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    Research ArticleAffiliations:1 where do i get propecia. Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China 2. ISGlobal Hospital Clínic, Universitat de Barcelona, Barcelona, Spain, Manhiça Health Research Hospital, Ministry of Health, National Tuberculosis Control Program, Maputo, Mozambique , Email.

    [email protected]Publication where do i get propecia date:01 September 2020More about this publication?. The International Journal of Tuberculosis and Lung Disease publishes articles on all aspects of lung health, including public health-related issues such as training programmes, cost-benefit analysis, legislation, epidemiology, intervention studies and health systems research. The IJTLD is dedicated to the continuing education of physicians and health personnel and the dissemination of information on lung health world-wide.

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    No Supplementary Data.No Article MediaNo MetricsDocument where do i get propecia Type. Research ArticleAffiliations:1. Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK 2.

    German Central Committee against Tuberculosis, Berlin, Germany , Email. [email protected]Publication date:01 September 2020More about this publication?. The International Journal of Tuberculosis and Lung Disease publishes articles on all aspects of lung health, including public health-related issues such as training programmes, cost-benefit analysis, legislation, epidemiology, intervention studies and health systems research.

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    5.1 Pre-TAVR Assessment5.1.1 Identifying Patients at Risk for http://www.amisdepasteur.fr/buy-generic-propecia-in-australia/ Conduction DisturbancesIn an effort to propecia and having a baby anticipate the potential need for PPM, a pre-TAVR evaluation is important. The clinical presentation and symptoms of aortic stenosis and bradyarrhythmia overlap significantly. Especially common in propecia and having a baby both entities are fatigue, lightheadedness, and syncope. A careful history to assess if these symptoms are related to bradyarrhythmia needs to be obtained as part of the planning process for TAVR. A history suggestive of cardiac syncope, particularly exertional syncope, propecia and having a baby is concerning in patients with severe aortic stenosis.

    However, implicating the aortic valve or a bradyarrhythmia or tachyarrhythmia is often challenging (11).The electrocardiogram (ECG) is a useful tool for evaluating baseline conduction abnormalities and can help predict need for post-TAVR PPM. There is no consensus for routine ambulatory monitoring prior to TAVR. However, if available, it is helpful to review any ambulatory cardiac monitoring performed in the recent propecia and having a baby past. Twenty-four-hour continuous electrocardiographic monitoring can potentially identify episodes of transient AV block or severe bradycardia that are unlikely to resolve after TAVR without a PPM. These episodes propecia and having a baby may serve as evidence to support guideline-directed PPM implantation and lead to an overall reduction in the length of hospital stay (12).

    Beyond history and baseline conduction system disease, imaging characteristics, choice of device, and procedural factors can help to predict pacing needs (13–18).5.1.2 Anatomic ConsiderationsThe risk factors for PPM after TAVR can be better appreciated by understanding the regional anatomy of the conduction system and the atrioventricular septum. When AV block occurs during TAVR, the risk is higher and the chance for recovery is lower than in other circumstances due to the proximity of the aortic valve (relative to the mitral valve) to the bundle propecia and having a baby of His. The penetrating bundle of His is a ventricular structure located within the membranous portion of the ventricular septum. The right bundle emerges at an obtuse angle to the bundle of His. It is a cord-like structure that runs superficially through the upper third of the right ventricular endocardium up to the level of the septal propecia and having a baby papillary muscle of the tricuspid valve, where it courses deeper into the interventricular septum.

    The AV component of the membranous septum is a consistent location at which the bundle of His penetrates the left ventricle (LV). The membranous septum is propecia and having a baby formed between the 2 valve commissures. On the left side, it is the commissure between the right and noncoronary cusps, while on the right side, it is the commissure between the septal and anterior leaflets of the tricuspid valve (19). The tricuspid annulus propecia and having a baby is located more apical to the mitral annulus (See Figure 3). This AV septum separates the right atrium and the LV with septal tissue that is composed primarily of LV myocardium, with contribution from right atrial and ventricular myocardium (20).

    The AV septum is unique as it is part of neither the interatrial septum nor the interventricular septum. Therefore, valve implantation that overlaps with the distal AV septum may affect both the right and left bundles and lead to complete propecia and having a baby AV block (see Figure 4). Similarly, a relatively smaller LV outflow tract diameter or calcification below the noncoronary cusp may create an anatomic substrate for compression by the valve near the membranous septum or at the left bundle on the LV side of the muscular septum, leading to AV block or left bundle branch block (LBBB) (21).Specimen of AV Septum Gross specimen depicting how the AV septum separates the RA and the LV with septal tissue that is composed primarily of LV myocardium, with contribution from right atrial and ventricular myocardium. AV = propecia and having a baby atrioventricular. LV = left ventricle.

    RA = right atrium." data-icon-position data-hide-link-title="0">Figure 3 Specimen of AV SeptumGross specimen depicting how the AV septum separates the RA and the LV with septal tissue that is composed primarily of LV myocardium, propecia and having a baby with contribution from right atrial and ventricular myocardium.AV = atrioventricular. LV = left ventricle. RA = right atrium.Reproduced with permission from Hai et al. (22).Specimen of the Membranous Septum Between the Right Coronary and Noncoronary Leaflets Gross specimen showing the position of the membranous septum (transilluminated) between the right coronary and noncoronary leaflets propecia and having a baby. Ao = aorta.

    AV = propecia and having a baby atrioventricular. LV = left ventricle. MS = propecia and having a baby membranous septum. N = noncoronary leaflet. R = right coronary leaflet.

    RA = propecia and having a baby right atrium. RV = right ventricle." data-icon-position data-hide-link-title="0">Figure 4 Specimen of the Membranous Septum Between the Right Coronary and Noncoronary LeafletsGross specimen showing the position of the membranous septum (transilluminated) between the right coronary and noncoronary leaflets.Ao = aorta. AV = propecia and having a baby atrioventricular. LV = left ventricle. MS = membranous propecia and having a baby septum.

    N = noncoronary leaflet. R = right coronary leaflet. RA = right propecia and having a baby atrium. RV = right ventricle.Reproduced with permission from Hai et al. (22).These anatomic relationships are clinically propecia and having a baby relevant.

    In a retrospective review of 485 patients who underwent TAVR with a self-expanding prosthesis, 77 (16%) experienced high-degree AVB and underwent PPM implantation before discharge. A higher prosthesis-to-LV outflow tract diameter ratio and the utilization of aortic valvuloplasty during propecia and having a baby the procedure were significantly associated with PPM implantation (23). Similar findings have been reported with balloon-expandable valves (17). Although the prosthesis to LV outflow tract diameters in these studies were statistically different, they did not vary by a considerable margin (<5%) between the PPM and no PPM groups. This, together with the lack of implantation depth conveyed in these reports, limits the utility of these observations for pre-TAVR planning.Similarly, the length of the membranous septum has also been propecia and having a baby implicated in PPM rates.

    Specifically, the most inferior portion of the membranous septum serves as the exit point for the bundle of His, and compression of this area is associated with higher PPM implantation rates. In a propecia and having a baby retrospective review of patients undergoing TAVR, a strong predictor of the need for PPM before TAVR was the length of the membranous septum. After TAVR, the difference between membranous septum length and implant depth was the most powerful predictor of PPM implantation (24). Given these and other observations (16,25), lower PPM implantation rates may be realized by emphasizing higher implantation depths in patients in whom there is considerable tapering of the LV outflow tract just below the aortic annulus, a risk of juxtaposing the entire membranous septum with valve deployment, and/or considerable calcium under the noncoronary cusp (26).5.1.3 The ECG as a Screening ToolMultiple studies have noted that the presence of right bundle branch block (RBBB) is a strong independent predictor for PPM after TAVR (17,27), and some have suggested that RBBB is a marker for all-cause mortality in this population (2,6,28). A report from a multicenter registry (n = 3,527) noted the presence of pre-existing RBBB in 362 TAVR patients (10.3%) and associated it with increased 30-day propecia and having a baby rates of PPM (40.1% vs.

    13.5%. P < propecia and having a baby. 0.001) and death (10.2% vs. 6.9%. P = 0.024) (29).

    At a mean follow-up of 18 months, pre-existing RBBB was also independently associated with higher all-cause mortality (hazard ratio [HR]. 1.31, 95% confidence interval [CI]. 1.06 to 1.63. P = 0.014) and cardiovascular mortality (HR. 1.45.

    95% CI. 1.11 to 1.89. P = 0.006). Patients with pre-existing RBBB and without a PPM at discharge from the index hospitalization had the highest 2-year risk for cardiovascular death (27.8%. 95% CI.

    20.9% to 36.1%. P = 0.007) (28). In a subgroup analysis of 1,245 patients without a PPM at discharge from the index hospitalization and with complete follow-up regarding the need for a PPM, pre-existing RBBB was independently associated with the composite of sudden cardiac death and a PPM (HR. 2.68. 95% CI.

    1.16 to 6.17. P = 0.023) (30). The OCEAN-TAVI (Optimized Transcatheter Valvular Intervention) registry from 8 Japanese centers (n = 749) reported a higher rate of pacing in the RBBB group (17.6% vs. 2.9%. P <.

    0.01). Mortality was greater in the early phase after discharge in the RBBB group without a PPM. However, having a PPM in RBBB increased cardiovascular mortality at midterm follow-up (31).Pre-existing LBBB is present in about 10% to 13% of the population undergoing TAVR (32). Its presence has not been shown to predict PPM implantation consistently (13,27). Patients with LBBB were older (82.0 ± 7.1 years), had a higher Society of Thoracic Surgeons score (6.2 ± 4.0), and had a lower baseline left ventricular ejection fraction (LVEF) (48.8 ± 16.3%) (p <0.03 for all) than those without LBBB.

    In a multicenter study (n = 3,404), pre-existing LBBB was present in 398 patients (11.7%) and was associated with an increased risk of PPM need (21.1% vs. 14.8%. Adjusted odds ratio [OR]. 1.51. 95% CI.

    1.12 to 2.04) but not death (7.3% vs. 5.5%. OR. 1.33. 95% CI.

    0.84 to 2.12) at 30 days (32).The aggregate rate of PPM implantation was higher in the pre-existing LBBB group than in the non-LBBB group (22.9% vs. 16.5%. HR. 1.40. 95% CI.

    1.11 to 1.78. P = 0.006). However, this was likely driven by the increased PPM implantation rate early after TAVR (median time before PPM 4 days. Interquartile range. 1 to 7 days), and no differences were noted between groups in the PPM implantation rate after the first 30 days post-TAVR (pre-existing LBBB 2.2%.

    No pre-existing LBBB 1.9%. Adjusted HR. 0.95. 95% CI. 0.45 to 2.03.

