Citations

A large number of variants identified through clinical genetic testing in disease susceptibility genes are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion) can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analysis of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC) and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity—findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared with classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and preformatted Excel calculators for implementation of the method for rare variants in BRCA1, BRCA2, and other high-risk genes with known penetrance.

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

Objective To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. Methods This international multidisciplinary initiative included 4 phases: 1) Phase I, criteria generation by surveys and literature review; 2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; 3) Phase III, criteria definition, further reduction with the guidance of real‐world patient scenarios, and weighting via consensus‐based multicriteria decision analysis, and threshold identification; and 4) Phase IV, validation using independent adjudicators’ consensus as the gold standard. Results The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL‐associated clinical criterion, followed by additive weighted criteria (score range 1–7 points each) clustered into 6 clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and 2 laboratory domains (lupus anticoagulant functional coagulation assays, and solid‐phase enzyme‐linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti–β 2 ‐glycoprotein I antibodies). Patients accumulating at least 3 points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria versus the 2006 revised Sapporo classification criteria had a specificity of 99% versu s 86%, and a sensitivity of 84% versus 99%. Conclusion These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk‐stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.

Background Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. Methods We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. Results In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). Conclusions Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.

Abstract Background Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC‐specific survival (BCSS) compared to non‐carriers. Aim To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Methods Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow‐up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi‐state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. Results There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi‐state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non‐carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09–1.56)]. Conclusion Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.

Background: Forty percent of women will experience prolapse in their lifetime. Vaginal pessaries are considered the first line of treatment in selected patients. Major complications of vaginal pessaries rarely occur. Methods: PubMed and Embase were searched from 1961 to 2022 for major complications of vaginal pessaries using Medical Subject Headings (MeSH) and free-text terms. The keywords were pessary or pessaries and: vaginal discharge, incontinence, entrapment, urinary infections, fistula, complications, and vaginal infection. The exclusion criteria were other languages than English, pregnancy, complications without a prior history of pessary placement, pessaries unregistered for clinical practice (herbal pessaries), or male patients. The extracted data included symptoms, findings upon examination, infection, type of complication, extragenital symptoms, and treatment. Results: We identified 1874 abstracts and full text articles; 54 were assessed for eligibility and 49 met the inclusion criteria. These 49 studies included data from 66 patients with pessary complications amenable to surgical correction. Clavien–Dindo classification was used to grade the complications. Most patients presented with vaginal symptoms such as bleeding, discharge, or ulceration. The most frequent complications were pessary incarceration and fistulas. Surgical treatment included removal of the pessary under local or general anesthesia, fistula repair, hysterectomy and vaginal repair, and the management of bleeding. Conclusions: Pessaries are a reasonable and durable treatment for pelvic organ prolapse. Complications are rare. Routine follow-ups are necessary. The ideal patient candidate must be able to remove and reintroduce their pessary on a regular basis; if not, this must be performed by a healthcare worker at regular intervals.

Introduction Postcardiotomy veno-arterial extracorporeal membrane oxygenation (V-A-ECMO) is associated with significant mortality. Identification of patients at very high risk for death is elusive and the decision to initiate V-A-ECMO is based on clinical judgment. The prognostic impact of pre-V-A-ECMO arterial lactate level in these critically ill patients has been herein evaluated. Methods A systematic review was conducted to identify studies on postcardiotomy VA-ECMO for the present individual patient data meta-analysis. Results Overall, 1269 patients selected from 10 studies were included in this analysis. Arterial lactate level at V-A-ECMO initiation was increased in patients who died during the index hospitalization compared to those who survived (9.3 vs 6.6 mmol/L, p < 0.0001). Accordingly, in hospital mortality increased along quintiles of pre-V-A-ECMO arterial lactate level (quintiles: 1, 54.9%; 2, 54.9%; 3, 67.3%; 4, 74.2%; 5, 82.2%, p < 0.0001). The best cut-off for arterial lactate was 6.8 mmol/L (in-hospital mortality, 76.7% vs. 55.7%, p < 0.0001). Multivariable multilevel mixed-effect logistic regression model including arterial lactate level significantly increased the area under the receiver operating characteristics curve (0.731, 95% CI 0.702–0.760 vs 0.679, 95% CI 0.648–0.711, DeLong test p < 0.0001). Classification and regression tree analysis showed the in-hospital mortality was 85.2% in patients aged more than 70 years with pre-V-A-ECMO arterial lactate level ≥6.8 mmol/L. Conclusions Among patients requiring postcardiotomy V-A-ECMO, hyperlactatemia was associated with a marked increase of in-hospital mortality. Arterial lactate may be useful in guiding the decision-making process and the timing of initiation of postcardiotomy V-A-ECMO.

