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The field of cardio-oncology aims to optimize the cardiac health of cancer patients. The goals of this study are to (1) describe the demographics of a cardio-oncology clinic and (2) apply the American Society of Clinical Oncology (ASCO) cardiac risk stratification guidelines among breast cancer patients to assess the development of cardiovascular events, primarily heart failure (HF). We performed a retrospective chart review on 203 consecutive cardio-oncology patients who were seen between January 2019 and March 2020. Mean follow-up for the cohort was 29.2 ± 3.1 months (range 0–113). We applied the ASCO guidelines to the breast cancer subgroup. The plurality of patients 82/203 (40%) referred to clinic had breast cancer. The most common reason for referral was asymptomatic left ventricular (LV) dysfunction or HF (40%). Only 36/203 (18%) of patients were referred for a pre-chemotherapy evaluation. In breast cancer patients, there was a trend toward significance in up-titrating or initiating beta-blockers in the high vs. low risk ASCO groups [46/69 (67%) vs. 5/13 (38%), p = 0.054]. Approximately 13/82 (16%) of breast cancer patients required alterations to their anti-cancer therapy. HF events occurred in 1/36 (3%) of cancer treatment naive patients and 14/167 (8%) of those with prior therapy, specifically 9% of the breast cancer subset. Our study provides insight into referral practices, interventions, and outcomes at a cardio-oncology clinic. Furthermore, breast cancer patients continue to have high rates of HF. These findings suggest a need to shift referral practices upstream for a pre-chemotherapy evaluation to optimize cardiovascular health.

Background Implementing an evidence-based hypertension program in primary healthcare centers (PHCs) in the Federal Capital Territory, Nigeria is an opportunity to improve hypertension diagnosis, treatment, and control and reduce deaths from cardiovascular diseases. This qualitative research study was conducted in Nigerian PHCs with patients, non-physician health workers, administrators and primary care physicians to inform contextual adaptations of Kaiser Permanente Northern California's hypertension model and the World Health Organization’s HEARTS technical package for the system-level, Hypertension Treatment in Nigeria (HTN) Program. Methods Purposive sampling in 8 PHCs identified patients (n = 8), non-physician health workers (n = 12), administrators (n = 3), and primary care physicians (n = 6) for focus group discussions and interviews. The Primary Health Care Performance Initiative (PHCPI) conceptual framework and Consolidated Framework for Implementation Research (CFIR) domains were used to develop semi-structured interviews (Appendix 1, Supplemental Materials) and coding guides. Content analysis identified multilevel factors that would influence program implementation. Results Participants perceived the need to strengthen four major health system inputs across CFIR domains for successful adaptation of the HTN Program components: (1) reliable drug supply and blood pressure measurement equipment, (2) enable and empower community healthcare workers to participate in team-based care through training and education, (3) information systems to track patients and medication supply chain, and (4) a primary healthcare system that could offer a broader package of health services to meet patient needs. Specific features of the PHCPI framework considered important included: accessible and person-centered care, provider availability and competence, coordination of care, and proactive community outreach. Participants also identified patient-level factors, such as knowledge and beliefs about hypertension, and financial and transportation barriers that could be addressed with better communication, home visits, and drug financing. Participants recommended using existing community structures, such as village health committees and popular opinion leaders, to improve knowledge and demand for the HTN Program. Conclusions These results provide information on specific primary care and community contextual factors that can support or hinder implementation and sustainability of an evidence-based, system-level hypertension program in the Federal Capital Territory, Nigeria, with the ultimate aim of scaling it to other parts of the country.