    P = 0.904) (32). It is proposed that the higher PPM rates observed represented preemptive pacing based on perceived, rather than actual, risk of high-grade AV block. There were no differences in overall mortality (adjusted HR. 0.94. 95% CI.

    0.75 to 1.18. P = 0.596) and cardiovascular mortality (adjusted HR. 0.90. 95% CI. 0.68 to 1.21.

    P = 0.509) in patients with and without pre-existing LBBB at mean follow-up of 22 ± 21 months (32).First-degree AV block has not been shown conclusively to be an independent predictor for PPM. However, change in PR interval, along with other factors, increases the risk of PPM implantation. A German report noted that in a multivariable analysis, postdilatation (OR. 2.219. 95% CI.

    1.106 to 3.667. P = 0.007) and a PR interval >178 ms (OR 0.412. 95% CI. 1.058 to 5.134. P = 0.027) remained independent predictors for pacing following TAVR (33).

    In a retrospective analysis of 611 patients, Mangieri et al. (34) showed that baseline RBBB and the magnitude of increase in the PR interval post-TAVR were predictors of late (>48 h) development of advanced conduction abnormalities. Multivariable analysis revealed baseline RBBB (OR. 3.56. 95% CI.

    1.07 to 11.77. P = 0.037) and change in PR interval (OR for each 10-ms increase. 1.31. 95% CI. 1.18 to 1.45.

    P = 0.0001) to be independent predictors of delayed advanced conduction disturbances (34). Prolonged QRS interval without a bundle branch block, however, has not been consistently noted as a marker for PPM (13).5.1.4 Preparation and Patient CounselingAll patients undergoing TAVR should be consented for a temporary pacemaker. Options, including the use of a temporary active fixation lead, need to be discussed.In patients with a high anticipated need for pacing, it is reasonable to prepare the anticipated site of access for employing an active fixation lead for safety considerations. Frequently, the right internal jugular vein is used. It is especially important to prepare the area a priori if the access site is going to be obscured by straps used for endotracheal tube stability or other http://www.amisdepasteur.fr/propecia-price/ forms of supportive ventilation.

    The hardware required—including vascular sheaths, pacing leads, connector cables, the pacing device itself (either a dedicated external pacemaker or implantable pacemaker used externally), and device programmers—should be immediately available. A physician proficient in placing and securing active fixation leads should be available. Allied health support for evaluating pacing parameters after lead placement and device programming should also be available (35).If the patient is at high risk for needing a PPM, a detailed discussion with the performing physicians about the anticipated need should be undertaken before TAVR. Although the ultimate decision regarding pacing will occur post-TAVR, the patient should be prepared and, in some cases, consented before the procedure. Discussion regarding the choice of pacing device—pacemaker versus implantable cardioverter-defibrillator (ICD) versus cardiac resynchronization therapy—should be undertaken with the involved implanting physician and in agreement with recent guideline updates (8,36).It is frequently noted that the LVEF in patients undergoing TAVR may not be normal (37).

    If the LVEF is severely reduced and the chance of incremental improvement is unclear or unlikely (due to factors such as prior extensive scarring and previous myocardial infarction), then a shared decision-making approach regarding the need for an ICD should be used (8). Similarly, if the patient is likely to have complete AV heart block after the procedure, especially in the setting of a reduced LVEF, then a discussion regarding cardiac resynchronization therapy or other physiological pacing needs to be held before the TAVR procedure (38). Due to the risks of reoperation, careful preprocedural evaluation, planning, and input from an electrophysiologist should be obtained to ensure that the correct type of cardiac implantable electronic device (CIED) is implanted for the patient's long-term needs. See Figure 5 for additional details.Pre-TAVR Patient Assessment and Guidance" data-icon-position data-hide-link-title="0">Figure 5 Pre-TAVR Patient Assessment and Guidance5.2 Intraprocedural TAVR ManagementPatients who are determined to have an elevated risk for complete AV heart block during pre-TAVR assessment require close perioperative electrocardiographic and hemodynamic monitoring. Aspects of the TAVR procedure itself that warrant consideration during the procedure in this group are listed in the following text (Figure 6).Intraprocedural TAVR Management" data-icon-position data-hide-link-title="0">Figure 6 Intraprocedural TAVR Management5.2.1 Negative Dromotropic and Chronotropic MedicationsYounis et al.

    (39) showed that discontinuation of chronic BB therapy in patients prior to TAVR was associated with increased need for pacing. Beta-adrenergic or calcium channel blocking drugs that affect the AV node (not the bundle of His, which is at risk for injury by TAVR) may be continued for those with pre-existing LBBB, RBBB, or bifascicular block with no advanced AV heart block or symptoms. In keeping with the anatomic considerations discussed in the previous text, these drugs should not affect AV conduction changes related to TAVR itself, since the aortic valve lies near the bundle of His and not the AV node. If these agents are provided in an evidence-based manner for related conditions (e.g., heart failure, coronary artery disease, atrial fibrillation), they should be continued. The dose should be titrated to heart rate and blood pressure goals, and this titration should occur prior to the day of procedure (40,41).5.2.2 AnesthesiaThere are no instances in which the presence of baseline conduction abnormalities would dictate type and duration of anesthesia during the procedure.

    Accordingly, the anesthetic technique most suited for the individual patient’s medical condition is best decided by the anesthesiologist in conjunction with the heart team.5.2.3 Procedural Temporary PacemakerCurrently, most centers implant a transvenous pacing wire electrode via the internal jugular or femoral vein to provide rapid ventricular pacing and thereby facilitate optimal valve implantation. For patients with ports, dialysis catheters, and/or hemodialysis fistulae, we recommend placement of temporary transvenous pacemaker via the femoral vein. Alternatively, recent data suggest that placing a guidewire directly into the LV can provide rapid ventricular pacing and overcome some of the complications arising from additional central venous access and right ventricular pacing (8,35,42). In a prospective multicenter randomized controlled trial, Faurie et al. (35) showed that LV pacing was associated with shorter procedure time (48.4 ± 16.9 min vs.

    55.6 ± 26.9 min. P = 0.0013), shorter fluoroscopy time (13.48 ± 5.98 min vs. 14.60 ± 5.59 min. P = 0.02), and lower cost (€18,807 ± 1,318 vs. ‚¬19,437 ± 2,318.

    P = 0.001) compared with right ventricular pacing with similar efficacy and safety (35). This approach has been FDA approved and is in early utilization (43). Given that LV pacing wire cannot be left in place postprocedure it is a less attractive option in patients at high risk for conduction disturbances. Although existing experience does not currently inform the optimal pacing site for those at high risk of procedural heart block, it is reasonable to select temporary pacemaker placement via the right internal jugular vein over the femoral vein given ease of patient mobility should it be necessary to retain the temporary pacemaker postprocedure.5.2.4 Immediate Postprocedure Transvenous PacingIn patients deemed high risk for conduction disturbances, it is reasonable to either maintain the pre-existing temporary pacemaker in the right internal jugular vein or insert one into that vein if the femoral vein has been used for rapid pacing. Procedural conduction disturbances and postimplant 12-lead ECG will help determine the need for a temporary but durable pacing lead (e.g., active fixation lead from the right internal jugular vein).

    For the purposes of procedural management, the following are 3 possible clinical scenarios:1. No new conduction disturbances (<20 ms change in PR or QRS duration) (44–49);2. New-onset LBBB and/or increase in PR or QRS duration ≥20 ms. And3. Development of transient or persistent complete heart block.In patients with normal sinus rhythm and no new conduction disturbances on an ECG performed immediately postprocedure, the risk of developing delayed AV block is <1% (48–50).

    In these cases, the temporary pacemaker and central venous sheath can be removed immediately postprocedure, although continuous cardiac monitoring for 24 hours and a repeat 12-lead ECG the following day are recommended. This recommendation also applies to patients with pre-existing first-degree AV block and/or pre-existing LBBB (3,27,42,48), provided that PR or QRS intervals do not increase in duration after the procedure. Krishnaswamy et al. (51) recently reported the utility of using the temporary pacemaker electrode for rapid atrial pacing up to 120 beats per minute to predict the need for permanent pacing, finding a higher rate within 30 days of TAVR among the patients who developed second-degree Mobitz I (Wenckebach) AV block (13.1% vs. 1.3%.

    P <. 0.001), with a negative predictive value for PPM implantation in the group without Wenckebach AV block of 98.7%. Patients receiving self-expanding valves required permanent pacing more frequently than those receiving a balloon-expandable valve (15.9% vs. 3.7%. P = 0.001).

    For those who did not develop Wenckebach AV block, the rates of PPM were low (2.9% and 0.8%, respectively). The authors concluded that patients who did not develop pacing-induced Wenckebach AV block have a very low need for of permanent pacing (51).In patients with pre-existing RBBB, the risk of developing high-degree AV block during hospitalization is high (as much as 24%) and has been associated with all-cause and cardiovascular mortality post-TAVR (30). This risk of high-degree AV block exists for up to 7 days, and the latent risk is greater with self-expanding valves (52). Hence, in the population with pre-existing RBBB, it is reasonable to maintain transvenous pacing ability with continuous cardiac monitoring irrespective of new changes in PR or QRS duration for at least 24 hours. If the care team elects to remove the transvenous pacemaker in these cases, the ability to provide emergent pacing is critical.

    Recovery location (e.g., step-down unit, intensive care unit) and indwelling vascular access should be managed to accommodate this.Patients without pre-existing RBBB who develop LBBB or an increase in PR/QRS duration of ≥20 ms represent the most challenging group in terms of predicting progression to high-grade AV block and need for permanent pacing. Two meta-analyses, the first by Faroux et al. (53) and the second by Megaly et al. (54), showed that new-onset LBBB post-TAVR was associated with increased risk of PPM implantation (RR. 1.89.

    95% CI. 1.58 to 2.27. P <. 0.001) at 1-year follow-up and higher incidence of PPM (19.7% vs. 7.1%.

    OR. 2.4 [95% CI. 1.64 to 3.52]. P <. 0.001) during a mean follow-up of 20.5 ± 14 months, respectively, compared with those without a new-onset LBBB.

    In addition to the paucity of data, there is significant variation in the reported PR/QRS prolongation that confers risk of early and delayed high-grade AV block (34,44–47,55). We propose that the development of new LBBB or an increase in PR/QRS duration ≥20 ms in patients without pre-existing RBBB warrants continued transvenous pacing for at least 24 hours, in conjunction with continuous cardiac monitoring and daily ECGs during hospitalization. In the event that the transvenous pacemaker is removed after the procedure in these cases, recovery location and indwelling vascular access need to be appropriate for emergent pacing should it become necessary.A recent study employed atrial pacing immediately post-TAVR to predict the need for permanent pacing within 30 days. If second degree Mobitz I (Wenckebach) AV block did not occur with right atrial pacing (up to 120 beats per minute), only 1.3% underwent PPM by 30 days. Conversely, if Wenckebach AV block did occur, the rate was 13.1% (p <.