Abstract Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. We aimed to assess the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Analyses were based on 82,701 women diagnosed with invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations of treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR(95%CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR(95%CI) :1.30 (1.09–1.56)]. In conclusion, systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk. (Main MS: 3201 words)

Abstract Background Hereditary transthyretin-mediated (hATTR) amyloidosis, also known as ATTRv amyloidosis, is a fatal, multisystem disease that presents with progressive polyneuropathy and/or cardiomyopathy. HELIOS-A (NCT03759379) assessed the efficacy of vutrisiran, an investigational RNA interference therapeutic, in patients with hATTR amyloidosis with polyneuropathy. Purpose To evaluate the effect of 18 months of vutrisiran treatment on exploratory cardiac endpoints in the HELIOS-A Phase 3 study. Methods Patients were randomised (3:1) to vutrisiran (25 mg SC, q3m) or patisiran (0.3 mg/kg IV, q3w), a reference comparator. The APOLLO placebo group (n=77) was an external control. Primary endpoint was change from baseline in the modified Neuropathy Impairment Score +7 (mNIS+7) at 9 months, vs. external placebo. Exploratory cardiac endpoints included change from baseline in NT-proBNP levels, echocardiography parameters, and technetium (Tc) scintigraphy parameters at 18 months. A prespecified cardiac subpopulation was included (baseline left ventricular wall thickness ≥1.3 cm and no medical history of aortic valve disease or hypertension). Results HELIOS-A enrolled 164 patients and the primary endpoint was met. In the cardiac subpopulation (n=40/122 vutrisiran; n=36/77 placebo), 18 months of vutrisiran treatment significantly improved NT-ProBNP levels vs. external placebo (adjusted geometric fold change ratio: 0.49; p=0.0004) and demonstrated a trend towards improvement in echocardiographic parameters vs. external placebo (including a significant difference in cardiac output [least squares mean difference: 0.41; p=0.043]). Of the 122 vutrisiran-treated patients, 99mTc scintigraphy assessment was captured for 64 vutrisiran-treated patients at baseline, 35 (54.7%) of whom had Perugini grade ≥2 (moderate/intense) cardiac uptake of 99mTc. Among patients with evaluable scintigraphy parameters repeated at 18 months (evaluable patients), heart-to-contralateral lung ratio and normalised LV total uptake on scintigraphy improved (decrease from baseline) in 64.6% (31/48) and 68.1% (32/47), respectively, at 18 months. Of the evaluable patients, 28.1% (16/57) had an improvement (reduction from baseline) in Perugini grade of cardiac uptake, 68.4% (39/57) had no change in grade, and 3.5% (2/57) worsened in grade. Of evaluable patients with baseline Perugini grade ≥2, the proportion with improvement in heart-to-contralateral lung ratio and normalised LV total uptake was 76.9% (20/26) and 100% (25/25) respectively. No cardiac safety concerns were identified with vutrisiran treatment. Conclusions In this exploratory analysis, vutrisiran treatment was associated with a positive impact on NT-ProBNP levels and echocardiographic parameters vs. external placebo in the cardiac subpopulation. Vutrisiran treatment also reduced cardiac uptake of 99mTc potentially suggesting reduction in cardiac amyloid, although the clinical significance of this is not yet clear.