the financial support means the U.S. Government would have certain rights over the patents. In other low cost zithromax words, U.S. Taxpayers would have an ownership stake in treatments developed by the company.advertisement “This clarifies the public’s right in the inventions,” said Jamie Love, who heads Knowledge Ecology International, a nonprofit that tracks patents and access to medicines issues.

€œThe disclosure (also) changes the narrative about who has financed the inventive activity, often the most low cost zithromax risky part of development.” One particular patent assigned to Moderna concerns methods and compositions that can be used specifically against antibioticses, including buy antibiotics. The patent names a Moderna scientist and a former Moderna scientist as inventors, both of which acknowledged performing work under the DARPA awards in two academic papers, according to the report by the advocacy group.advertisement The group examined the 126 patents assigned to Moderna or ModernaTx as well as 154 patent applications. €œDespite the http://www.bersta.at/service/ evidence that multiple inventions were conceived in the course of research supported by the DARPA awards, not a single one of the patents or applications assigned to Moderna disclose U.S. Federal government low cost zithromax funding,” the report stated.[UPDATE.

A DARPA spokesman sent us this over the weekend. €œIt appears that all past and present DARPA awards low cost zithromax to Moderna include the requirement to report the role of government funding for related inventions. Further, DARPA is actively researching agency awards to Moderna to identify which patents and pending patents, if any at all, may be associated with DARPA support. This effort is ongoing.”]We asked Moderna for comment and will update you accordingly.The missive to the Department of Defense follows a recent analysis by Public Citizen, another low cost zithromax advocacy group, indicating the National Institutes of Health may own mRNA-1273, the Moderna treatment candidate for buy antibiotics.

The advocacy group noted the federal government filed multiple patents covering the treatment and two patent applications, in particular, list federal scientists as co-inventors.The analyses are part of a larger campaign among advocacy groups and others in the U.S. And elsewhere to ensure that buy antibiotics medical products are available to poor populations around the low cost zithromax world. The concern reflects the unprecedented global demand for therapies and treatments, and a race among wealthy nations to snap up supplies from treatment makers. In the U.S., the effort has focused on low cost zithromax the extent to which the federal government has provided taxpayer dollars to different companies to help fund their discoveries.

In some cases, advocates argue that federal funding matters because it clarifies the rights that the U.S. Government has to ensure a therapy or treatment is available to Americans on reasonable terms.One low cost zithromax example has been remdesivir, the Gilead Sciences (GILD) treatment being given to hospitalized buy antibiotics patients. The role played by the U.S. Government in developing remdesivir to combat antibioticses involved contributions from government personnel at such agencies as the U.S low cost zithromax.

Army Medical Research Institute of Infectious Diseases.As for the Moderna treatment, earlier this month, the company was awarded a $1.525 billion contract by the Department of Defense and the Department of Health and Human Services to manufacture and deliver 100 million doses of its buy antibiotics treatment. The agreement also includes an option to purchase another 400 million doses, although the terms were not disclosed low cost zithromax. In announcing the agreement, the government said it would ensure Americans receive the buy antibiotics treatment at no cost, although they may be charged by health care providers for administering a shot.In this instance, however, Love said the “letter is not about price or profits. It’s about low cost zithromax (Moderna) not owning up to DARPA funding inventions.

If the U.S. Wants to pay for all of the development of Moderna’s treatment, as Moderna now acknowledges, and throw in a few more billion now, and an option to spend billions more, it’s not unreasonable to have some transparency over who paid for their inventions.”This low cost zithromax is not the first time Moderna has been accused of insufficient disclosure. Earlier this month, Knowledge Ecology International and Public Citizen maintained the company failed to disclose development costs in a $955 million contract awarded by BARDA for its buy antibiotics treatment. In all, the federal government has awarded the company approximately $2.5 billion to develop the treatment.The coming few weeks represent a crucial moment for an ambitious plan to try to secure buy antibiotics treatments for roughly 170 countries around the world without the deep pockets to compete for what will be scarce initial supplies.Under the plan, countries that want to pool resources to buy treatments must notify the World Health Organization and other organizers — Gavi, the treatment Alliance, as well as the Coalition for Epidemic Preparedness Innovations low cost zithromax — of their intentions by Monday.