    0.001). It is important to note that this group of patients included those with pre-existing and postimplant LBBB and RBBB (51). This is an interesting strategy and may ultimately inform routine length of monitoring in post-TAVR patients.During instances of transient high-grade AV block during valve deployment, it is reasonable to maintain the transvenous pacemaker in addition to continuous cardiac monitoring for at least 24 hours irrespective of the pre-existing conduction disturbance.For patients with transient or persistent high-grade AV block during or after TAVR, the temporary pacemaker should be left in place for at least 24 hours to assess for conduction recovery. If recurrent episodes of transient high-grade AV block occur in the intraoperative or postoperative period, PPM implantation should be considered prior to hospital discharge regardless of patient symptoms. Patients with persistent high-grade AV block should have PPM implanted.In patients with prior RBBB, transient or persistent procedural high-grade AV block is an indication for permanent pacing in the vast majority of cases, with an anticipated high requirement for ventricular pacing at follow-up (56,57).

    In these cases, a durable transvenous pacing lead is recommended prior to leaving the procedure suite.If permanent pacing is deemed necessary after TAVR, it is preferable to separate the procedures so that informed consent can occur and the procedures can be performed in their respective spaces with related necessary equipment and staff. When clinical and logistical circumstances warrant it, there are instances in which PPM implantation may be reasonable the same day as the TAVR (e.g., persistent complete heart block in patients with a pre-existing RBBB). When this has been anticipated, consent for PPM implantation may be obtained prior to TAVR. Otherwise, it is preferable that the patient is awake and able to provide consent before permanent device implantation.5.3 Conduction Disturbances After TAVR. Monitoring and ManagementDH-AVB has been reported in ∼10% of patients (47) and is conventionally defined as DH-AVB occurring >2 days after the procedure or after hospital discharge, the latter representing the larger proportion of this group.

    Whether this is a substrate for the observed rates of sudden cardiac death remains unclear, although syncope has been reported in tandem with devastating consequence (47). Although pre-existing RBBB and, in some reports, new LBBB are risk factors for DH-AVB (47,58), they do not reach sufficient sensitivity to identify those appropriate for preemptive pacing devices. Accordingly, different management strategies are often employed, ranging from electrophysiological studies (EPS) to prolonged inpatient monitoring and/or outpatient ambulatory event monitoring (AEM) (see Figure 7).Post-TAVR Management" data-icon-position data-hide-link-title="0">Figure 7 Post-TAVR ManagementThe role of EPS after TAVR to guide PPM has not been studied in a randomized prospective clinical trial. Although there are nonrandomized studies that describe metrics associated with PPM decisions, these metrics were determined retrospectively and without prospective randomization to PPM or no PPM on the basis of such measurements. In general, EPS is not needed for patients with a pre-existing or new indication for pacing, especially when the ECG finding is covered in the bradycardia pacing guidelines (6).

    In this setting, implantation can proceed without further study.At the other end of the spectrum are scenarios in which neither pacing nor EPS need be considered, such as for patients with sinus rhythm, chronotropic competence, no bradycardia, normal conduction, and no new conduction disturbance. Similarly, if there is first-degree AV block, second-degree Mobitz I (Wenckebach) AV block, a hemiblock by itself, or unchanged LBBB, neither a PPM nor EPS is indicated (27,48,55). Notably, Toggweiler et al. (48) reported that from a cohort of 1,064 patients who underwent TAVR, none of the 250 patients in sinus rhythm without conduction disorders developed DH-AVB. Only 1 of 102 patients with atrial fibrillation developed DH-AVB.

    And no patient with a stable ECG for ≥2 days developed DH-AVB. The authors suggested that since such patients without conduction disorders post-TAVR did not develop DH-AVB, they may not even require telemetry monitoring and that all others should be monitored until the ECG is stable for at least 2 days (48).Patients in the middle of the spectrum described in the previous text are those best suited for EPS because for them, the appropriateness of pacing is unclear. Predictors of need for pacing include new LBBB, new RBBB, old or new LBBB with an increase in PR duration >20 ms, an isolated increase in PR duration ≥40 ms, an increase in QRS duration ≥22 ms in sinus rhythm, and atrial fibrillation with a ventricular response <100 beats per minute in the presence of old or new LBBB (34,56,59,60). These individuals have, in some cases, been risk-stratified by EPS. Rivard et al.

    (61) found that a ≥13-ms increase in His-ventricular (HV) interval between pre- and post-TAVR measurements correlated with TAVR-associated AVB, and, especially for those with new LBBB, a post-TAVR HV interval ≥65 ms predicted subsequent AVB. Therefore, when these changes are identified on EPS, Rivard et al. (61) suggest that pacing is necessary or appropriate. A limitation of this study is that EPS is required pre-TAVR (61). Tovia-Brodie et al.

    (59) implanted PPM in post-TAVR patients with an HV interval ≥75 ms, but there was no control group with patients who did not receive a device. Rogers et al. (62) justified PPM in situations in which an HV interval ≥100 ms was recorded at post-TAVR EPS either without or after procainamide challenge, but the study was neither randomized nor controlled, and the 100-ms interval chosen was based on old electrophysiology data related to predicting heart block not associated with TAVR. In this study, intra- or infra-His block also led to PPM implantation (62). Finally, second-degree AV block provoked by atrial pacing at a rate <150 beats per minute (cycle length >400 ms) predicted PPM implantation (59).

    Limitations of these studies include their lack of a control group for comparison, meaning that outcomes without pacing are unknown.In the study by Makki et al. (63), 24 patients received a PPM in-hospital (14% of the total cohort) and 7 (29%) as the result of an abnormal EPS. The indications for EPS were new LBBB, second-degree AV block, and transient third-degree AV block. With a mean follow-up of 22 months and assessment of nonpaced rhythms in those with a PPM who both had and did not have EPS, the authors concluded that pacemaker dependency after TAVR is common among those who had demonstrated third-degree AV block pre-PPM but not among those with a prolonged HV delay during EPS. Limitations of this study are its small size and the fact that new LBBB was the primary indication for EPS.

    The observation that a minority of post-TAVR patients are pacemaker-dependent upon follow-up underscores the often transient nature of the myocardial injury and the complexity of identifying those who will benefit from a long-term indwelling device (64).Although algorithms for PPM implantation have been proposed that are based on ECG criteria without EPS (65) and with EPS (59,61,62), all are based on opinion and observational rather than prospective data. Provided one recognizes the limitations of the studies reviewed earlier, EPS can be used for decision making when a definitive finding is identified that warrants pacing, such as infra-His block during atrial pacing, a prolonged HV interval with split His potentials (intra-Hisian conduction disturbance with 2 distinct, separated electrogram potentials), or an extremely long HV interval with either RBBB or LBBB (6). Although studies are forthcoming, the currently available data do not support PPM indications specific to the TAVR population.A reassuring addition to the literature from Ream et al. (47) reported that although AV block developed ≥2 days post-TAVR in 18 (12%) of 150 consecutive patients, it occurred in only 1 patient between days 14 and 30. Importantly, of those with DH-AVB, only 5 had symptoms (dizziness in 3, syncope in 2) and there were no deaths.

    The greatest risk factor for developing DH-AVB was baseline RBBB (risk 26-fold). The PR interval and even the development of LBBB were not predictors of DH-AVB. The authors recommended electrophysiology consultation for EPS and/or PPM implantation for patients with high-risk pre-TAVR ECGs (e.g., with a finding of RBBB), those with intraprocedure high-degree AV block, and for those who, on monitoring, have high-degree AV block (47). Thus, for patients not receiving an early PPM, follow-up without EPS but with short-term monitoring is reasonable when there is not a clear indication for pacing immediately after TAVR.For those who are without clear pacemaker indications during their procedural hospitalization but are at risk for DH-AVB, prolonged monitoring is often employed. The length of inpatient telemetry monitoring varies but reflects the timing of AVB after TAVR, clustering within the first 7 to 8 days postprocedure (47,48,58).

    The cost and inherent risks of prolonged hospitalization for telemetry have prompted the evaluation of AEM strategies in 3 patient populations. 1) all patients without a pacemaker at the time of discharge after TAVR. 2) those with new LBBB. And 3) those with any new or progressive conduction abnormality after TAVR.The largest post-TAVR AEM study to date observed 118 patients after discharge for 30 days. Twelve of these (10%) had DH-AVB at a median of 6 days (range 3 to 24 days), with 10 of the 12 events occurring within 8 days.

    One of these patients with an event had no pre- or post-TAVR conduction abnormalities, and new LBBB was not identified as a risk factor for subsequent DH-AVB. The AEM and surveillance infrastructure employed in this study enabled the prompt identification of DH-AVB, and no serious adverse events occurred in the group that experienced it (47). However, in the observational experience preceding this study, the same group reported 4 patients (of 158 without a PPM at discharge) who experienced DH-AVB necessitating readmission, all within 10 days of the procedure (range 8 to 10 days). Three underwent uncomplicated PPM implantation, although 1 sustained syncope and fatal intracranial hemorrhage. Importantly, for this group, routine AEM was not in place, and none of these patients had baseline or postprocedure conduction disturbances (46).

    While others have observed no DH-AVB in those without pre-existing or post-TAVR conduction disturbances, or with a stable ECG 2 days after TAVR (0 of 250 patients), AEM postdischarge was not employed, raising the possibility of under-reporting (48).The MARE (Ambulatory Electrocardiographic Monitoring for the Detection of High-Degree Atrio-Ventricular Block in Patients With New-onset PeRsistent LEft Bundle Branch Block After Transcatheter Aortic Valve Implantation) trial enrolled patients (n = 103) with new-onset and persistent LBBB after TAVR, a common conduction abnormality post-TAVR and one associated with DH-AVB and sudden death in some observations (6,27,34,48,55,58,59). Patients meeting these criteria had a loop recorder implanted at discharge. Ten patients (10%) underwent permanent pacing due to DH-AVB (n = 9) or bradycardia (n = 1) at a median of 30 days post-TAVR (range 5 to 281 days). Although the rate of PPM implantation was relatively consistent throughout the observational period, it is important to note that the median length of stay in this cohort was 7 days, whereas the current median in the United States is approximately 2 days (66). There was a single sudden cardiac death 10 months after discharge, and presence or absence of an arrhythmogenic origin was not determined as the patient’s implantable loop recorder was not interrogated (58).A third prospective observational study enrolled patients with new conduction disturbances (first- or second-degree heart block, or new bundle branch block) after TAVR that did not progress to conventional pacemaker indications during hospitalization.

