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Lung transplantation in the United States has steadily grown over the last decade. Major attention has been with the understanding of lung ischemia–reperfusion injury and how it relates to primary graft dysfunction. In 2015, our institution implemented the use of a pulmonoplegia solution during recipient surgery of lung transplantation. A unique circuit utilizing the heart lung machine is used to deliver the pulmonoplegia solution. This system is considered to be a key contributing factor to the success of our lung transplant program.

Cardiometabolic diseases are highly comorbid, but their relationship with female-specific health conditions (breast cancer, endometriosis, pregnancy complications) is understudied. Using electronic health record data from 71,008 ancestrally diverse females, we examined relationships between 23 obstetrical/gynecological conditions and 4 cardiometabolic phenotypes (body mass index [BMI], coronary artery disease [CAD], type 2 diabetes [T2D], and hypertension) using cross-trait genetic correlation analyses, polygenic risk scores (PRSs), Mendelian randomization (MR), and chronology analyses. We observed 29 significant associations between cardiometabolic PRSs and obstetrical/gynecological conditions (BMI and endometrial cancer; BMI and polycystic ovarian syndrome [PCOS)]; T2D and gestational diabetes; T2D and PCOS). MR analysis provided additional evidence of independent causal effects. We also identified an inverse association between CAD and breast cancer. High cardiometabolic PRSs were associated with early development of PCOS and gestational hypertension. We conclude that polygenic susceptibility to cardiometabolic traits is associated with elevated risk of certain female-specific health conditions.

BackgroundEarly clinical reports have suggested that the prevalence of thrombotic complications in the pathogenesis of COVID-19 may be as high as 30% in intensive care unit (ICU)-admitted patients and could be a major factor contributing to mortality. However, mechanisms underlying COVID-19-associated thrombo-coagulopathy, and its impact on patient morbidity and mortality, are still poorly understood.MethodsWe performed a comprehensive analysis of coagulation and thromboinflammatory factors in plasma from COVID-19 patients with varying degrees of disease severity. Furthermore, we assessed the functional impact of these factors on clot formation and clot lysis.ResultsAcross all COVID-19 disease severities (mild, moderate and severe) we observed a significant increase (6-fold) in the concentration of ultra-large von Willebrand factor (UL-VWF) multimers compared to healthy controls. This is likely the result of an interleukin (IL)-6 driven imbalance of VWF and the regulatory protease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13). Upregulation of this key pro-coagulant pathway may also be influenced by the observed increase (~6-fold) in plasma α-defensins, a consequence of increased numbers of neutrophils and neutrophil activation. Markers of endothelial, platelet and leukocyte activation were accompanied by increased plasma concentrations of Factor XIII (FXIII) and plasminogen activator inhibitor (PAI)-1. In patients with high FXIII we observed alteration of the fibrin network structure in in vitro assays of clot formation, which coupled with increased PAI-1, prolonged the time to clot lysis by the t-PA/plasmin fibrinolytic pathway by 52% across all COVID-19 patients (n=23).ConclusionsWe show that an imbalance in the VWF/ADAMTS13 axis causing increased VWF reactivity may contribute to the formation of platelet-rich thrombi in the pulmonary vasculature of COVID-19 patients. Through immune and inflammatory responses, COVID-19 also alters the balance of factors involved in fibrin generation and fibrinolysis which accounts for the persistent fibrin deposition previously observed in post-mortem lung tissue.What is new?In all COVID-19 patients, even mild cases, UL-VWF is present in plasma due to the alteration of VWF and ADAMTS13 concentrations, likely driven by increased IL-6 and α-defensins.Increased plasma FXIII alters fibrin structure and enhances incorporation of VWF into fibrin clusters.Defective fibrin structure, coupled with increased plasma PAI-1 and α2-antiplasmin, inhibits fibrinolysis by t-PA/plasmin.What are the clinical implications?Prophylactic anticoagulation and management of thrombotic complications in COVID-19 patients are ongoing challenges requiring a better understanding of the coagulopathic mechanisms involved.We have identified FXIII and VWF as potential therapeutic targets for treating fibrin formation defects in COVID-19 patients.We have identified a multifaceted fibrinolytic resistance in COVID-19 patient plasma with potential implications in the treatment of secondary thrombotic events such as acute ischaemic stroke or massive pulmonary embolism.

Colonoscopy surveillance after adenoma removal is an increasing burden in many countries. Surveillance recommendations consider characteristics of removed adenomas, but not colonoscopist performance. We investigated the impact of colonoscopist performance on colorectal cancer risk after adenoma removal.We compared colorectal cancer risk after removal of high-risk adenomas, low-risk adenomas, and after negative colonoscopy for all colonoscopies performed by colonoscopists with low vs high performance quality (adenoma detection rate20% vs ≥20%) in the Polish screening program between 2000 and 2011, with follow-up until 2017. Findings were validated in the Austrian colonoscopy screening program.A total of 173,288 Polish colonoscopies were included in the study. Of 262 colonoscopists, 160 (61.1%) were low performers, and 102 (38.9%) were high performers; 11.1% of individuals had low-risk and 6.6% had high-risk adenomas removed at screening; 82.2% had no adenomas. During 10 years of follow-up, 443 colorectal cancers were diagnosed. For low-risk adenoma individuals, colorectal cancer incidence was 0.55% (95% confidence interval [CI] 0.40-0.75) with low-performing colonoscopists vs 0.22% (95% CI 0.14-0.34) with high-performing colonoscopists (hazard ratio [HR] 2.35; 95% CI 1.31-4.21; P = .004). For individuals with high-risk adenomas, colorectal cancer incidence was 1.14% (95% CI 0.87-1.48) with low-performing colonoscopists vs 0.43% (95% CI 0.27-0.69) with high-performing colonoscopists (HR 2.69; 95% CI 1.62-4.47; P.001). After negative colonoscopy, colorectal cancer incidence was 0.30% (95% CI 0.27-0.34) for individuals examined by low-performing colonoscopists, vs 0.15% (95% CI 0.11-0.20) for high-performing (HR 2.10; 95% CI 1.52-2.91; P.001). The observed trends were reproduced in the Austrian validation cohort.Our results suggest that endoscopist performance may be an important contributor in addition to polyp characteristics in determining colorectal cancer risk after colonoscopy screening.