That means it’s fish-or-cut-bait time for the so-called COVAX facility.Already, wealthy countries — the United States, the United Kingdom, Japan, Canada, and Australia, among others, as well as the European Union — have opted to buy their own treatment, signing bilateral contracts with manufacturers that have secured billions of doses of treatment already. That raises the low cost zithromax possibility that less wealthy countries will be boxed out of supplies.advertisement And yet Richard Hatchett, the CEO of CEPI, insists there is a path to billions of doses of treatment for the rest of the world in 2021. STAT spoke with Hatchett this week. A transcript of the conversation, low cost zithromax lightly edited for clarity and length, follows.

You said this is a critical time for CEPI. Can you explain what needs to happen between now and mid-September for this joint purchasing approach to be a success?. Advertisement The critical moment is now for countries to commit to the COVAX facility, because that will enable us to secure ample quantities of treatment and then to be able to convey when that treatment is likely to become available based on current information.What we’re now here asking countries to do is to indicate their intent to participate by Aug low cost zithromax. 31, and to make a binding commitment by Sept.

18. And to provide funds in support of that binding commitment by early October. Our negotiations with companies are already taking place and it will be important for us from a planning purpose that countries indicate their intent to participate.Those binding commitments we think will be sufficient to allow us to then secure the advance purchase agreements, particularly with those companies that don’t have a prior contractual obligation to COVAX. And then obviously, we need the funds to live up to those advance purchase agreements.Is it possible this thing could still fall apart?.

There appears to be some concern COVAX has been boxed out by rich countries. There was always a possibility that there wouldn’t be sufficient uptake. But I think we’re very encouraged at this point by the level of commitment, both from countries that would be beneficiaries of the advance market commitment — that’s the lower-income, lower-middle-income countries — as well as the self-financing countries. To have over 170 countries expressing interest in participating — they see the value.We’re much more encouraged now that it’s not going to fall apart.

We still need to bring it off to maximize its value. And we’re right at the crunch moment where countries are going to have to make these commitments. So, the next month is really absolutely critical to the facility. I am confident at this point that the world recognizes the value and wants it to work.I’ve been keeping tabs on advance purchase agreements that have been announced.

And at this point, a small number of rich countries have nailed down a lot of treatment — more than 3 billion doses. How hard does that make your job?. The fact that they’re doing it creates anxiety among other countries. And that in itself can accelerate the pace.

So, I’m not going to say that we’re not watching that with concern.I will say that for COVAX and the facility, this is absolutely critical moment. I think we still have a window of opportunity between now and mid-September — when we’re asking that the self-financing countries to make their commitments — to make the facility real and to make it work. Between doses that are committed to COVAX through the access agreements and other agreements — these are discussions with partners that CEPI has funded as well as partners that CEPI has not funded — we still see a pathway for COVAX to well over 3 billion doses in 2021.I think it’s really important to bear in mind is that there are at least a few countries — and I think the U.S. And the U.K.

Most publicly — that may be in a situation of significant oversupply. I believe the U.S. And U.K. Numbers, if you add them together, would result in enough treatment for 600 million people to receive two doses of treatment each.

And, you know, there is no possible way that the U.S. Or the U.K. Can use that much treatment.So, there may be a lot of extra supply that looks like it’s been tied up sloshing around later. I don’t think that the bilateral deals that have been struck are going to prevent COVAX from achieving its goals.But if so much treatment has been pre-ordered by rich countries, can countries in the COVAX pool get enough for their needs?.

