Citations

Abstract Aims Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder. Methods and results We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors. Conclusion We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-β signalling molecules and spectrin β. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention.

Abstract Stroke represents a considerable burden of disease for both men and women. However, a growing body of literature suggests clinically relevant sex differences in the underlying causes, presentations and outcomes of acute ischaemic stroke. In a recent study, we reported sex divergences in lesion topographies: specific to women, acute stroke severity was linked to lesions in the left-hemispheric posterior circulation. We here determined whether these sex-specific brain manifestations also affect long-term outcomes. We relied on 822 acute ischaemic patients [age: 64.7 (15.0) years, 39% women] originating from the multi-centre MRI-GENIE study to model unfavourable outcomes (modified Rankin Scale >2) based on acute neuroimaging data in a Bayesian hierarchical framework. Lesions encompassing bilateral subcortical nuclei and left-lateralized regions in proximity to the insula explained outcomes across men and women (area under the curve = 0.81). A pattern of left-hemispheric posterior circulation brain regions, combining left hippocampus, precuneus, fusiform and lingual gyrus, occipital pole and latero-occipital cortex, showed a substantially higher relevance in explaining functional outcomes in women compared to men [mean difference of Bayesian posterior distributions (men – women) = −0.295 (90% highest posterior density interval = −0.556 to −0.068)]. Once validated in prospective studies, our findings may motivate a sex-specific approach to clinical stroke management and hold the promise of enhancing outcomes on a population level.

Objective: To analyze insulin delivery and glycemic metrics throughout the menstrual cycle for women with type 1 diabetes using closed loop control (CLC) insulin delivery. Methods: Menstruating women using a CLC system in a clinical trial were invited to record their menstrual cycles through a cycle-tracking application. Sixteen participants provided data for this secondary analysis over three or more complete cycles. Insulin delivery and continuous glucose monitoring (CGM) data were analyzed in relation to reported cycle phases. Results: Insulin delivery and CGM metrics remained consistent during cycle phases. Intraparticipant variability of CGM metrics and weight-based insulin delivery did not change through cycle phases. Conclusions: For this sample of menstruating women with type 1 diabetes using a CLC system, insulin delivery and glycemic metrics remained stable throughout menstrual cycle phases. Additional studies in this population are needed, particularly among women who report variable glycemic control during their cycles. Trial Registration: NCT03591354.

Non-small-cell lung cancer (NSCLC) is a heterogeneous disease, and therapeutic management has advanced to identify various critical oncogenic mutations that promote lung cancer tumorigenesis. Subsequent studies have developed targeted therapies against these oncogenes in the hope of personalized treatment based on the tumor’s molecular genomics. This review presents a comprehensive review of the biology, new therapeutic interventions, and resistance patterns of two well-defined subgroups, tumors with KRAS and MET alterations. We also discuss the status of molecular testing practices for these two key oncogenic drivers, considering the progressive introduction of next-generation sequencing (NGS) and RNA sequencing in regular clinical practice.

Abstract Type 2 diabetes has reached endemic proportions and is a substantial burden for the affected patients and the society. Along with lifestyle factors, a number of genetic loci predisposing to type 2 diabetes have been identified, including SORCS1 that encodes the transmembrane receptor SorCS1. The ectodomain of SorCS1 (sol-SorCS1) is shed from plasma membranes but the biological function of this fragment is unknown. Here we show that sol-SorCS1 acts as a high-affinity binding partner for the insulin receptor to stabilize the receptor and increase insulin affinity, protein kinase B activation, and glucose uptake in myocytes. Sol-SorCS1 is liberated from adipocytes, and in diabetic patients the plasma concentration positively correlates with body mass index, but inversely with plasma glucose. In mouse models of insulin resistance, exogenous sol-SorCS1 restored insulin sensitivity. We conclude that sol-SorCS1 increases peripheral insulin sensitivity and propose sol-SorCS1 as a novel insulin sensitizing adipokine and potential antidiabetic agent.