    These patients were offered AEM for 30 days after discharge. Among the 54 patients, 3 (6%) underwent PPM within 30 days. Two of the patients had asymptomatic DH-AVB, and 1 had elected not to wear the AEM and suffered a syncopal event in the context of DH-AVB. No sudden cardiac death or other sequelae of DH-AVB were observed (47).Given these results, in patients with new or worsened conduction disturbance after TAVR (PR or QRS interval increase ≥10%), early discharge after TAVR is less likely to be safe. We recommend inpatient monitoring with telemetry for at least 2 days if the rhythm disturbance does not progress, and up to 7 days if AEM is not going to be employed.

    We suggest that it is appropriate to provide AEM to any patient with a PR or QRS interval that is new or extended by ≥10%, and that this monitoring should occur for at least 14 days postdischarge. The heart team and the AEM monitor employed should have the capacity to receive and respond to DH-AVB within an hour and to dispatch appropriate emergency medical services.We also acknowledge the shortcomings of existing observational experience. These include that DH-AVB has been identified in patients with normal ECGs pre- and post-TAVR, and that 14 or even 30 days of monitoring is unlikely to be sufficient to capture all occurrences of DH-AVB. Ongoing and forthcoming studies and technology will enable the development of more sophisticated protocols and of device systems that facilitate adherence, real-time monitoring, and effective response times in an economically viable manner.Source Search for this keyword Search.

    5.1 Pre-TAVR Assessment5.1.1 Identifying Patients at Risk for Conduction DisturbancesIn an effort to anticipate where do i get propecia the potential need for PPM, a go to my blog pre-TAVR evaluation is important. The clinical presentation and symptoms of aortic stenosis and bradyarrhythmia overlap significantly. Especially common in both entities where do i get propecia are fatigue, lightheadedness, and syncope. A careful history to assess if these symptoms are related to bradyarrhythmia needs to be obtained as part of the planning process for TAVR.

    A history suggestive of cardiac syncope, particularly exertional syncope, is concerning in patients with severe where do i get propecia aortic stenosis. However, implicating the aortic valve or a bradyarrhythmia or tachyarrhythmia is often challenging (11).The electrocardiogram (ECG) is a useful tool for evaluating baseline conduction abnormalities and can help predict need for post-TAVR PPM. There is no consensus for routine ambulatory monitoring prior to TAVR. However, if available, it is helpful to review any ambulatory cardiac monitoring performed in where do i get propecia the recent past.

    Twenty-four-hour continuous electrocardiographic monitoring can potentially identify episodes of transient AV block or severe bradycardia that are unlikely to resolve after TAVR without a PPM. These episodes may serve as evidence to support guideline-directed PPM implantation and lead to an where do i get propecia overall reduction in the length of hospital stay (12). Beyond history and baseline conduction system disease, imaging characteristics, choice of device, and procedural factors can help to predict pacing needs (13–18).5.1.2 Anatomic ConsiderationsThe risk factors for PPM after TAVR can be better appreciated by understanding the regional anatomy of the conduction system and the atrioventricular septum. When AV block occurs where do i get propecia during TAVR, the risk is higher and the chance for recovery is lower than in other circumstances due to the proximity of the aortic valve (relative to the mitral valve) to the bundle of His.

    The penetrating bundle of His is a ventricular structure located within the membranous portion of the ventricular septum. The right bundle emerges at an obtuse angle to the bundle of His. It is a cord-like structure that runs superficially through the upper third of the right ventricular endocardium up to the level of the septal papillary muscle of the tricuspid valve, where it courses deeper into the where do i get propecia interventricular septum. The AV component of the membranous septum is a consistent location at which the bundle of His penetrates the left ventricle (LV).

    The membranous septum is formed between the where do i get propecia 2 valve commissures. On the left side, it is the commissure between the right and noncoronary cusps, while on the right side, it is the commissure between the septal and anterior leaflets of the tricuspid valve (19). The tricuspid where do i get propecia annulus is located more apical to the mitral annulus (See Figure 3). This AV septum separates the right atrium and the LV with septal tissue that is composed primarily of LV myocardium, with contribution from right atrial and ventricular myocardium (20).

    The AV septum is unique as it is part of neither the interatrial septum nor the interventricular septum. Therefore, valve implantation that overlaps with the distal AV septum may affect both the right and left bundles and lead to complete AV block where do i get propecia (see Figure 4). Similarly, a relatively smaller LV outflow tract diameter or calcification below the noncoronary cusp may create an anatomic substrate for compression by the valve near the membranous septum or at the left bundle on the LV side of the muscular septum, leading to AV block or left bundle branch block (LBBB) (21).Specimen of AV Septum Gross specimen depicting how the AV septum separates the RA and the LV with septal tissue that is composed primarily of LV myocardium, with contribution from right atrial and ventricular myocardium. AV = where do i get propecia atrioventricular.

    LV = left ventricle. RA = right atrium." data-icon-position data-hide-link-title="0">Figure 3 Specimen of AV SeptumGross specimen depicting how the AV septum separates the RA and the LV with septal where do i get propecia tissue that is composed primarily of LV myocardium, with contribution from right atrial and ventricular myocardium.AV = atrioventricular. LV = left ventricle. RA = right atrium.Reproduced with permission from Hai et al.

    (22).Specimen of the Membranous Septum Between the Right Coronary and Noncoronary Leaflets where do i get propecia Gross specimen showing the position of the membranous septum (transilluminated) between the right coronary and noncoronary leaflets. Ao = aorta. AV = atrioventricular where do i get propecia. LV = left ventricle.

    MS = membranous septum where do i get propecia. N = noncoronary leaflet. R = right coronary leaflet. RA = right atrium where do i get propecia.

    RV = right ventricle." data-icon-position data-hide-link-title="0">Figure 4 Specimen of the Membranous Septum Between the Right Coronary and Noncoronary LeafletsGross specimen showing the position of the membranous septum (transilluminated) between the right coronary and noncoronary leaflets.Ao = aorta. AV = atrioventricular where do i get propecia. LV = left ventricle. MS = where do i get propecia membranous septum.

    N = noncoronary leaflet. R = right coronary leaflet. RA = right where do i get propecia atrium. RV = right ventricle.Reproduced with permission from Hai et al.

    (22).These anatomic relationships are where do i get propecia clinically relevant. In a retrospective review of 485 patients who underwent TAVR with a self-expanding prosthesis, 77 (16%) experienced high-degree AVB and underwent PPM implantation before discharge. A higher prosthesis-to-LV outflow tract where do i get propecia diameter ratio and the utilization of aortic valvuloplasty during the procedure were significantly associated with PPM implantation (23). Similar findings have been reported with balloon-expandable valves (17).

    Although the prosthesis to LV outflow tract diameters in these studies were statistically different, they did not vary by a considerable margin (<5%) between the PPM and no PPM groups. This, together with the lack of implantation depth conveyed in these reports, limits the utility of these where do i get propecia observations for pre-TAVR planning.Similarly, the length of the membranous septum has also been implicated in PPM rates. Specifically, the most inferior portion of the membranous septum serves as the exit point for the bundle of His, and compression of this area is associated with higher PPM implantation rates. In a where do i get propecia retrospective review of patients undergoing TAVR, a strong predictor of the need for PPM before TAVR was the length of the membranous septum.

    After TAVR, the difference between membranous septum length and implant depth was the most powerful predictor of PPM implantation (24). Given these and other observations (16,25), lower PPM implantation rates may be realized by emphasizing higher implantation depths in patients in whom there is considerable tapering of the LV outflow tract just below the aortic annulus, a risk of juxtaposing the entire membranous septum with valve deployment, and/or considerable calcium under the noncoronary cusp (26).5.1.3 The ECG as a Screening ToolMultiple studies have noted that the presence of right bundle branch block (RBBB) is a strong independent predictor for PPM after TAVR (17,27), and some have suggested that RBBB is a marker for all-cause mortality in this population (2,6,28). A report from a multicenter registry (n = 3,527) noted the presence of pre-existing RBBB in 362 TAVR patients (10.3%) and associated where do i get propecia it with increased 30-day rates of PPM (40.1% vs. 13.5%.

    P < where do i get propecia. 0.001) and death (10.2% vs. 6.9%. P = 0.024) (29).

    At a mean follow-up of 18 months, pre-existing RBBB was also independently associated with higher all-cause mortality (hazard ratio [HR]. 1.31, 95% confidence interval [CI]. 1.06 to 1.63. P = 0.014) and cardiovascular mortality (HR.

    Patients with pre-existing RBBB and without a PPM at discharge from the index hospitalization had the highest 2-year risk for cardiovascular death (27.8%. 95% CI. 20.9% to 36.1%. P = 0.007) (28).

    In a subgroup analysis of 1,245 patients without a PPM at discharge from the index hospitalization and with complete follow-up regarding the need for a PPM, pre-existing RBBB was independently associated with the composite of sudden cardiac death and a PPM (HR. 2.68. 95% CI. 1.16 to 6.17.

    P = 0.023) (30). The OCEAN-TAVI (Optimized Transcatheter Valvular Intervention) registry from 8 Japanese centers (n = 749) reported a higher rate of pacing in the RBBB group (17.6% vs. 2.9%. P <.

    0.01). Mortality was greater in the early phase after discharge in the RBBB group without a PPM. However, having a PPM in RBBB increased cardiovascular mortality at midterm follow-up (31).Pre-existing LBBB is present in about 10% to 13% of the population undergoing TAVR (32). Its presence has not been shown to predict PPM implantation consistently (13,27).

    Patients with LBBB were older (82.0 ± 7.1 years), had a higher Society of Thoracic Surgeons score (6.2 ± 4.0), and had a lower baseline left ventricular ejection fraction (LVEF) (48.8 ± 16.3%) (p <0.03 for all) than those without LBBB. In a multicenter study (n = 3,404), pre-existing LBBB was present in 398 patients (11.7%) and was associated with an increased risk of PPM need (21.1% vs. 14.8%. Adjusted odds ratio [OR].

    1.51. 95% CI. 1.12 to 2.04) but not death (7.3% vs. 5.5%.

    OR. 1.33. 95% CI. 0.84 to 2.12) at 30 days (32).The aggregate rate of PPM implantation was higher in the pre-existing LBBB group than in the non-LBBB group (22.9% vs.

    1.11 to 1.78. P = 0.006). However, this was likely driven by the increased PPM implantation rate early after TAVR (median time before PPM 4 days. Interquartile range.

    1 to 7 days), and no differences were noted between groups in the PPM implantation rate after the first 30 days post-TAVR (pre-existing LBBB 2.2%. No pre-existing LBBB 1.9%. Adjusted HR. 0.95.

    95% CI. 0.45 to 2.03. P = 0.904) (32). It is proposed that the higher PPM rates observed represented preemptive pacing based on perceived, rather than actual, risk of high-grade AV block.

    There were no differences in overall mortality (adjusted HR. 0.94. 95% CI. 0.75 to 1.18.

    P = 0.596) and cardiovascular mortality (adjusted HR. 0.90. 95% CI. 0.68 to 1.21.