One of the things that we’ve argued through COVAX is that to control the zithromax or to end the acute phase of the zithromax to allow normalcy to start to reassert itself, you don’t have to vaccinate 100% of your population.You need to vaccinate those at greatest risk for bad outcomes and you need to vaccinate certain critical workers, particularly your health care workforce. And if you can achieve that goal, which for most countries means vaccinating between 20% and maybe 30% of the population, then you can transform the zithromax into something that is much more manageable. Then you can buy yourself time to vaccinate everybody who wants to be vaccinated.We’ve argued the COVAX facility really offers the world the best shot at doing that globally in the fastest possible way, as well as providing for equitable access. This is a case where doing the equitable thing is also doing the efficient thing.CEPI has provided funding to nine treatments.

Is it true that all those manufacturers aren’t required to provide the COVAX facility with treatment?. That is correct. One of the things that we did, and I think it was an important role that CEPI played early on, was that we moved money very, very quickly, in small increments. You know, some of the early contracts were only $5 million or $10 million, to get programs up and running while we potentially put in place much larger-scale, longer-term contracts.If you were doing it over again, would you have given money without strings attached?.

Yes, I think I would have. I think that was critically important to initiating programs.Our contract with Moderna was established in about 48 hours. And that provided critical funding to them to manufacture doses that got them into clinical trials within nine weeks of the genetic sequences [of the antibiotics zithromax] being released.And if you look at the nine programs that we’ve invested in, seven are in clinical trials. Two — the AstraZeneca program now and the Moderna program — are among the handful in Phase 3 clinical trials.

And, I think the number of projects that that we funded initially, which started in kind of a biotech or academic phase that have now been picked up by large multinational corporations, there’s at least four. The Themis program being picked up by Merck, Oxford University by AstraZeneca, the University of Queensland by CSL, and Clover being in partnership with GSK, I think that speaks to the quality of the programs that we selected.So, I think that combination of rapid review, speed of funding, getting those programs started, getting them oriented in the right direction, I think all of that is critical to where we are now.Companies that got money from CEPI to build out production capacity — that money came with strings attached, right?. Yes, exactly. So, where CEPI has made investments that create manufacturing, or secure manufacturing capacity, the commitment has been that the capacity that is attributable to the CEPI investment is committed — at least right of first refusal — to the global procurement facility.WASHINGTON — The Trump administration removed a top Food and Drug Administration communications official from her post on Friday in the wake of several controversial agency misstatements, a senior administration official confirmed to STAT.The spokeswoman, Emily Miller, had played a lead role in defending the FDA commissioner, Stephen Hahn, after he misrepresented data regarding the use of blood plasma from recovered buy antibiotics patients.

The New York Times first reported Miller’s ouster. Miller’s tenure at as the top FDA spokeswoman lasted only 11 days. Her appointment was viewed with alarm by agency officials who felt her presence at the agency was emblematic of broader political pressure from the Trump administration, STAT first reported earlier this week.advertisement Before joining the FDA, Miller had no experience in health or medicine. Her former role as assistant commissioner for media affairs is typically not an appointment filled by political appointees.

The FDA’s communications arm typically maintains a neutral, nonpolitical tone.Miller’s appointment particularly alarmed FDA staff and outside scientists given her history in right-wing political advocacy and conservatism journalism. Her résumé included a stint as a Washington Times columnist, where she penned columns with titles that include “New Obamacare ads make young women look like sluts,” and a 2013 book on gun rights titled “Emily Gets Her Gun. But Obama Wants to Take Yours.”advertisement She also worked as a reporter for One America News Network, a right-wing cable channel that frequently espouses conspiracy theories and has declared an open alliance with President Trump.Miller quickly made her presence known at the FDA. In the wake of Hahn’s misstatements on blood plasma, she aggressively defended the commissioner, falsely claiming in a tweet that the therapy “has shown to be beneficial for 35% of patients.” An FDA press release on blood plasma, issued less than a week after her appointment, similarly alarmed agency insiders by trumpeting the emergency authorization as “Another Achievement in Administration’s Fight Against [the] zithromax.”.