Introduction: The concepts of collaboration and interprofessional (IP) education were introduced to healthcare professions in the 1970s; however, it was not until the late 1990's that the care provided by IP teams was recognized as important to the delivery of patient care. When institutions of higher learning include IP education in the curricula, students have the opportunity to immerse in collaborative learning experiences rather than being isolated in the traditional "siloes" of individual healthcare professions. The purpose of this work is to report the ongoing implementation, assessment, and improvement of an annual inter-university, multi-department simulation exercise developed to promote collaboration, collegiality, and communication within a healthcare setting.Methods: Faculty from two universities in west Texas collaborated to provide a clinical simulation experience focusing on IP teamwork and cultural and spiritual diversity. Multiple scenarios were created and developed by faculty from the participating disciplines who were aided by the latest Clinical Practice guidelines. The evidence-based scenarios addressed various chronic medical conditions and gender, ethnic, religious, psychosocial, and cultural competence issues.Results: Several themes emerged through the multiple debrief sessions and analysis of qualitative data: a) increased knowledge of the others' discipline and role, b) communication skills, c) increased cultural awareness, d) trust, and e) increased knowledge of disease process as it related to their own and others' disciplines.Conclusions:The findings suggest an unanticipated opportunity arising from the simulation experience for faculty and students to develop the skillset necessary to work within experimental medicine.

Spinal muscular atrophy with congenital bone fractures 2 (SMABF2), a type of arthrogryposis multiplex congenita (AMC), is characterized by congenital joint contractures, prenatal fractures of long bones, and respiratory distress and results from biallelic variants in ASCC1. Here, we describe an infant with severe, diffuse hypotonia, congenital contractures, and pulmonary hypoplasia characteristic of SMABF2, with the unique features of cleft palate, small spleen, transverse liver, and pulmonary thromboemboli with chondroid appearance. This infant also had impaired coagulation with diffuse petechiae and ecchymoses which has only been reported in one other infant with AMC. Using trio whole genome sequencing, our proband was identified to have biallelic variants in ASCC1. Using deep next generation sequencing of parental cDNA, we characterized alteration of splicing encoded by the novel, maternally inherited ASCC1 variant (c.297-8 T > G) which provides a mechanism for functional pathogenicity. The paternally inherited ASCC1 variant is a rare nonsense variant (c.466C > T; p.Arg156*) that has been previously identified in one other infant with AMC. This report extends the phenotypic characteristics of ASCC1-associated AMC (SMABF2) and describes a novel intronic variant that partially disrupts RNA splicing.

Aims The CANVAS Program identified the effect of canagliflozin on major adverse cardiovascular events (MACE) differed according to whether participants were using diuretics at study commencement. We sought to further evaluate this finding related to baseline differences, treatment effects, safety, and risk factor changes.Methods and results The CANVAS Program enrolled 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk. Participants were randomized to canagliflozin or placebo and followed for a mean of 188 weeks. The primary outcome was major cardiovascular events, a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included multiple cardiovascular, renal, and safety events. In this post hoc subgroup analysis, participants were categorized according to baseline use of any diuretic. The effect on outcomes was compared using Cox proportional hazards models, while risk factor changes were compared using mixed-effect models. At baseline, 4490 (44.3%) participants were using a diuretic. Compared with those not using a diuretic, participants using a diuretic were more likely to be older (mean age +/- standard deviation, 64.3 +/- 8.0 vs. 62.5 +/- 8.3), be female (38.9% vs. 33.4%), and have heart failure (19.6% vs. 10.3%) (all P-difference < 0.0001). The effect of canagliflozin on major cardiovascular events was greater for those using diuretic at baseline than for those who were not [adjusted hazard ratio 0.65 (95% confidence interval 0.54-0.78) vs. adjusted hazard ratio 1.13 (95% confidence interval 0.93-1.36), P-heterogeneity < 0.0001]. Changes in most risk factors, including blood pressure, body weight, and urine albumin-to-creatinine ratio, were similar between groups (all P-difference > 0.11), although the effect of canagliflozin on haemoglobin A1c reduction was slightly weaker in participants using compared with not using diuretics at baseline (-0.52% vs. -0.64%, P-heterogeneity = 0.0007). Overall serious adverse events and key safety outcomes, including adverse renal events, were also similar (all P-heterogeneity > 0.07).Conclusions Participants on baseline diuretics derived a greater benefit for major cardiovascular events from canagliflozin, which was not fully explained by differences in participant characteristics nor risk factor changes.