    P = 0.509) in patients with and without pre-existing LBBB at mean follow-up of 22 ± 21 months (32).First-degree AV block has not been shown conclusively to be an independent predictor for PPM. However, change in PR interval, along with other factors, increases the risk of PPM implantation. A German report noted that in a multivariable analysis, postdilatation (OR. 2.219.

    95% CI. 1.106 to 3.667. P = 0.007) and a PR interval >178 ms (OR 0.412. 95% CI.

    1.058 to 5.134. P = 0.027) remained independent predictors for pacing following TAVR (33). In a retrospective analysis of 611 patients, Mangieri et al. (34) showed that baseline RBBB and the magnitude of increase in the PR interval post-TAVR were predictors of late (>48 h) development of advanced conduction abnormalities.

    Multivariable analysis revealed baseline RBBB (OR. 3.56. 95% CI. 1.07 to 11.77.

    P = 0.037) and change in PR interval (OR for each 10-ms increase. 1.31. 95% CI. 1.18 to 1.45.

    P = 0.0001) to be independent predictors of delayed advanced conduction disturbances (34). Prolonged QRS interval without a bundle branch block, however, has not been consistently noted as a marker for PPM (13).5.1.4 Preparation and Patient CounselingAll patients undergoing TAVR should be consented for a temporary pacemaker. Options, including the use of a temporary active fixation lead, need to be discussed.In patients with a high anticipated need for pacing, it is reasonable to prepare the anticipated site of access for employing an active fixation lead for safety considerations. Frequently, the right internal jugular vein is used.

    It is especially important to prepare the area a http://www.amisdepasteur.fr/walmart-pharmacy-propecia-price/ priori if the access site is going to be obscured by straps used for endotracheal tube stability or other forms of supportive ventilation. The hardware required—including vascular sheaths, pacing leads, connector cables, the pacing device itself (either a dedicated external pacemaker or implantable pacemaker used externally), and device programmers—should be immediately available. A physician proficient in placing and securing active fixation leads should be available. Allied health support for evaluating pacing parameters after lead placement and device programming should also be available (35).If the patient is at high risk for needing a PPM, a detailed discussion with the performing physicians about the anticipated need should be undertaken before TAVR.

    Although the ultimate decision regarding pacing will occur post-TAVR, the patient should be prepared and, in some cases, consented before the procedure. Discussion regarding the choice of pacing device—pacemaker versus implantable cardioverter-defibrillator (ICD) versus cardiac resynchronization therapy—should be undertaken with the involved implanting physician and in agreement with recent guideline updates (8,36).It is frequently noted that the LVEF in patients undergoing TAVR may not be normal (37). If the LVEF is severely reduced and the chance of incremental improvement is unclear or unlikely (due to factors such as prior extensive scarring and previous myocardial infarction), then a shared decision-making approach regarding the need for an ICD should be used (8). Similarly, if the patient is likely to have complete AV heart block after the procedure, especially in the setting of a reduced LVEF, then a discussion regarding cardiac resynchronization therapy or other physiological pacing needs to be held before the TAVR procedure (38).

    Due to the risks of reoperation, careful preprocedural evaluation, planning, and input from an electrophysiologist should be obtained to ensure that the correct type of cardiac implantable electronic device (CIED) is implanted for the patient's long-term needs. See Figure 5 for additional details.Pre-TAVR Patient Assessment and Guidance" data-icon-position data-hide-link-title="0">Figure 5 Pre-TAVR Patient Assessment and Guidance5.2 Intraprocedural TAVR ManagementPatients who are determined to have an elevated risk for complete AV heart block during pre-TAVR assessment require close perioperative electrocardiographic and hemodynamic monitoring. Aspects of the TAVR procedure itself that warrant consideration during the procedure in this group are listed in the following text (Figure 6).Intraprocedural TAVR Management" data-icon-position data-hide-link-title="0">Figure 6 Intraprocedural TAVR Management5.2.1 Negative Dromotropic and Chronotropic MedicationsYounis et al. (39) showed that discontinuation of chronic BB therapy in patients prior to TAVR was associated with increased need for pacing.

    Beta-adrenergic or calcium channel blocking drugs that affect the AV node (not the bundle of His, which is at risk for injury by TAVR) may be continued for those with pre-existing LBBB, RBBB, or bifascicular block with no advanced AV heart block or symptoms. In keeping with the anatomic considerations discussed in the previous text, these drugs should not affect AV conduction changes related to TAVR itself, since the aortic valve lies near the bundle of His and not the AV node. If these agents are provided in an evidence-based manner for related conditions (e.g., heart failure, coronary artery disease, atrial fibrillation), they should be continued. The dose should be titrated to heart rate and blood pressure goals, and this titration should occur prior to the day of procedure (40,41).5.2.2 AnesthesiaThere are no instances in which the presence of baseline conduction abnormalities would dictate type and duration of anesthesia during the procedure.

    Accordingly, the anesthetic technique most suited for the individual patient’s medical condition is best decided by the anesthesiologist in conjunction with the heart team.5.2.3 Procedural Temporary PacemakerCurrently, most centers implant a transvenous pacing wire electrode via the internal jugular or femoral vein to provide rapid ventricular pacing and thereby facilitate optimal valve implantation. For patients with ports, dialysis catheters, and/or hemodialysis fistulae, we recommend placement of temporary transvenous pacemaker via the femoral vein. Alternatively, recent data suggest that placing a guidewire directly into the LV can provide rapid ventricular pacing and overcome some of the complications arising from additional central venous access and right ventricular pacing (8,35,42). In a prospective multicenter randomized controlled trial, Faurie et al.

    (35) showed that LV pacing was associated with shorter procedure time (48.4 ± 16.9 min vs. 55.6 ± 26.9 min. P = 0.0013), shorter fluoroscopy time (13.48 ± 5.98 min vs. 14.60 ± 5.59 min.

    P = 0.02), and lower cost (€18,807 ± 1,318 vs. ‚¬19,437 ± 2,318. P = 0.001) compared with right ventricular pacing with similar efficacy and safety (35). This approach has been FDA approved and is in early utilization (43).

    Given that LV pacing wire cannot be left in place postprocedure it is a less attractive option in patients at high risk for conduction disturbances. Although existing experience does not currently inform the optimal pacing site for those at high risk of procedural heart block, it is reasonable to select temporary pacemaker placement via the right internal jugular vein over the femoral vein given ease of patient mobility should it be necessary to retain the temporary pacemaker postprocedure.5.2.4 Immediate Postprocedure Transvenous PacingIn patients deemed high risk for conduction disturbances, it is reasonable to either maintain the pre-existing temporary pacemaker in the right internal jugular vein or insert one into that vein if the femoral vein has been used for rapid pacing. Procedural conduction disturbances and postimplant 12-lead ECG will help determine the need for a temporary but durable pacing lead (e.g., active fixation lead from the right internal jugular vein). For the purposes of procedural management, the following are 3 possible clinical scenarios:1.

    No new conduction disturbances (<20 ms change in PR or QRS duration) (44–49);2. New-onset LBBB and/or increase in PR or QRS duration ≥20 ms. And3. Development of transient or persistent complete heart block.In patients with normal sinus rhythm and no new conduction disturbances on an ECG performed immediately postprocedure, the risk of developing delayed AV block is <1% (48–50).

    In these cases, the temporary pacemaker and central venous sheath can be removed immediately postprocedure, although continuous cardiac monitoring for 24 hours and a repeat 12-lead ECG the following day are recommended. This recommendation also applies to patients with pre-existing first-degree AV block and/or pre-existing LBBB (3,27,42,48), provided that PR or QRS intervals do not increase in duration after the procedure. Krishnaswamy et al. (51) recently reported the utility of using the temporary pacemaker electrode for rapid atrial pacing up to 120 beats per minute to predict the need for permanent pacing, finding a higher rate within 30 days of TAVR among the patients who developed second-degree Mobitz I (Wenckebach) AV block (13.1% vs.

    1.3%. P <. 0.001), with a negative predictive value for PPM implantation in the group without Wenckebach AV block of 98.7%. Patients receiving self-expanding valves required permanent pacing more frequently than those receiving a balloon-expandable valve (15.9% vs.

    3.7%. P = 0.001). For those who did not develop Wenckebach AV block, the rates of PPM were low (2.9% and 0.8%, respectively). The authors concluded that patients who did not develop pacing-induced Wenckebach AV block have a very low need for of permanent pacing (51).In patients with pre-existing RBBB, the risk of developing high-degree AV block during hospitalization is high (as much as 24%) and has been associated with all-cause and cardiovascular mortality post-TAVR (30).

    This risk of high-degree AV block exists for up to 7 days, and the latent risk is greater with self-expanding valves (52). Hence, in the population with pre-existing RBBB, it is reasonable to maintain transvenous pacing ability with continuous cardiac monitoring irrespective of new changes in PR or QRS duration for at least 24 hours. If the care team elects to remove the transvenous pacemaker in these cases, the ability to provide emergent pacing is critical. Recovery location (e.g., step-down unit, intensive care unit) and indwelling vascular access should be managed to accommodate this.Patients without pre-existing RBBB who develop LBBB or an increase in PR/QRS duration of ≥20 ms represent the most challenging group in terms of predicting progression to high-grade AV block and need for permanent pacing.

    Two meta-analyses, the first by Faroux et al. (53) and the second by Megaly et al. (54), showed that new-onset LBBB post-TAVR was associated with increased risk of PPM implantation (RR. 1.89.

    95% CI. 1.58 to 2.27. P <. 0.001) at 1-year follow-up and higher incidence of PPM (19.7% vs.

    P <. 0.001) during a mean follow-up of 20.5 ± 14 months, respectively, compared with those without a new-onset LBBB. In addition to the paucity of data, there is significant variation in the reported PR/QRS prolongation that confers risk of early and delayed high-grade AV block (34,44–47,55). We propose that the development of new LBBB or an increase in PR/QRS duration ≥20 ms in patients without pre-existing RBBB warrants continued transvenous pacing for at least 24 hours, in conjunction with continuous cardiac monitoring and daily ECGs during hospitalization.

    In the event that the transvenous pacemaker is removed after the procedure in these cases, recovery location and indwelling vascular access need to be appropriate for emergent pacing should it become necessary.A recent study employed atrial pacing immediately post-TAVR to predict the need for permanent pacing within 30 days. If second degree Mobitz I (Wenckebach) AV block did not occur with right atrial pacing (up to 120 beats per minute), only 1.3% underwent PPM by 30 days. Conversely, if Wenckebach AV block did occur, the rate was 13.1% (p <. 0.001).