How to use zithromax

The threat how to use zithromax of buy antibiotics and the coordinated policy responses playing out in real time around Can you buy zithromax over the counter the globe are unprecedented. Evidence can help light the path forward. Together with our partners, Mathematica is applying our unique knowledge and experience at the intersection of data, analytics, policy, and practice to help address today’s complex challenges related to buy antibiotics. Mathematica, Comagine Health, and Allegis recently joined the Department of Health and other stakeholders to how to use zithromax implement the Washington State buy antibiotics Contact Tracing Partnership. In addition, the state of Connecticut engaged Mathematica to assess and improve its response to buy antibiotics in long-term care facilities.

And by working in partnership with OnPacePlus, Mathematica has implemented a workforce-readiness dashboard for employers to help ensure the safety and efficiency of their workforce. Here are some additional projects that help address the zithromax.Getting back to school safelyUniversity of California, San Diego, Return to Learn programInformed decisions about how we can safely return to how to use zithromax schools and college campuses require leading-edge, evidence-based approaches. Universities, in particular, face important decisions regarding conditions for reopening and strategies to detect and prevent outbreaks. We’re working closely with researchers at the University of California, San Diego (UCSD), on aspects of their Return to Learn program. The program encompasses an adaptive strategy of risk mitigation, viral monitoring, and public health intervention to detect buy antibiotics outbreaks early and prevent their spread on campus.Mathematica’s buy antibiotics agent-based computational model (ABM) for how to use zithromax educational institutions can simulate the campus at opening and throughout the year under hundreds of scenarios.

Mathematica’s simulations allow UCSD to bring data-driven decision making to its campus reopening plan, informing decisions surrounding student housing density, in-person class structure, general campus-wide buy antibiotics policy, and student testing frequency. The ABM will also support UCSD as students return to campus. The Return to Learn program will continuously monitor and integrate real-time data—including asymptomatic and symptomatic testing, wastewater analyses, proximity data, how to use zithromax molecular data, survey data, contact-tracing data, and campus data (such as housing and class registration). The program monitoring also incorporates contextual information about geography, contact structure, behavior, and epidemiology. Mathematica’s ABM will evolve with the data stream from the wider Return to Learn effort, refining forecasts, answering new questions, and anticipating outbreaks.K–12 guidanceIn May 2020, the Pennsylvania Department of Education (PDE) approached the Regional Educational Laboratory (REL) Mid-Atlantic, led by Mathematica, for analytic support of its effort to produce guidance for reopening school buildings in the midst of the buy antibiotics zithromax.

REL Mid-Atlantic partnered with PDE on a three-part project, which included (1) examining emerging evidence on buy antibiotics’s public-health and educational implications for schools, (2) interviewing a wide range of Pennsylvania stakeholders to assess concerns and challenges related to reopening school buildings, and (3) modifying Mathematica’s buy antibiotics ABM to assess likely disease spread among students and school staff under various approaches to reopening school buildings. Findings are available in a memo and serve as the foundation for a publicly available tool for exploring the spread of buy antibiotics among students, faculty, and staff at K–12 schools under different approaches to school reopenings.Using wastewater to detect outbreaksApplying lessons from more than three years of work on the opioid epidemic and successfully tracking community-level wastewater measures, Mathematica is working to develop insights how to use zithromax for buy antibiotics zithromax management. With more than 15,000 wastewater treatment plants around the country already collecting samples to measure environmental pollutants, wastewater surveillance holds promise for efficiently conducting rapid, repeated, community-wide buy antibiotics testing using infrastructure that many municipalities already have in place.To validate our approach to translating wastewater data for zithromax management, we recently completed a wastewater pilot study to assess buy antibiotics exposure in a rural North Carolina community that is home to a major university population. In partnership with the Tuckaseigee Water and Sewer Authority, Jackson County Department of Public Health, and the University of Wisconsin’s School of Freshwater Sciences, we examined how trends in antibiotics viral levels measured in wastewater aligned with trends in confirmed buy antibiotics case counts and a proxy measure based on doctor visits and buy antibiotics-like symptom reports. To contextualize the wastewater data for public health officials, Mathematica built a generalizable how to use zithromax dynamic wastewater dashboard.