Purpose The NIH Undiagnosed Diseases Network (UDN) evaluates participants with disorders that have defied diagnosis, applying personalized clinical and genomic evaluations and innovative research. The clinical sites of the UDN are essential to advancing the UDN mission; this study assesses their contributions relative to standard clinical practices. Methods We analyzed retrospective data from four UDN clinical sites, from July 2015 to September 2019, for diagnoses, new disease gene discoveries and the underlying investigative methods. Results Of 791 evaluated individuals, 231 received 240 diagnoses and 17 new disease-gene associations were recognized. Straightforward diagnoses on UDN exome and genome sequencing occurred in 35% (84/240). We considered these tractable in standard clinical practice, although genome sequencing is not yet widely available clinically. The majority (156/240, 65%) required additional UDN-driven investigations, including 90 diagnoses that occurred after prior nondiagnostic exome sequencing and 45 diagnoses (19%) that were nongenetic. The UDN-driven investigations included complementary/supplementary phenotyping, innovative analyses of genomic variants, and collaborative science for functional assays and animal modeling. Conclusion Investigations driven by the clinical sites identified diagnostic and research paradigms that surpass standard diagnostic processes. The new diagnoses, disease gene discoveries, and delineation of novel disorders represent a model for genomic medicine and science.

BACKGROUND Informal caregiving of stroke survivors often begins with intensity compared with the linear caregiving trajectories in progressive conditions. Informal caregivers of stroke survivors are often inadequately prepared for their caregiving role, which can have detrimental effects on their well-being. A greater depth of understanding about caregiving burden is needed to identify caregivers in most need of intervention. The purpose of this study was to examine caregiver burden and associated factors among a cohort of informal caregivers of stroke survivors. METHODS A cross-sectional study of 88 informal caregivers of stroke survivors was completed. Caregiver burden was determined with the Zarit Burden Interview, caregiver depressive symptoms were measured with the Patient Health Questionnaire-9, and stroke survivor functional disability was assessed with the Barthel Index. Ordinal logistic regression was used to identify independent factors associated with caregiver burden. RESULTS Forty-three informal caregivers (49%) reported minimal or no caregiver burden, 30 (34%) reported mild to moderate caregiver burden, and 15 (17%) reported moderate to severe caregiver burden. Stroke survivor functional disability was associated with informal caregiver burden (P = .0387). The odds of having mild to moderate caregiver burden were 3.7 times higher for informal caregivers of stroke survivors with moderate to severe functional disability than for caregivers of stroke survivors with no functional disability. The presence of caregiver depressive symptoms was highly correlated with caregiver burden (P < .001). CONCLUSION Caregivers of stroke survivors with functional disabilities and caregivers experiencing depressive symptoms may have severer caregiver burden. Trials of interventions aimed at decreasing informal caregiver burden should consider the potential impact of stroke survivors' functional disability and the presence of depressive symptoms.

Objectives To enhance reproducible research by creating a broadly accessible, free, open-source software tool for connecting Microsoft Word to statistical programs (R/R Markdown, Python, SAS, Stata) so that results may be automatically updated in a manuscript. Materials and Methods We developed StatTag for Windows as a Microsoft Word plug-in using C# and for macOS as a native application using Objective-C. Source code is available under the MIT license at https://github.com/stattag. Results StatTag links analysis file(s) (R/R Markdown, SAS, Stata, or Python) and a Word document, invokes the statistical program(s) to obtain results, and embeds selected output in the document. StatTag can accommodate multiple statistical programs with a single document and features an interface to view, edit, and rerun statistical code directly from Word. Discussion and Conclusion StatTag may facilitate reproducibility within increasingly multidisciplinary research teams, improve research transparency through review and publication, and complement data-sharing initiatives.

