Citations

AbstractObjectivesPersistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well‐characterized samples of individuals with BD.MethodsThirteen cohorts from 7 countries included n = 5882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived “higher versus lower function” as the dependent variable and selected clinical and demographic variables as predictors.ResultsWe found high rates of functional impairment, ranging from 41 to 75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, the presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning.ConclusionsThe bipolar clinical research community is poised to work together to characterize the multi‐dimensional contributors to impairment and address the barriers that impede patients' complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large‐scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness.

Introduction: Estrogens have been associated with risk of stroke in both men and women. Estradiol and estrone are synthesized from testosterone via the aromatase enzyme in both men and postmenopausal women. Genetic variation affecting function of the aromatase gene (CYP19A1) has been linked to elevated estradiol levels. We tested the hypothesis that these variants, as well as a modifying gene, are associated with ischemic stroke in three cohorts: the Vitamin Intervention for Stroke Prevention trial (VISP), Women’s Health Initiative (WHI), and Genetic Susceptibility to Early-Onset Stroke study (GEOS). Methods: Genomic data for individuals of European descent with ischemic stroke was compared against an equal number of controls: VISP (1723 cases - 65% men), WHI (436 cases - all postmenopausal women), GEOS (557 cases - all men age <55). Genotyping was funded through the Genomics and Randomized Trials Network (GARNET) and Gene Environment Association Studies (GENEVA) consortia. All cohorts used the Illumina Omni1-Quad chip for genotyping with imputation as needed. Eight candidate single nucleotide polymorphisms (SNPs) in CYP19A1 on chromosome 15 and an additional regulatory SNP in a modifier locus on chromosome 8 were chosen for analysis due to coding status or previous association with estradiol levels. Analyses were adjusted for age, hormone therapy use (women), and the top three principal components. Association results were determined as odds ratios for individual SNPs (effect allele = minor), with significance level of p<0.05. Results: GWAS results are tabulated. There were no significant differences in allele frequency for four SNPs in CYP19A1 among stroke patients and controls. The additional four SNPs were monomorphic in all three populations. The modifier gene SNP (rs1864729) was less common among young men with prior stroke in GEOS, but not men in VISP or in women. Conclusions: Aromatase genetic variation was not associated with risk of stroke in these three cohorts. One SNP that modifies aromatase function was less common among young, but not older men with stroke. Replication in other studies is necessary.

Background: Myocarditis may predispose to dilated cardiomyopathy (DCM) and sudden cardiac death (SCD). Familial data indicate a potential genetic susceptibility shared with arrhythmogenic cardiomyopathy (ACM). We present the first large-scale genotype-phenotype study of adults with acute myocarditis. Methods: A cohort comprising 336 consecutive patients with acute myocarditis was enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterised cardiomyopathy-associated genes. The burden of rare protein altering variants (PAV) in ACM genes, DCM genes, and TTN specifically, were compared with local healthy controls sequenced on the same platform (n=1053). Case ascertainment was assessed against national hospital admission data. Results: We identified rare protein-altering variants in 23% of cases compared to 16% in controls (Δ+6.8%; p=0.021), with rare truncating variants (tv) in 6% of cases compared to <1% of controls ((Δ+5%; p=0.0097). In London (n=230; median left ventricular ejection fraction (LVEF) 63%), which was representative of national myocarditis admissions, 4.8% of cases carried rare tv, particularly within ACM genes (3% cases vs 0% controls; odds ratio 8.2; p=0.001). This was predominantly driven by desmoplakin (DSP)-tv in patients with normal LVEF. In Maastricht (n=106; median LVEF 30%), rare tv in DCM genes were enriched, particularly TTN-tv found in 7% (all with LVEF<50%) compared to 1% in controls (OR 3.6; p=0.0116). During a median follow-up of 1.9 years, all-cause mortality was greatest in those with a DCM variant (18% vs 4% with no variant; OR 5.0; p=0.004). Conclusion: We identified enrichment of cardiomyopathy gene variants in acute myocarditis patients, dominated by DSP-tv in those with normal LVEF and TTN-tv in those with reduced LVEF. Incorporation of genetic testing may be beneficial to identify such high-risk individuals and guide family screening in acute myocarditis patients.