    It is important to note that this group of patients included those with pre-existing and postimplant LBBB and RBBB (51). This is an interesting strategy and may ultimately inform routine length of monitoring in post-TAVR patients.During instances of transient high-grade AV block during valve deployment, it is reasonable to maintain the transvenous pacemaker in addition to continuous cardiac monitoring for at least 24 hours irrespective of the pre-existing conduction disturbance.For patients with transient or persistent high-grade AV block during or after TAVR, the temporary pacemaker should be left in place for at least 24 hours to assess for conduction recovery. If recurrent episodes of transient high-grade AV block occur in the intraoperative or postoperative period, PPM implantation should be considered prior to hospital discharge regardless of patient symptoms. Patients with persistent high-grade AV block should have PPM implanted.In patients with prior RBBB, transient or persistent procedural high-grade AV block is an indication for permanent pacing in the vast majority of cases, with an anticipated high requirement for ventricular pacing at follow-up (56,57).

    In these cases, a durable transvenous pacing lead is recommended prior to leaving the procedure suite.If permanent pacing is deemed necessary after TAVR, it is preferable to separate the procedures so that informed consent can occur and the procedures can be performed in their respective spaces with related necessary equipment and staff. When clinical and logistical circumstances warrant it, there are instances in which PPM implantation may be reasonable the same day as the TAVR (e.g., persistent complete heart block in patients with a pre-existing RBBB). When this has been anticipated, consent for PPM implantation may be obtained prior to TAVR. Otherwise, it is preferable that the patient is awake and able to provide consent before permanent device implantation.5.3 Conduction Disturbances After TAVR.

    Monitoring and ManagementDH-AVB has been reported in ∼10% of patients (47) and is conventionally defined as DH-AVB occurring >2 days after the procedure or after hospital discharge, the latter representing the larger proportion of this group. Whether this is a substrate for the observed rates of sudden cardiac death remains unclear, although syncope has been reported in tandem with devastating consequence (47). Although pre-existing RBBB and, in some reports, new LBBB are risk factors for DH-AVB (47,58), they do not reach sufficient sensitivity to identify those appropriate for preemptive pacing devices. Accordingly, different management strategies are often employed, ranging from electrophysiological studies (EPS) to prolonged inpatient monitoring and/or outpatient ambulatory event monitoring (AEM) (see Figure 7).Post-TAVR Management" data-icon-position data-hide-link-title="0">Figure 7 Post-TAVR ManagementThe role of EPS after TAVR to guide PPM has not been studied in a randomized prospective clinical trial.

    Although there are nonrandomized studies that describe metrics associated with PPM decisions, these metrics were determined retrospectively and without prospective randomization to PPM or no PPM on the basis of such measurements. In general, EPS is not needed for patients with a pre-existing or new indication for pacing, especially when the ECG finding is covered in the bradycardia pacing guidelines (6). In this setting, implantation can proceed without further study.At the other end of the spectrum are scenarios in which neither pacing nor EPS need be considered, such as for patients with sinus rhythm, chronotropic competence, no bradycardia, normal conduction, and no new conduction disturbance. Similarly, if there is first-degree AV block, second-degree Mobitz I (Wenckebach) AV block, a hemiblock by itself, or unchanged LBBB, neither a PPM nor EPS is indicated (27,48,55).

    Notably, Toggweiler et al. (48) reported that from a cohort of 1,064 patients who underwent TAVR, none of the 250 patients in sinus rhythm without conduction disorders developed DH-AVB. Only 1 of 102 patients with atrial fibrillation developed DH-AVB. And no patient with a stable ECG for ≥2 days developed DH-AVB.

    The authors suggested that since such patients without conduction disorders post-TAVR did not develop DH-AVB, they may not even require telemetry monitoring and that all others should be monitored until the ECG is stable for at least 2 days (48).Patients in the middle of the spectrum described in the previous text are those best suited for EPS because for them, the appropriateness of pacing is unclear. Predictors of need for pacing include new LBBB, new RBBB, old or new LBBB with an increase in PR duration >20 ms, an isolated increase in PR duration ≥40 ms, an increase in QRS duration ≥22 ms in sinus rhythm, and atrial fibrillation with a ventricular response <100 beats per minute in the presence of old or new LBBB (34,56,59,60). These individuals have, in some cases, been risk-stratified by EPS. Rivard et al.

    (61) found that a ≥13-ms increase in His-ventricular (HV) interval between pre- and post-TAVR measurements correlated with TAVR-associated AVB, and, especially for those with new LBBB, a post-TAVR HV interval ≥65 ms predicted subsequent AVB. Therefore, when these changes are identified on EPS, Rivard et al. (61) suggest that pacing is necessary or appropriate. A limitation of this study is that EPS is required pre-TAVR (61).

    Tovia-Brodie et al. (59) implanted PPM in post-TAVR patients with an HV interval ≥75 ms, but there was no control group with patients who did not receive a device. Rogers et al. (62) justified PPM in situations in which an HV interval ≥100 ms was recorded at post-TAVR EPS either without or after procainamide challenge, but the study was neither randomized nor controlled, and the 100-ms interval chosen was based on old electrophysiology data related to predicting heart block not associated with TAVR.

    In this study, intra- or infra-His block also led to PPM implantation (62). Finally, second-degree AV block provoked by atrial pacing at a rate <150 beats per minute (cycle length >400 ms) predicted PPM implantation (59). Limitations of these studies include their lack of a control group for comparison, meaning that outcomes without pacing are unknown.In the study by Makki et al. (63), 24 patients received a PPM in-hospital (14% of the total cohort) and 7 (29%) as the result of an abnormal EPS.

    The indications for EPS were new LBBB, second-degree AV block, and transient third-degree AV block. With a mean follow-up of 22 months and assessment of nonpaced rhythms in those with a PPM who both had and did not have EPS, the authors concluded that pacemaker dependency after TAVR is common among those who had demonstrated third-degree AV block pre-PPM but not among those with a prolonged HV delay during EPS. Limitations of this study are its small size and the fact that new LBBB was the primary indication for EPS. The observation that a minority of post-TAVR patients are pacemaker-dependent upon follow-up underscores the often transient nature of the myocardial injury and the complexity of identifying those who will benefit from a long-term indwelling device (64).Although algorithms for PPM implantation have been proposed that are based on ECG criteria without EPS (65) and with EPS (59,61,62), all are based on opinion and observational rather than prospective data.

    Provided one recognizes the limitations of the studies reviewed earlier, EPS can be used for decision making when a definitive finding is identified that warrants pacing, such as infra-His block during atrial pacing, a prolonged HV interval with split His potentials (intra-Hisian conduction disturbance with 2 distinct, separated electrogram potentials), or an extremely long HV interval with either RBBB or LBBB (6). Although studies are forthcoming, the currently available data do not support PPM indications specific to the TAVR population.A reassuring addition to the literature from Ream et al. (47) reported that although AV block developed ≥2 days post-TAVR in 18 (12%) of 150 consecutive patients, it occurred in only 1 patient between days 14 and 30. Importantly, of those with DH-AVB, only 5 had symptoms (dizziness in 3, syncope in 2) and there were no deaths.

    The greatest risk factor for developing DH-AVB was baseline RBBB (risk 26-fold). The PR interval and even the development of LBBB were not predictors of DH-AVB. The authors recommended electrophysiology consultation for EPS and/or PPM implantation for patients with high-risk pre-TAVR ECGs (e.g., with a finding of RBBB), those with intraprocedure high-degree AV block, and for those who, on monitoring, have high-degree AV block (47). Thus, for patients not receiving an early PPM, follow-up without EPS but with short-term monitoring is reasonable when there is not a clear indication for pacing immediately after TAVR.For those who are without clear pacemaker indications during their procedural hospitalization but are at risk for DH-AVB, prolonged monitoring is often employed.

    The length of inpatient telemetry monitoring varies but reflects the timing of AVB after TAVR, clustering within the first 7 to 8 days postprocedure (47,48,58). The cost and inherent risks of prolonged hospitalization for telemetry have prompted the evaluation of AEM strategies in 3 patient populations. 1) all patients without a pacemaker at the time of discharge after TAVR. 2) those with new LBBB.

    And 3) those with any new or progressive conduction abnormality after TAVR.The largest post-TAVR AEM study to date observed 118 patients after discharge for 30 days. Twelve of these (10%) had DH-AVB at a median of 6 days (range 3 to 24 days), with 10 of the 12 events occurring within 8 days. One of these patients with an event had no pre- or post-TAVR conduction abnormalities, and new LBBB was not identified as a risk factor for subsequent DH-AVB. The AEM and surveillance infrastructure employed in this study enabled the prompt identification of DH-AVB, and no serious adverse events occurred in the group that experienced it (47).

    However, in the observational experience preceding this study, the same group reported 4 patients (of 158 without a PPM at discharge) who experienced DH-AVB necessitating readmission, all within 10 days of the procedure (range 8 to 10 days). Three underwent uncomplicated PPM implantation, although 1 sustained syncope and fatal intracranial hemorrhage. Importantly, for this group, routine AEM was not in place, and none of these patients had baseline or postprocedure conduction disturbances (46). While others have observed no DH-AVB in those without pre-existing or post-TAVR conduction disturbances, or with a stable ECG 2 days after TAVR (0 of 250 patients), AEM postdischarge was not employed, raising the possibility of under-reporting (48).The MARE (Ambulatory Electrocardiographic Monitoring for the Detection of High-Degree Atrio-Ventricular Block in Patients With New-onset PeRsistent LEft Bundle Branch Block After Transcatheter Aortic Valve Implantation) trial enrolled patients (n = 103) with new-onset and persistent LBBB after TAVR, a common conduction abnormality post-TAVR and one associated with DH-AVB and sudden death in some observations (6,27,34,48,55,58,59).

    Patients meeting these criteria had a loop recorder implanted at discharge. Ten patients (10%) underwent permanent pacing due to DH-AVB (n = 9) or bradycardia (n = 1) at a median of 30 days post-TAVR (range 5 to 281 days). Although the rate of PPM implantation was relatively consistent throughout the observational period, it is important to note that the median length of stay in this cohort was 7 days, whereas the current median in the United States is approximately 2 days (66). There was a single sudden cardiac death 10 months after discharge, and presence or absence of an arrhythmogenic origin was not determined as the patient’s implantable loop recorder was not interrogated (58).A third prospective observational study enrolled patients with new conduction disturbances (first- or second-degree heart block, or new bundle branch block) after TAVR that did not progress to conventional pacemaker indications during hospitalization.

    These patients were offered AEM for 30 days after discharge. Among the 54 patients, 3 (6%) underwent PPM within 30 days. Two of the patients had asymptomatic DH-AVB, and 1 had elected not to wear the AEM and suffered a syncopal event in the context of DH-AVB. No sudden cardiac death or other sequelae of DH-AVB were observed (47).Given these results, in patients with new or worsened conduction disturbance after TAVR (PR or QRS interval increase ≥10%), early discharge after TAVR is less likely to be safe.