Language is crucial for human intelligence, but what exactly is its role? We take language to be a part of a system for understanding and communicating about situations. In humans, these abilities emerge gradually from experience and depend on domain-general principles of biological neural networks: connection-based learning, distributed representation, and context-sensitive, mutual constraint satisfaction-based processing. Current artificial language processing systems rely on the same domain general principles, embodied in artificial neural networks. Indeed, recent progress in this field depends on query-based attention, which extends the ability of these systems to exploit context and has contributed to remarkable breakthroughs. Nevertheless, most current models focus exclusively on language-internal tasks, limiting their ability to perform tasks that depend on understanding situations. These systems also lack memory for the contents of prior situations outside of a fixed contextual span. We describe the organization of the brain’s distributed understanding system, which includes a fast learning system that addresses the memory problem. We sketch a framework for future models of understanding drawing equally on cognitive neuroscience and artificial intelligence and exploiting query-based attention. We highlight relevant current directions and consider further developments needed to fully capture human-level language understanding in a computational system.

Introduction Since 2013, the First Care Provider (FCP) model has successfully educated the non-medical population on how to recognize life-threatening injuries and perform interventions recommended by the Committee for Tactical Emergency Casualty Care (C-TECC) and the Hartford Consensus in the disaster setting. Recent programs, such as the federal "Stop The Bleed" campaign, have placed the emphasis of public training on hemorrhage control. However, recent attacks demonstrate that access to wounded, recognition of injury, and rapid evacuation are equally as important as hemorrhage control in minimizing mortality. To date, no training programs have produced a validated study with regard to training a community population in these necessary principles of disaster response. Methods In our study, we created a reproducible community training model for implementation into prehospital systems. Two matched demographic groups were chosen and divided into "trained" and "untrained" groups. The trained group was taught the FCP curriculum, which the Department of Homeland Security recognizes as a Stop the Bleed program, while the untrained group received no instruction. Both groups then participated in a simulated mass casualty event, which required evaluation of multiple victims with varying degree of injury, particularly a patient with an arterial bleed and a patient with an airway obstruction. Results The objective measures in comparing the two groups were the time elapse until their first action was taken (T1A) and time to their solution of the simulation (TtS). We compared their times using one-sided t-test to demonstrate their responses were not due to chance alone. At the arterial bleed simulation, the T1A for the trained and untrained groups, respectively, were 34.75 seconds and 111 seconds (p-value = .1064), while the TtS were 3 minutes and 33 seconds in the trained group and eight minutes in the untrained groups (physiologic cutoff) (p-value = .0014). At the airway obstruction simulation, the T1A for the trained and untrained groups, respectively, were 20.5 seconds and 43 seconds (p-value = .1064), while the TtS were 32.6 seconds in the trained group and 7 minutes and 3 seconds in the untrained group (p-value = .0087). Simulation values for recently graduated nursing students and a local fire department engine company (emergency medical services [EMS]) were also given for reference. The trained group's results mirrored times of EMS. Conclusion This study demonstrates an effective training model to civilian trauma response, while adhering to established recommendations. We offer our model as a potential solution for accomplishing the Stop The Bleed mission while advancing the potential of public disaster response.

Supplemental Digital Content is available in the text., Background. We sought to compare change over time (baseline to 2 y) in health-related quality of life (HRQOL) between older (60–80 y) patients awaiting heart transplantation (HT) with mechanical circulatory support (MCS) versus without MCS and their caregivers and caregiver burden. Methods. This study was conducted at 13 United States sites. Patient HRQOL was examined using the EuroQol 5-dimensional questionnaire (EQ-5D-3L) and Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12). Caregiver measures included the EQ-5D-3L and Oberst Caregiving Burden Scale, measuring time on task and difficulty. Analyses included analysis of variance, χ2, and linear regression. Results. We enrolled 239 HT candidates (n = 118 with MCS and n = 121 without MCS) and 193 caregivers (n = 92 for candidates with MCS and n = 101 for candidates without MCS). Baseline differences in HRQOL were observed between HT candidates with and without MCS: EQ-5D-3L visual analog scale (VAS) score (67.7 ± 17.6 versus 54.1 ± 23.3, P < 0.001) and KCCQ-12 overall summary score (59.9 ± 21.0 versus 48.9 ± 21.6, P < 0.001), respectively. HT candidates with MCS had significantly higher EQ-5D-3L VAS scores and KCCQ-12 overall summary score across time versus without MCS. Baseline EQ-5D-3L VAS scores did not differ significantly between caregivers of HT candidates with and without MCS (84.6 ± 12.9 versus 84.3 ± 14.4, P = 0.9), respectively, nor were there significant between-group differences over time. Caregivers for HT candidates with MCS reported more task difficulty (range: 1 = not difficult to 5 = extremely difficult) versus caregivers for those without MCS at baseline (1.4 ± 0.5 versus 1.2 ± 0.3, P = 0.004) and over time. Conclusions. Understanding differences in HRQOL and caregiver burden among older HT candidates with and without MCS and their caregivers may inform strategies to enhance HRQOL and reduce burden.