Introduction: Transcatheter mitral valve replacement (TMVR) using aortic transcatheter heart valves (THV) is developing as an alternative to surgery for patients with severely degenerated mitral valve (MV) bioprostheses. Retrospective self-reported registries have collected outcomes on these TMVR procedures in the STS/ACC Transcatheter Valve Therapy Registry and in the Valve-in-Valve International Database. Most reported TMVR procedures for failed surgical bioprostheses have been performed using a transapical access approach. A prospective comprehensive evaluation of mitral Valve-in-Valve (VIV) outcomes, including transseptal access has not previously been conducted. Objectives: To evaluate in-hospital and 30-day clinical outcomes of transseptal mitral VIV with SAPIEN 3 THV in patients with very high surgical risk. Methods: Prospective enrollment of very high surgical risk patients with symptomatic severely degenerated MV surgical bioprostheses in 30 patients at 15 sites in the U.S. Candidates were assessed by a case review committee prior to approval. Baseline qualifying echocardiograms and cardiac CT studies were analyzed by independent core labs. Echocardiograms, cardiac CT studies and neurology evaluations were also performed after mitral VIV procedures. Clinical events were adjudicated by a clinical events committee and safety was monitored by a data safety monitoring board. Results: 26 patients have been enrolled between July 2016 and June 2017. Mean age was 83 years, 62% female, mean STS score was 10% and 62% were in New York Heart Association class III or IV. Transseptal access was used in all procedures. Technical success was achieved in all patients and there was no in-hospital mortality. There was no 30-day cardiovascular mortality and 4% (1 patient) 30-day all-cause mortality (1 patient died of asphyxia on day 29 after choking on pills at home), which was lower than the 30-day mortality in the TVT registry (9%). Detailed procedural, in-hospital and 30-day outcomes will be presented on the complete cohort of 30 patients. Conclusions: In patients without surgical alternatives, transseptal mitral ViV procedures in failed surgical bioprostheses are associated with high technical and procedural success and low 30-day mortality.

Abstract We report a case of a 19-year-old man who presented with severe scrotal swelling. His medical history was notable for severe global edema at birth. Most areas of swelling had resolved by adolescence with exception of the scrotum and the left lower extremity. 99mTc-filtered sulfur colloid lymphoscintigraphy of the lower extremities demonstrated prominent dermal backflow into the superficial scrotum and thighs, which were confirmed on the SPECT/CT images, and correlated with findings on MR lymphangiogram. Lymphoscintigram and MR lymphangiogram may provide complementary information to aid diagnosis and management of primary scrotal lymphedema.

AimsBarrett's oesophagus with indefinite for dysplasia (BE‐IND) is a subjective diagnosis with a low interobserver agreement (IOA) among pathologists and uncertain clinical implications. This study aimed to assess the utility of p53 immunohistochemistry (p53‐IHC) in assessing BE‐IND specimens.Methods and resultsArchive endoscopic biopsies with a BE‐IND diagnosis from two academic centres were analysed. First, haematoxylin and eosin‐stained slides (H&E) were reviewed by four expert gastrointestinal (GI) pathologists allocated into two groups (A and B). After a washout period of at least 8 weeks, H&E slides were reassessed side‐to‐side with p53‐IHC available. We compared the rate of changed diagnosis and the IOA for all BE grades before and after p53‐IHC. We included 216 BE‐IND specimens from 185 patients, 44.0 and 32.9% of which were confirmed after H&E slide revision by groups A and B, respectively. More than half the cases were reclassified to a non‐dysplastic BE (NDBE), while 5.6% of cases in group A and 7.4% in group B were reclassified to definite dysplasia. The IOA for NDBE, BE‐IND, low‐grade dysplasia (LGD) and high‐grade dysplasia (HGD)/intramucosal cancer (IMC) was 0.31, 0.21, −0.03 and −0.02, respectively. Use of p53‐IHC led to a >40% reduction in BE‐IND diagnoses (P < 0.001) and increased IOA for all BE grades [κ = 0.46 (NDBE), 0.26 (BE‐IND), 0.49 (LGD), 0.35 (HGD/IMC)]. An aberrant p53‐IHC pattern significantly increased the likelihood of reclassifying BE‐IND to definite dysplasia (odds ratio = 44.3, 95% confidence interval = 18.8–113.0).ConclusionP53‐IHC reduces the rate of BE‐IND diagnoses and improves the IOA among pathologists when reporting BE with equivocal epithelial changes.

Background Recent studies have shown improved outcomes in cardiogenic shock through protocols directed toward early identification and initiation of mechanical circulatory support. However, objective therapeutic targets—based on clinical and/or laboratory data—to guide real‐time clinical decision making are lacking. Lactate clearance has been suggested as a potential treatment target because of its independent association with mortality. Methods and Results In a post hoc analysis of the DOREMI (Dobutamine Compared to Milrinone in the Treatment of Cardiogenic Shock) trial—a randomized, double‐blind, controlled trial comparing milrinone to dobutamine in the treatment of cardiogenic shock—we used prospectively collected lactate data to evaluate lactate clearance as a surrogate marker for in‐hospital mortality. In total, 82 (57.7%) patients survived to hospital discharge (survivors). In multivariate logistic regression analysis, complete lactate clearance, percentage lactate clearance, and percentage lactate clearance per hour were independently associated with survival beginning as early as 8 hours after enrollment. Complete lactate clearance was the strongest predictor of survival at all time points, with odds ratios ranging between 2.46 (95% CI, 1.09–5.55; P =0.03) at 8 hours to 5.44 (95% CI, 2.14–13.8; P <0.01) at 24 hours. Conclusions Complete lactate clearance is a strong and independent predictor of in‐hospital survival in patients with cardiogenic shock. Together with previously published data, these results further support the validity of lactate clearance as an appropriate surrogate for mortality and as a potential therapeutic target in future cardiogenic shock trials. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03207165.