Abstract Background Use of inflammatory biomarkers is common practice in ulcerative colitis (UC) management1. This study examined the utility of faecal calprotectin (FCP), C-reactive protein (CRP), and albumin biomarkers and their combination, for predicting outcomes of clinical remission and disease control (composite of clinical, endoscopic and histologic disease activity measures2) in patients (pts) with UC under therapy with vedolizumab (VDZ) or adalimumab (ADA) in the VARSITY study. Methods VARSITY was a phase 3b, randomized, double-blind, double-dummy, active-control trial evaluating VDZ (anti-α 4β 7 integrin) vs ADA (anti-tumour necrosis factor-α) treatment in pts aged 18–85 years with moderate-to-severe UC (NCT02497469; EudraCT:2015-000939-33). Pts received either VDZ IV infusions (300 mg) on Day 1 and at Weeks (WKs) 2, 6, 14, 22, 30, 38, and 46 or ADA SC injections (40 mg), total dose 160 mg at WK1, 80 mg at WK2, and 40 mg every 2 weeks thereafter until WK50. In this post hoc analysis of data from 769 pts, the probability of clinical remission (total Mayo score ≤2, no subscore >1) and disease control (pt-reported outcome-2 [PRO2, Mayo subscores of stool frequency and rectal bleeding]; Mayo endoscopic subscore ≤1 [endoscopic improvement], and Robarts Histopathology Index score <5, [absence of histologic active disease]) were assessed at WK52 based on baseline and WK14 levels of dichotomized FCP (high-risk: ≥100 µg/g), CRP (high-risk: ≥5mg/L), and albumin (high-risk: <45 g/L) including the composite of high-risk CRP and FCP termed ‘inflammatory burden’ (IB). Results In comparison with biomarkers measured at baseline, FCP at WK14 was the most predictive of WK52 clinical remission after VDZ or ADA treatment3; WK14 FCP was also predictive of disease control using a combined endpoint of PRO2, endoscopy and histologic remission/response. VDZ-treated pts with low-risk FCP (<100 µg/g) at WK14 had a 76% chance of achieving WK52 clinical remission vs 35% for pts with high-risk FCP (70% vs 33% for ADA-treated pts with low and high-risk FCP, respectively). VDZ-treated pts with IB (high-risk levels of FCP and CRP) at WK14 had a 16% chance of clinical remission at WK52 vs a 57% probability for this endpoint in pts without IB at WK14; the risk difference for this composite biomarker was 42% (Table). Conclusion The addition of CRP to FCP as a composite biomarker of IB at WK14 after treatment initiation can be a useful negative predictor of pts who are likely to achieve significant long-term benefits, including remission and disease control, with VDZ or ADA treatment. References 1. Turner D, et al. Gastroenterology 2021;160(5):1570-38. 2. Danese S, et al. J Crohn’s Colitis 2021;15(Suppl1):S305–S305. 3. Dulai PS, et al. Gastroenterology 2021;160(6):S-46–7.

Abstract Background With a growing prevalence of inflammatory bowel disease (IBD) in elderly patients, there is a clinical requirement to understand the impact of treatment in this population.1 Filgotinib (FIL) is an oral Janus kinase 1 preferential inhibitor. This post hoc analysis of data collected in the phase 2b/3 SELECTION programme evaluated the efficacy and safety of FIL in patients with ulcerative colitis (UC) stratified by age. Methods The SELECTION programme includes two Induction Studies, a Maintenance Study (NCT02914522) and a long-term extension (LTE) study (NCT02914535). Adults aged 18–75 years with moderately to severely active UC were randomized 2:2:1 to receive FIL 200 mg or 100 mg or placebo once daily for 11 weeks. Responders at week 10 were re-randomized 2:1 to continue assigned FIL treatment or placebo from week 11–58. In LTE, patients with disease worsening and those completing week 58 continued assigned treatment before receiving open-label FIL. We assessed the efficacy and safety of FIL at any dose in the overall cohort of SELECTION and LTE, stratified into five age groups: <30, ≥30–<40, ≥40–<50, ≥50–<60 and ≥60 years. Clinical remission was evaluated at week 10 and pMCS remission was assessed at week 10, 58 and LTE weeks 2, 4, 12 and 24. Exposure-adjusted incidence rates (EAIRs) were calculated for adverse events (AEs). A data cut-off of 28 February 2020 was used. Results Baseline disease activity and previous and concomitant treatments were comparable across age groups in each treatment arm. While there were fewer patients in the ≥60 years group, patient distribution was similar in all other age groups. FIL induced clinical (~16%) and pMCS (~36%) remission in similar proportions of patients across all age groups at week 10 (Figure 1). At week 58, pMCS remission was achieved in ~53% of FIL-treated patients across age groups (Figure 2). In LTE, the proportion of FIL-treated patients in pMCS remission generally increased with time and remained similar across all age groups (Figure 3). FIL-treated patients aged ≥60 years had higher EAIRs of any AE, infections, herpes zoster, malignancies, NMSC and MACE than younger patients (Table). One thromboembolic event occurred in a FIL-treated patient aged <30 years. Three deaths related to cardiovascular disease occurred in FIL-treated patients aged ≥50 years. Conclusion These findings suggest FIL is efficacious in inducing and maintaining symptomatic remission and could have an acceptable safety profile in adults with UC of all ages, including ≥60 years old. Age-related increases in incidences of certain AEs might be expected in patients with IBD; however, the number of patients ≥60 years limits comparison of these data with reported rates. Reference 1Zammarchi et al. BMC Gastroenterol 2020;20;147