Detecting anomalies and outliers in data has a number of applications including hazard sensing, fraud detection, and systems management. While generative adversarial networks seem like a natural fit for addressing these challenges, we find that existing GAN based anomaly detection algorithms perform poorly due to their inability to handle multimodal patterns. For this purpose we introduce an infinite Gaussian mixture model coupled with (bi-directional) generative adversarial networks, IGMM-GAN, that facilitates multimodal anomaly detection. We illustrate our methodology and its improvement over existing GAN anomaly detection on the MNIST dataset.

Background Extracorporeal life support (ECLS) has been utilized as a rescue strategy for patients with cardiac arrest unresponsive to conventional cardiopulmonary resuscitation. Objective We sought to describe our institution's experience with implementation of ECLS for out-of-hospital and emergency department (ED) cardiac arrests. Our primary outcome was survival to hospital discharge. Methods Consecutive patients placed on ECLS in the ED or within one hour of admission after out-of-hospital or ED cardiac arrest were enrolled at two urban academic medical centers in the United States from July 2007–April 2014. Results During the study period, 26 patients were included. Average age was 40 ± 15 years, 54% were male, and 42% were white. Initial cardiac rhythms were ventricular fibrillation or pulseless ventricular tachycardia in 42%. The average time from initial cardiac arrest to initiation of ECLS was 77 ± 51 min (range 12–180 min). ECLS cannulation was unsuccessful in two patients. Eighteen (69%) had complications related to ECLS, most commonly bleeding and ischemic events. Four patients (15%) survived to discharge, three of whom were neurologically intact at 6 months. Conclusion ECLS shows promise as a rescue strategy for refractory out-of-hospital or ED cardiac arrest but is not without challenges. Further investigations are necessary to refine the technique, patient selection, and ancillary therapeutics.

Background Metabolic syndrome (MS) is a set of risk factors that includes obesity and insulin resistance and has been implicated in the development of prostate cancer. Its impact on androgen deprivation therapy (ADT) efficacy has not been studied. Patients and methods Retrospective study of prostate cancer patients seen from 1998 to 2005 in a medical oncology clinic. MS, as defined by modified Adult Treatment Panel III criteria, was assessed at the time of initiation of ADT. The study end points were time to prostate-specific antigen (PSA) progression and overall survival (OS) from time of starting ADT. Results Eighty-two patients treated with ADT and data to assess for presence of MS were identified. Median age in men with and without MS was 70 years and 49% of the patients evaluated met criteria for MS. Median time to PSA progression for patients with MS was 16 versus 36 months without MS (P = 0.003). The median OS for patients with MS was 36.5 months after commencing ADT compared with 46.7 months for those patients without MS (P = 0.061). Conclusions This preliminary data suggest that MS is a risk factor for earlier development of castration-resistant prostate cancer and support the need for a prospective evaluation of this finding.

Objective: To examine the effects of human leukocyte antigen (HLA) alleles on HIV-1―related disease progression and central nervous system (CNS) impairment in children. Design: Five hundred seventy-two HIV-1―infected children, identified as disease progressors or nonprogressors, were selected from PACTG P152 and P300 through a case―cohort sampling scheme. Study endpoints were HIV-1―related disease progression-free survival and time to CNS impairment. Methods: DNA was genotyped for HLA alleles using a Luminex 100 platform. Weighted Kaplan―Meier methods, and Cox proportional hazards models were used to assess the effects of HLA alleles on study endpoints. Results: Presence of the B-27 allele (n = 20) was associated with complete protection against disease progression and CNS impairment over the median follow-up of 26 months (P < 0.0001 for both). These findings held in multivariate analyses controlling for baseline covariates including race, gender, age, log HIV-1 RNA, CD4 + lymphocyte count and percent, weight for age z score and treatment, and for other genotypes shown to affect HIV1―related disease progression. Also, although the Cw-2 allele protected against disease progression [Hazard ratio (HR), 0.48; 95% confidence interval (CI): 0.28 to 0.81; P = 0.006], the A-24 allele was associated with more rapid CNS impairment (HR: 2.01; 95% CI: 1.04 to 3.88; P = 0.04). The HLA class II DQB1-2 allele was associated with a delayed disease progression (HR: 0.66; 95% CI: 0.47-0.92; P = 0.01) and CNS impairment (HR: 0.58; 95% CI: 0.36 to 0.93; P = 0.02). Conclusions: Presence of B-27, Cw-2, or DQB1-2 alleles was associated with delayed HIV-1 disease progression, while B-27, A-24, and DQB1-2 alleles were associated with altered progression to CNS impairment in children.