People navigating in unfamiliar buildings take advantage of myriad visual, spatial and semantic cues to efficiently achieve their navigation goals. Towards equipping computational agents with similar capabilities, we introduce Pathdreamer, a visual world model for agents navigating in novel indoor environments. Given one or more previous visual observations, Pathdreamer generates plausible high-resolution 360 visual observations (RGB, semantic segmentation and depth) for viewpoints that have not been visited, in buildings not seen during training. In regions of high uncertainty (e.g. predicting around corners, imagining the contents of an unseen room), Pathdreamer can predict diverse scenes, allowing an agent to sample multiple realistic outcomes for a given trajectory. We demonstrate that Pathdreamer encodes useful and accessible visual, spatial and semantic knowledge about human environments by using it in the downstream task of Vision-and-Language Navigation (VLN). Specifically, we show that planning ahead with Pathdreamer brings about half the benefit of looking ahead at actual observations from unobserved parts of the environment. We hope that Pathdreamer will help unlock model-based approaches to challenging embodied navigation tasks such as navigating to specified objects and VLN., Comment: In ICCV 2021

Background: Sex differences in presentation, management, and outcomes of heart failure (HF) have been observed, but it is uncertain whether these differences exist in South India.Objective: We describe sex differences in presentation, management, and in-hospital outcomes in patients hospitalized with HF in South India and explore sex-based differences in the effect of the quality improvement intervention in a secondary analysis of a prospective, interrupted time series study.Methods: The Heart Failure Quality Improvement in Kerala (HF QUIK) study evaluated the effect of a quality improvement toolkit on process of care measures and clinical outcomes in patients hospitalized with HF in eight hospitals in Kerala using an interrupted time series design from February 2018 to August 2018. The primary outcome was guideline-directed medical therapy (GDMT) at hospital discharge for patients with HF with reduced ejection fraction (HFrEF). We performed sex-stratified analyses using mixed effect logistic regression models.Results: Among 1,400 patients, 536 (38.3%) were female. Female patients were older (69.6 vs. 65 years, p < 0.001), were less likely to have an ischemic etiology of HF (control period: 78.2% vs. 87.5%; intervention period: 83.6% vs. 91.5%; p < 0.05 for both) and were less likely to undergo coronary angiography or percutaneous coronary intervention. The quality improvement intervention had similar effects on the odds of GDMT at discharge in females with HFrEF (adjusted OR 1.79, 95% CI 0.92, 3.47) and males with HFrEF (adjusted OR 1.68, 95% CI 1.07, 2.64, pinteraction = 0.69).Conclusions: We observed sex-specific differences in presentation and procedural management of patients with HF but no differences in the effect of the quality improvement intervention on discharge GDMT rates. Both male and female patients with HFrEF remained undertreated in the study intervention period, demonstrating the need for implementation strategies to close the HFrEF treatment gap in South India.