The dashboard brings together wastewater data with community data on numbers of tests conducted, confirmed cases, hospitalizations, and deaths. Jackson County’s zithromax vulnerability. Changes in how to use zithromax population mobility. And the prevalence of risk factors for severe buy antibiotics presentation. Our results revealed strong trend alignment between the data sources over the four-week sampling period.

Moreover, the study confirms findings from Yale University researchers that wastewater data can serve as a leading indicator for changes in buy antibiotics risk—the wastewater data provided a lead time of eight to how to use zithromax nine days for changes in antibiotics viral levels compared to confirmed case counts or proxy indicators.Evaluation Technical Assistance Brief #5 Publisher. Princeton, NJ. Mathematica Sep 10, 2020 Authors Russell Cole Impact evaluations in child welfare and other fields often struggle because of smaller-than-planned sample sizes. Multiple factors might contribute to the how to use zithromax problem. The program’s target population might be smaller than was projected, or recruiting and enrolling eligible participants into the study might have proven unexpectedly difficult.

Small sample sizes can create difficulties and limitations when estimating the impacts of programs—especially when you had not planned for them during the evaluation design phase. This brief, presented as a series of questions and answers, addresses this specific problem and offers guidance for analyzing data and reporting findings when it occurs..

The threat of buy antibiotics and the coordinated policy responses playing out in real time around low cost zithromax the globe are http://www.ggs-regenbogen.bobi.net/can-you-buy-zithromax-over-the-counter/ unprecedented. Evidence can help light the path forward. Together with our partners, Mathematica is applying our unique knowledge and experience at the intersection of data, analytics, policy, and practice to help address today’s complex challenges related to buy antibiotics. Mathematica, Comagine Health, and Allegis recently joined the Department low cost zithromax of Health and other stakeholders to implement the Washington State buy antibiotics Contact Tracing Partnership. In addition, the state of Connecticut engaged Mathematica to assess and improve its response to buy antibiotics in long-term care facilities.

And by working in partnership with OnPacePlus, Mathematica has implemented a workforce-readiness dashboard for employers to help ensure the safety and efficiency of their workforce. Here are some additional projects that help address the zithromax.Getting back to school safelyUniversity of California, San Diego, low cost zithromax Return to Learn programInformed decisions about how we can safely return to schools and college campuses require leading-edge, evidence-based approaches. Universities, in particular, face important decisions regarding conditions for reopening and strategies to detect and prevent outbreaks. We’re working closely with researchers at the University of California, San Diego (UCSD), on aspects of their Return to Learn program. The program encompasses an adaptive strategy of risk mitigation, viral monitoring, and public health intervention to detect buy antibiotics outbreaks early and prevent their spread on low cost zithromax campus.Mathematica’s buy antibiotics agent-based computational model (ABM) for educational institutions can simulate the campus at opening and throughout the year under hundreds of scenarios.

Mathematica’s simulations allow UCSD to bring data-driven decision making to its campus reopening plan, informing decisions surrounding student housing density, in-person class structure, general campus-wide buy antibiotics policy, and student testing frequency. The ABM will also support UCSD as students return to campus. The Return to Learn program will continuously monitor and integrate real-time data—including asymptomatic and symptomatic testing, wastewater analyses, proximity low cost zithromax data, molecular data, survey data, contact-tracing data, and campus data (such as housing and class registration). The program monitoring also incorporates contextual information about geography, contact structure, behavior, and epidemiology. Mathematica’s ABM will evolve with the data stream from the wider Return to Learn effort, refining forecasts, answering new questions, and anticipating outbreaks.K–12 guidanceIn May 2020, the Pennsylvania Department of Education (PDE) approached the Regional Educational Laboratory (REL) Mid-Atlantic, led by Mathematica, for analytic support of its effort to produce guidance for reopening school buildings in the midst of the buy antibiotics zithromax.