    We recommend inpatient monitoring with telemetry for at least 2 days if the rhythm disturbance does not progress, and up to 7 days if AEM is not going to be employed. We suggest that it is appropriate to provide AEM to any patient with a PR or QRS interval that is new or extended by ≥10%, and that this monitoring should occur for at least 14 days postdischarge. The heart team and the AEM monitor employed should have the capacity to receive and respond to DH-AVB within an hour and to dispatch appropriate emergency medical services.We also acknowledge the shortcomings of existing observational experience. These include that DH-AVB has been identified in patients with normal ECGs pre- and post-TAVR, and that 14 or even 30 days of monitoring is unlikely to be sufficient to capture all occurrences of DH-AVB.

    Ongoing and forthcoming studies and technology will enable the development of more sophisticated protocols and of device systems that facilitate adherence, real-time monitoring, and effective response times in an economically viable manner.Source Search for this keyword Search.

    What should my health care professional know before I take Propecia?

    They need to know if you have any of these conditions:

    • if you are female (finasteride is not for use in women)
    • kidney disease or
    • liver disease
    • prostate cancer
    • an unusual or allergic reaction to finasteride, other medicines, foods, dyes, or preservatives

    Can propecia cause hair loss

    NONE

    IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ in the composition of the multidisciplinary can propecia cause hair loss teams that provide care for patients who have propecia best results a DSD.11 14 Several projects have now worked to resolve this variability in care. The European can propecia cause hair loss 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 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 can propecia cause hair loss 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 can propecia cause hair loss across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature thus far because they reflect evolving technologies or less visible stakeholders. For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant referral to a specialised team may be challenging, especially for professionals with limited experience in DSD.22 23 can propecia cause hair loss 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 can propecia cause hair loss the postnatal team and from the paediatric to the adult team requires optimal communication between the specialists involved. Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed can propecia cause hair loss with all members responsible for updating the literature for a specific part of the guideline.

    Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in can propecia cause hair loss testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper. Abstracts had to be written in English and were identified using a broad range of Medical Subject Headings terms (eg, DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, can propecia cause hair loss 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 can propecia cause hair loss 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 can propecia cause hair loss points of discussion, revised into a final draft.

    This version was sent to a broad group of professionals from academic centres and DSD teams whose members had volunteered to review the draft guideline. After receiving and incorporating their input, the final version can propecia cause hair loss was presented to the paediatric and genetic associations for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur earlier, for example, when a commercial ultrasound is performed at the request of the parents.Another way DSD can be diagnosed before birth is when can propecia cause hair loss 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 can propecia cause hair loss findings. NIPT screens for CNVs in the fetus. However, depending on legal restrictions can propecia cause hair loss and/or ethical considerations, the X and Y chromosomes are not always included in NIPT analysis and reports.

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

    The procedure(s) that can be followed, including the risks associated with an amniocentesis. And the can propecia cause hair loss type of information genetic testing can and cannot provide. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved. The clinical geneticist should be experienced in prenatal counselling and well informed about can propecia cause hair loss 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 pregnancy.

    Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting parents may also consider termination of can propecia cause hair loss 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 can propecia cause hair loss knowing exactly what the child’s genitalia will look like and uncertainty about the diagnosis, treatment and prognosis cannot be avoided completely. Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images.

    In our experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a contact person before birth.After expert prenatal counselling, a significant number of pregnant can propecia cause hair loss couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist. The terminology used in communication with parents should be carefully chosen,22 23 and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for can propecia cause hair loss 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 can propecia cause hair loss anomalies and fetal growth restriction being particularly common.27 28 If additional anomalies are seen, the geneticist can consider specific gene defects that may underlie a known genetic syndrome or carry out NGS. NGS-based techniques have also now made their appearance in prenatal diagnosis of congenital anomalies.29 30 Panels using these techniques can be specific for genes involved in DSD, or be larger panels covering multiple congenital anomalies, and are usually employed with trio-analysis to compare variants identified in the child with the parents’ genetics.29–31 Finding a genetic cause before delivery can help reduce parental stress in the neonatal period and speed up decisions regarding gender assignment. In such cases there is no tight time limit, and we propose completing the analysis well before the expected delivery.Disorders/differences of sex development can propecia cause hair loss (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 http://www.amisdepasteur.fr/propecia-online-in-canada/ contrast to cancers of most other sites, cancer-specific mortality has risen by approximately 2% every year since 2008 related to the rapidly rising incidence.2Endometrial cancer has traditionally been classified into type I and type II based on morphology.3 The more common subtype, type I, is mostly comprised of endometrioid tumours and is oestrogen-driven, arises from a hyperplastic endometrium, presents at an early stage and has an excellent 5 year survival rate.4 By contrast, type II includes non-endometrioid tumours, specifically serous, carcinosarcoma and clear cell subtypes, which are biologically aggressive tumours with a poor prognosis that are often diagnosed at an advanced stage.5 Recent efforts have focused on a molecular classification system for more accurate categorisation of endometrial tumours into four groups with distinct prognostic profiles.6 7The majority of endometrial cancers arise through the interplay of familial, genetic and lifestyle factors. Two inherited cancer predisposition syndromes, Lynch syndrome and the much rarer Cowden syndrome, substantially increase the lifetime risk of endometrial cancer, but these only account for around 3–5% of cases.8–10 Having first or second degree relative(s) with endometrial or colorectal cancer increases endometrial cancer risk, although a large European twin study failed to demonstrate a strong heritable link.11 The authors failed to show that there was greater concordance in monozygotic than dizygotic twins, but the study was based on relatively small numbers of endometrial cancers. Lu and colleagues reported an association between common single nucleotide polymorphisms (SNPs) and endometrial cancer risk, revealing the potential role of SNPs in explaining part of the risk in both the familial and general populations.12 Thus far, many SNPs have been reported to modify susceptibility to endometrial cancer. However, much of this work predated genome wide association studies and is of variable quality.

    Understanding genetic predisposition to endometrial cancer could facilitate personalised risk assessment with a view to targeted prevention and screening interventions.13 This emerged as the most important unanswered research question in endometrial cancer according to patients, carers and healthcare professionals in our recently completed James Lind Womb Cancer Alliance Priority Setting Partnership.14 It would be particularly useful for non-endometrioid endometrial cancers, for which advancing age is so far the only predictor.15We therefore conducted a comprehensive systematic review of the literature to provide an overview of the relationship between SNPs and endometrial cancer risk. We compiled a list of the most robust endometrial cancer-associated SNPs. We assessed the applicability of this panel of SNPs with a theoretical polygenic risk score (PRS) calculation. We also critically appraised the meta-analyses investigating the most frequently reported SNPs in MDM2.

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

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

    Chronbach’s α score was calculated between reviewers and indicated high consistency at 0.92. Case–control, prospective and retrospective studies, genome-wide association studies (GWAS), and both discovery and validation studies were selected for full-text evaluation. Non-English articles, editorials, conference abstracts and proceedings, letters and correspondence, case reports and review articles were excluded.Candidate-gene studies with at least 100 women and GWAS with at least 1000 women in the case arm were selected to ensure reliability of the results, as explained by Spencer et al.18 To construct a panel of up to 30 SNPs with the strongest evidence of association, those with the strongest p values were selected. For the purpose of an SNP panel, articles utilising broad European or multi-ethnic cohorts were selected.

    Where overlapping populations were identified, the most comprehensive study was included.Data extraction and synthesisFor each study, the following data were extracted. SNP ID, nearby gene(s)/chromosome location, OR (95% CI), p value, minor or effect allele frequency (MAF/EAF), EA (effect allele) and OA (other allele), adjustment, ethnicity and ancestry, number of cases and controls, endometrial cancer type, and study type including discovery or validation study and meta-analysis. For risk estimates, a preference towards most adjusted results was applied. For candidate-gene studies, a standard p value of<0.05 was applied and for GWAS a p value of <5×10-8, indicating genome-wide significance, was accepted as statistically significant.

    However, due to the limited number of SNPs with p values reaching genome-wide significance, this threshold was then lowered to <1×10-5, allowing for marginally significant SNPs to be included. As shown by Mavaddat et al, for breast cancer, SNPs that fall below genome-wide significance may still be useful for generating a PRS and improving the models.19We estimated the potential value of a PRS based on the most significant SNPs by comparing the predicted risk for a woman with a risk score in the top 1% of the distribution to the mean predicted risk. Per-allele ORs and MAFs were taken from the publications and standard errors (SEs) for the lnORs were derived from published 95% CIs. The PRS was assumed to have a Normal distribution, with mean 2∑βipI and SE, σ, equal to √2∑βi2pI(1−pi), according to the binomial distribution, where the summation is over all SNPs in the risk score.

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

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

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

    PLoS Med 6(6). E1000097. Doi:10.1371/journal.pmed1000097." data-icon-position data-hide-link-title="0">Figure 1 Study selection flow diagram. *Reasons.

    Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009).

    Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement. PLoS Med 6(6). E1000097.

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

    Those having a multi-ethnic cohort also consisted primarily of broad European populations. Only four of the variants in table 1 are located in coding regions of a gene, or in regulatory flanking regions around the gene. Thus, most of these variants would not be expected to cause any functional effects on the gene or the resulting protein. An eQTL search using GTEx Portal showed that some of the SNPs are significantly associated (p<0.05) with modified transcription levels of the respective genes in various tissues such as prostate (rs11263761), thyroid (rs9668337), pituitary (rs2747716), breast mammary (rs882380) and testicular (rs2498794) tissue, as summarised in table 2.View this table:Table 2 List of eQTL hits for the selected panel of SNPsThe only variant for which there was an indication of a specific association with non-endometrioid endometrial cancer was rs148261157 near the BCL11A gene.

    The A allele of this SNP had a moderately higher association in the non-endometrioid arm (OR 1.64, 95% CI 1.32 to 2.04. P=9.6×10-6) compared with the endometrioid arm (OR 1.25, 95% CI 1.14 to 1.38. P=4.7×10-6).21Oestrogen receptors α and β encoded by ESR1 and ESR2, respectively, have been extensively studied due to the assumed role of oestrogens in the development of endometrial cancer. O’Mara et al reported a lead SNP (rs79575945) in the ESR1 region that was associated with endometrial cancer (p=1.86×10-5).24 However, this SNP did not reach genome-wide significance in a more recent larger GWAS.21 No statistically significant associations have been reported between endometrial cancer and SNPs in the ESR2 gene region.AKT is an oncogene linked to endometrial carcinogenesis.