Oral infection with Toxoplasma gondii results in dysbiosis and enteritis, both of which revert to normal during chronic infection. However, whether infection leaves a lasting impact on mucosal responses remains uncertain. Here we examined the effect of the chemical irritant dextran sodium sulfate (DSS) on intestinal damage and wound healing in chronically infected mice. Our findings indicate that prior infection with T. gondii exacerbates damage to the colon caused by DSS and impairs wound healing by suppressing stem cell regeneration of the epithelium. Enhanced tissue damage was attributable to inflammatory monocytes that emerge preactivated from bone marrow, migrate to the intestine, and release inflammatory mediators, including nitric oxide. Tissue damage was reversed by neutralization of inflammatory monocytes or nitric oxide, revealing a causal mechanism for tissue damage. Our findings suggest that chronic infection with T. gondii enhances monocyte activation to increase inflammation associated with a secondary environmental insult.

Mutations in the torsinA-interacting protein 1 (TOR1AIP1) gene result in a severe muscular dystrophy with minimal literature in the pediatric population. We review a case of TOR1AIP1 gene mutation in a 16-year-old Caucasian female with a long history of muscle weakness. Extensive clinical workup was performed and MRI at time of initial presentation demonstrated no significant muscular atrophy with heterogenous STIR hyperintensity of the lower extremity muscles. MRI findings seven years later included extensive atrophy of the lower extremities, with severe progression, including the gluteal muscles, iliopsoas, rectus femoris, and obturator internus. There was also significant atrophy of the rectus abdominis and internal and external oblique muscles, and iliacus muscles. The MRI findings showed more proximal involvement of lower extremities and no atrophy of the tibialis anterior, making TOR1AIP1 the more likely genetic cause. Muscle biopsy findings supported TOR1AIP1 limb-girdle muscular dystrophy. Though rare, TOR1AIP1 gene mutation occurs in pediatric patients and MRI can aid in diagnosis and help differentiate from other types of muscular dystrophy. Genetic and pathology workup is also crucial to accurate diagnosis and possible treatment of these patients.

Noroviruses are major causes of gastroenteritis, with epidemic outbreaks occurring frequently. They are an important global health concern, especially for pediatric and immunocompromised populations, and are challenging pathogens to target immunologically due to their rapid rates of genetic and antigenic evolution and failure to stimulate durable protective immunity. In this Review, we summarize our current understanding of norovirus pathogenesis, noting the prominent role of murine norovirus as a small animal model for norovirus research. We highlight intriguing data supporting the possible involvement of norovirus in sequelae including irritable bowel syndrome and inflammatory bowel diseases, and describe the innate and adaptive immune mechanisms involved in control of both human and murine norovirus infection. Furthermore, we discuss the potential implications of recent discoveries regarding norovirus interactions with the gut microbiota, and briefly detail current understanding of noroviral evolution and its influence on viral pathogenesis. Our mechanistic understanding of norovirus pathogenesis continues to improve with increasing availability of powerful model systems, which will ultimately facilitate development of effective preventive and therapeutic approaches for this pathogen.

Background The ACS QUIK trial showed that a multicomponent quality improvement toolkit intervention resulted in improvements in processes of care for patients with acute myocardial infarction in Kerala but did not improve clinical outcomes in the context of background improvements in care. We describe the development of the ACS QUIK intervention and evaluate its implementation, acceptability, and sustainability. Methods We performed a mixed methods process evaluation alongside a cluster randomized, stepped-wedge trial in Kerala, India. The ACS QUIK intervention aimed to reduce the rate of major adverse cardiovascular events at 30 days compared with usual care across 63 hospitals (n = 21,374 patients). The ACS QUIK toolkit intervention, consisting of audit and feedback report, admission and discharge checklists, patient education materials, and guidelines for the development of code and rapid response teams, was developed based on formative qualitative research in Kerala and from systematic reviews. After four or more months of the center’s participation in the toolkit intervention phase of the trial, an online survey and physician interviews were administered. Physician interviews focused on evaluating the implementation and acceptability of the toolkit intervention. A framework analysis of transcripts incorporated context and intervening mechanisms. Results Among 63 participating hospitals, 22 physicians (35%) completed online surveys. Of these, 17 (77%) respondents reported that their hospital had a cardiovascular quality improvement team, 18 (82%) respondents reported having read an audit report, admission checklist, or discharge checklist, and 19 (86%) respondents reported using patient education materials. Among the 28 interviewees (44%), facilitators of toolkit intervention implementation were physicians’ support and leadership, hospital administrators’ support, ease-of-use of checklists and patient education materials, and availability of training opportunities for staff. Barriers that influenced the implementation or acceptability of the toolkit intervention for physicians included time and staff constraints, Internet access, patient volume, and inadequate understanding of the quality improvement toolkit intervention. Conclusions Implementation and acceptability of the ACS QUIK toolkit intervention were enhanced by hospital-level management support, physician and team support, and usefulness of checklists and patient education materials. Wider and longer-term use of the toolkit intervention and its expansion to potentially other cardiovascular conditions or other locations where the quality of care is not as high as in the ACS QUIK trial may be useful for improving acute cardiovascular care in Kerala and beyond. Trial registration NCT02256657 Electronic supplementary material The online version of this article (10.1186/s13012-019-0857-7) contains supplementary material, which is available to authorized users.