REL Mid-Atlantic partnered with PDE on a three-part project, which included (1) examining emerging evidence on buy antibiotics’s public-health and educational implications for schools, (2) interviewing a wide range of Pennsylvania stakeholders to assess concerns and challenges related to reopening school buildings, and (3) modifying Mathematica’s buy antibiotics ABM to assess likely disease spread among students and school staff under various approaches to reopening school buildings. Findings are available in a memo and serve as the foundation for a publicly available tool for exploring the spread of buy antibiotics among students, faculty, and staff at K–12 schools under different approaches to school reopenings.Using wastewater to detect outbreaksApplying lessons from more than three years of work on the opioid epidemic and successfully tracking community-level wastewater measures, Mathematica low cost zithromax is working to develop insights for buy antibiotics zithromax management. With more than 15,000 wastewater treatment plants around the country already collecting samples to measure environmental pollutants, wastewater surveillance holds promise for efficiently conducting rapid, repeated, community-wide buy antibiotics testing using infrastructure that many municipalities already have in place.To validate our approach to translating wastewater data for zithromax management, we recently completed a wastewater pilot study to assess buy antibiotics exposure in a rural North Carolina community that is home to a major university population. In partnership with the Tuckaseigee Water and Sewer Authority, Jackson County Department of Public Health, and the University of Wisconsin’s School of Freshwater Sciences, we examined how trends in antibiotics viral levels measured in wastewater aligned with trends in confirmed buy antibiotics case counts and a proxy measure based on doctor visits and buy antibiotics-like symptom reports. To contextualize the wastewater data for public health officials, Mathematica built a generalizable low cost zithromax dynamic wastewater dashboard.

The dashboard brings together wastewater data with community data on numbers of tests conducted, confirmed cases, hospitalizations, and deaths. Jackson County’s zithromax vulnerability. Changes in population mobility low cost zithromax. And the prevalence of risk factors for severe buy antibiotics presentation. Our results revealed strong trend alignment between the data sources over the four-week sampling period.

Moreover, the study confirms findings from Yale University researchers that wastewater data can serve as a leading indicator for changes in buy antibiotics risk—the wastewater data provided a lead time of eight to nine days for changes in antibiotics viral levels compared to confirmed case counts or proxy indicators.Evaluation Technical Assistance low cost zithromax Brief #5 Publisher. Princeton, NJ. Mathematica Sep 10, 2020 Authors Russell Cole Impact evaluations in child welfare and other fields often struggle because of smaller-than-planned sample sizes. Multiple factors might low cost zithromax contribute to the problem. The program’s target population might be smaller than was projected, or recruiting and enrolling eligible participants into the study might have proven unexpectedly difficult.

Small sample sizes can create difficulties and limitations when estimating the impacts of programs—especially when you had not planned for them during the evaluation design phase. This brief, presented as a series of questions and answers, addresses this specific problem and offers guidance for analyzing data and reporting findings when it occurs..

How quickly does zithromax work

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 http://becomingtheiceman.com/photos/in-the-media.html has how quickly does zithromax work 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 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 how quickly does zithromax work 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 quickly does zithromax work (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 how quickly does zithromax work 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 how quickly does zithromax work 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 the postnatal how quickly does zithromax work team and from the paediatric to the adult team requires optimal communication between the specialists involved. Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline how quickly does zithromax work 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 how quickly does zithromax work the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper. Abstracts had to be written in English and were identified using a broad range of Medical Subject Headings terms (eg, DSD, genetic, review, how quickly does zithromax work 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 through institutional how quickly does zithromax work access. Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft was discussed by the writing committee and, after having obtained agreement on remaining points of discussion, how quickly does zithromax work 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 how quickly does zithromax work for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur earlier, for example, when a commercial how quickly does zithromax work ultrasound is performed at the request of the parents.Another way DSD can be diagnosed before birth is when invasive prenatal genetic testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex and the phenotypic sex seen by ultrasound.