    It is involved in the PI3K/AKT/mTOR pro-proliferative signalling pathway to inactivate apoptosis and allow cell survival. The A allele of rs2494737 and G allele of rs2498796 were reported to be associated with increased and decreased risk of endometrial cancer in 2016, respectively.22 30 However, this association was not replicated in a larger GWAS in 2018.21 Nevertheless, given the previous strong indications, and biological basis that could explain endometrial carcinogenesis, we decided to include an AKT1 variant (rs2498794) in our results.PTEN is a multi-functional tumour suppressor gene that regulates the AKT/PKB signalling pathway and is commonly mutated in many cancers including endometrial cancer.32 Loss-of-function germline mutations in PTEN are responsible for Cowden syndrome, which exerts a lifetime risk of endometrial cancer of up to 28%.9 Lacey and colleagues studied SNPs in the PTEN gene region. However, none showed significant differences in frequency between 447 endometrial cancer cases and 439 controls of European ancestry.33KRAS mutations are known to be present in endometrial cancer. These can be activated by high levels of KLF5 (transcriptional activator).

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

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

    Two more original studies were identified through our full-text evaluation. However, these were not included here as they did not meet our inclusion criteria—one due to small sample size, the other due to studying rs2279744 status dependent on another SNP.36 37 Even so, the two studies were described in multiple meta-analyses that are listed in table 3. Different permutations of these eight original studies appear in at least eight published meta-analyses. However, even the largest meta-analysis contained <2000 cases (table 3)38View this table:Table 3 Characteristics of studies that examined MDM2 SNP rs2279744In comparison, a GWAS including nearly 13 000 cases found no evidence of an association with OR and corresponding 95% CI of 1.00 (0.97 to 1.03) and a p value of 0.93 (personal communication).21 Nevertheless, we cannot completely rule out a role for MDM2 variants in endometrial cancer predisposition as the candidate-gene studies reported larger effects in Asians, whereas the GWAS primarily contained participants of European ancestry.

    There is also some suggestion that the SNP309 variant is in linkage disequilibrium with another variant, SNP285, which confers an opposite effect.It is worth noting that the SNP285C/SNP309G haplotype frequency was observed in up to 8% of Europeans, thus requiring correction for the confounding effect of SNP285C in European studies.39 However, aside from one study conducted by Knappskog et al, no other study including the meta-analyses corrected for the confounding effect of SNP285.40 Among the studies presented in table 3, Knappskog et al (2012) reported that after correcting for SNP285, the OR for association of this haplotype with endometrial cancer was much lower, though still significant. Unfortunately, the meta-analyses which synthesised Knappskog et al (2012), as part of their analysis, did not correct for SNP285C in the European-based studies they included.38 41 42 It is also concerning that two meta-analyses using the same primary articles failed to report the same result, in two instances.38 42–44DiscussionThis article represents the most comprehensive systematic review to date, regarding critical appraisal of the available evidence of common low-penetrance variants implicated in predisposition to endometrial cancer. We have identified the most robust SNPs in the context of endometrial cancer risk. Of those, only 19 were significant at genome-wide level and a further five were considered marginally significant.

    The largest GWAS conducted in this field was the discovery- and meta-GWAS by O’Mara et al, which utilised 12 096 cases and 108 979 controls.21 Despite the inclusion of all published GWAS and around 5000 newly genotyped cases, the total number did not reach anywhere near what is currently available for other common cancers such as breast cancer. For instance, BCAC (Breast Cancer Association Consortium) stands at well over 200 000 individuals with more than half being cases, and resulted in identification of ~170 SNPs in relation to breast cancer.19 45 A total of 313 SNPs including imputations were then used to derive a PRS for breast cancer.19 Therefore, further efforts should be directed to recruit more patients, with deep phenotypic clinical data to allow for relevant adjustments and subgroup analyses to be conducted for better precision.A recent pre-print study by Zhang and colleagues examined the polygenicity and potential for SNP-based risk prediction for 14 common cancers, including endometrial cancer, using available summary-level data from European-ancestry datasets.46 They estimated that there are just over 1000 independent endometrial cancer susceptibility SNPs, and that a PRS comprising all such SNPs would have an area under the receiver-operator curve of 0.64, similar to that predicted for ovarian cancer, but lower than that for the other cancers in the study. The modelling in the paper suggests that an endometrial cancer GWAS double the size of the current largest study would be able to identify susceptibility SNPs together explaining 40% of the genetic variance, but that in order to explain 75% of the genetic variance it would be necessary to have a GWAS comprising close to 150 000 cases and controls, far in excess of what is currently feasible.We found that the literature consists mainly of candidate-gene studies with small sample sizes, meta-analyses reporting conflicting results despite using the same set of primary articles, and multiple reports of significant SNPs that have not been validated by any larger GWAS. The candidate-gene studies were indeed the most useful and cheaper technique available until the mid to late 2000s.

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

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

    It is therefore unequivocal that the literature is crowded with numerous small candidate-gene studies and conflicting data. This makes it particularly hard to detect novel SNPs and conduct meaningful meta-analyses.We found convincing evidence for 19 variants that indicated the strongest association with endometrial cancer, as shown in table 1. The associations between endometrial cancer and variants in or around HNF1B, CYP19A1, SOX4, MYC, KLF and EIF2AK found in earlier GWAS were then replicated in the latest and largest GWAS. These SNPs showed promising potential in a theoretical PRS we devised based on published data.

    Using all 24 or genome-wide significant SNPs only, women with a PRS in the top 1% of the distribution would be predicted to have a risk of endometrial cancer 3.16 and 2.09 times higher than the mean risk, respectively.However, the importance of these variants and relevance of the proximate genes in a functional or biological context is challenging to evaluate. Long distance promoter regulation by enhancers may disguise the genuine target gene. In addition, enhancers often do not loop to the nearest gene, further complicating the relevance of nearby gene(s) to a GWAS hit. In order to elucidate biologically relevant candidate target genes in endometrial cancer, O’Mara et al looked into promoter-associated chromatin looping using a modern HiChIP approach.47 The authors utilised normal and tumoural endometrial cell lines for this analysis which showed significant enrichment for endometrial cancer heritability, with 103 candidate target genes identified across the 13 risk loci identified by the largest ECAC GWAS.

    Notable genes identified here were CDKN2A and WT1, and their antisense counterparts. The former was reported to be nearby of rs1679014 and the latter of rs10835920, as shown in table 1. Moreover, of the 36 candidate target genes, 17 were found to be downregulated while 19 were upregulated in endometrial tumours.The authors also investigated overlap between the 13 endometrial cancer risk loci and top eQTL variants for each target gene.47 In whole blood, of the two particular lead SNPs, rs8822380 at 17q21.32 was a top eQTL for SNX11 and HOXB2, whereas rs937213 at 15q15.1 was a top eQTL for SRP14. In endometrial tumour, rs7579014 at 2p16.1 was found to be a top eQTL for BCL11A.

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

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

    This poses a problem for developing risk prediction models that are equally valuable and predictive across populations. Thus, our results also are of limited applicability to non-European populations.Furthermore, considering that non-endometrioid cases comprise a small proportion (~20%) of all endometrial cancer cases, much larger cohort sizes are needed to detect any genuine signals for non-endometrioid tumours. Most of the evaluated studies looked at either overall/mixed endometrial cancer subtypes or endometrioid histology, and those that looked at variant associations with non-endometrioid histology were unlikely to have enough power to detect any signal with statistical significance. This is particularly concerning because non-endometrioid subtypes are biologically aggressive tumours with a much poorer prognosis that contribute disproportionately to mortality from endometrial cancer.

    It is particularly important that attempts to improve early detection and prevention of endometrial cancer focus primarily on improving outcomes from these subtypes. It is also worth noting that, despite the current shift towards a molecular classification of endometrial cancer, most studies used the overarching classical Bokhman’s classification system, type I versus type II, or no histological classification system at all. Therefore, it is important to create and follow a standardised and comprehensive classification system for reporting tumour subtypes for future studies.This study compiled and presented available information for an extensively studied, yet unproven in large datasets, SNP309 variant in MDM2. Currently, there is no convincing evidence for an association between this variant and endometrial cancer risk.

    Additionally, of all the studies, only one accounted for the opposing effect of a nearby variant SNP285 in their analyses. Thus, we conclude that until confirmed by a sufficiently large GWAS, this variant should not be considered significant in influencing the risk of endometrial cancer and therefore not included in a PRS. This is also true for the majority of the SNPs reported in candidate-gene studies, as the numbers fall far short of being able to detect genuine signals.This systematic review presents the most up-to-date evidence for endometrial cancer susceptibility variants, emphasising the need for further large-scale studies to identify more variants of importance, and validation of these associations. Until data from larger and more diverse cohorts are available, the top 24 SNPs presented here are the most robust common genetic variants that affect endometrial cancer risk.

    The multiplicative effects of these SNPs could be used in a PRS to allow personalised risk prediction models to be developed for targeted screening and prevention interventions for women at greatest risk of endometrial cancer..

    IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ in the composition of the multidisciplinary increasing propecia dosage teams that provide care for patients who have a DSD.11 14 Several projects where do i get propecia 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 where do i get propecia common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them.

    Nonetheless, four DSD (expert) centres located in the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline where do i get propecia 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 where do i get propecia or less visible stakeholders.

    For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant where do i get propecia 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 adult team requires optimal communication between where do i get propecia 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 where do i get propecia the literature for a specific part of the guideline.

    Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to substantiate where do i get propecia 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, where do i get propecia DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, guideline, multidisciplinary care). Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were excluded, as were articles that were not open access or retrievable through where do i get propecia 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 where do i get propecia the writing committee and, after having obtained agreement on remaining points of discussion, revised into a final draft. This version was sent to a broad group of professionals from academic centres and DSD teams whose members had volunteered to review the draft guideline.

    After receiving and incorporating their input, the final version where do i get propecia was presented to the paediatric and genetic associations for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur earlier, for example, when a commercial ultrasound is performed at the request of the parents.Another way DSD can be diagnosed before birth is where do i get propecia 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 where do i get propecia 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 where do i get propecia 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 where do i get propecia (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team.

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

    And the where do i get propecia type of information genetic testing can and cannot provide. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved. The clinical geneticist should be experienced in prenatal counselling and well informed about the diagnostic possibilities given the limited time span in which test results need to be available to allow parents to make a well-informed decision about whether or not where do i get propecia to continue the pregnancy.

    Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting parents may also consider termination of pregnancy, which, although considered controversial by some, is legal where do i get propecia 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 where do i get propecia what the child’s genitalia will look like and uncertainty about the diagnosis, treatment and prognosis cannot be avoided completely.

    Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images. In our experience, parents appreciate having already spoken to some members where do i get propecia of the DSD team during pregnancy and having a contact person before birth.After expert prenatal counselling, a significant number of pregnant couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist.

    The terminology used in communication with parents should be carefully chosen,22 23 and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for where do i get propecia 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 where do i get propecia being particularly common.27 28 If additional anomalies are seen, the geneticist can consider specific gene defects that may underlie a known genetic syndrome or carry out NGS.

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