In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately. More often, the discrepancy will be due to sex-chromosome mosaicism or a true form of DSD.A situation now how quickly does zithromax work 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 how quickly does zithromax work are not always included in NIPT analysis and reports.

If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the time that NIPT is performed (usually 11–13 weeks), genital how quickly does zithromax work development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team. After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on how quickly does zithromax work 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 how quickly does zithromax work 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 how quickly does zithromax work in which test results need to be available to allow parents to make a well-informed decision about whether or not to continue the pregnancy.

Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs as an apparently isolated condition, how quickly does zithromax work 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, how quickly does zithromax work treatment and prognosis cannot be avoided completely. Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images.

In our experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a contact person before birth.After expert prenatal counselling, a significant number of pregnant how quickly does zithromax work 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 how quickly does zithromax work long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array.

It was recently estimated that >30% of individuals who have a DSD have additional structural anomalies, with cardiac and neurological anomalies and fetal growth restriction being particularly common.27 28 If additional anomalies are seen, the geneticist can consider specific gene defects that may underlie a known how quickly does zithromax work 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 how quickly does zithromax work 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 http://stephaniehosford.com/the-reviews-for-bfc-are-inand-theyre-great/ 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 best place to buy zithromax online 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 that low cost zithromax 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 low cost zithromax 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 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 low cost zithromax 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 similarly structured healthcare systems and similar resources. Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues. International networks such as the European Reference Network for rare endocrine conditions (EndoERN), in which DSD is embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature thus far because they reflect evolving technologies or less low cost zithromax 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 low cost zithromax 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 the postnatal team and from the paediatric to the low cost zithromax adult team requires optimal communication between the specialists involved. Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed with all members responsible for updating the literature for low cost zithromax 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 low cost zithromax evidence due to the rapid changes in testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper.

Abstracts had to be written in English and were identified using a broad range of Medical Subject Headings low cost zithromax 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 low cost zithromax or retrievable through institutional access.

Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft was discussed by the writing committee and, after having obtained agreement on remaining points of discussion, revised into low cost zithromax 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 low cost zithromax version was presented to the paediatric and genetic associations for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur earlier, for example, low cost zithromax 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 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 low cost zithromax. NIPT screens for CNVs in the fetus.

However, depending low cost zithromax on legal restrictions and/or ethical considerations, the X and Y chromosomes are not always included in NIPT analysis and reports. If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the time that NIPT is performed (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, so low cost zithromax any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team.

After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on the ultrasound findings and the limitations low cost zithromax of this technique. The procedure(s) that can be followed, including the risks associated with an amniocentesis.

And the type of information genetic low cost zithromax 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 to make a well-informed decision about whether or not to continue the low cost zithromax 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 low cost zithromax 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 low cost zithromax what the child’s genitalia will look like and uncertainty about the diagnosis, treatment and prognosis cannot be avoided completely.

Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images. In our experience, low cost zithromax 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 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 low cost zithromax used in communication with parents should be carefully chosen,22 23 and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed in figure 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 low cost zithromax anomalies are seen, the geneticist can consider specific gene defects that may underlie a known genetic syndrome or carry out NGS.

NGS-based techniques have also now made their appearance in prenatal diagnosis of congenital anomalies.29 30 Panels using these techniques can be specific for genes involved in DSD, or be larger panels covering multiple congenital anomalies, and are usually employed with trio-analysis to compare variants identified in the child with the parents’ genetics.29–31 Finding a genetic cause before delivery can help reduce parental stress in the neonatal period and speed up decisions regarding gender assignment. In such cases there is no tight time low cost zithromax 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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