To deliver high quality health care to Muslim patients requires providers have a basic awareness of the Islamic faith and beliefs. This paper reports on how five academic programs from two universities in Rural West Texas have developed, implemented, assessed, and continue to develop an interprofessional simulation (IPS) program that incorporates challenges specifically related to the medical assessment of Muslim patients. It is through this process that social work, nursing, pharmacy, occupational therapy, and speech and language pathologists will be better prepared to assess and treat Muslim patients in a culturally competent manner, in an attempt to address discrimination and improve medical results.

Coreference resolution is an important task for natural language understanding, and the resolution of ambiguous pronouns a longstanding challenge. Nonetheless, existing corpora do not capture ambiguous pronouns in sufficient volume or diversity to accurately indicate the practical utility of models. Furthermore, we find gender bias in existing corpora and systems favoring masculine entities. To address this, we present and release GAP, a gender-balanced labeled corpus of 8,908 ambiguous pronoun–name pairs sampled to provide diverse coverage of challenges posed by real-world text. We explore a range of baselines that demonstrate the complexity of the challenge, the best achieving just 66.9% F1. We show that syntactic structure and continuous neural models provide promising, complementary cues for approaching the challenge.

Human knowledge and use of language is inextricably connected to perception, action and the organization of the brain, yet natural language processing is still dominated by text! More research involving language-including speech-in the context of other modalities and environments is needed, and there has never been a better time to do it. Without ever invoking the worn-out, overblown phrase ”how babies learn” in the talk, I’ll cover three of my team’s efforts involving language, vision and action. First: our work on speech-image representation learning and retrieval, where we demonstrate settings in which directly encoding speech outperforms the hard-to-beat strategy of using automatic speech recognition and strong text encoders. Second: two models for text-to-image generation: a multi-stage model which exploits user-guidance in the form of mouse traces and a single-stage one which uses cross-modal contrastive losses. Third: Room-across-Room, a multilingual dataset for vision-and-language navigation, for which we collected spoken navigation instructions, high-quality text transcriptions, and fine-grained alignments between words and pixels in high-definition 360-degree panoramas. I’ll wrap up with some thoughts on how work on computational language grounding more broadly presents new opportunities to enhance and advance our scientific understanding of language and its fundamental role in human intelligence.

The influence of the gut microbiota on traumatic brain injury (TBI) is presently unknown. This knowledge gap is of paramount clinical significance as TBI patients are highly susceptible to alterations in the gut microbiota by antibiotic exposure. Antibiotic-induced gut microbial dysbiosis established prior to TBI significantly worsened neuronal loss and reduced microglia activation in the injured hippocampus with concomitant changes in fear memory response. Importantly, antibiotic exposure for 1 week after TBI reduced cortical infiltration of Ly6Chigh monocytes, increased microglial pro-inflammatory markers, and decreased T lymphocyte infiltration, which persisted through 1 month post-injury. Moreover, microbial dysbiosis was associated with reduced neurogenesis in the dentate gyrus 1 week after TBI. By 3 months after injury (11 weeks after discontinuation of the antibiotics), we observed increased microglial proliferation, increased hippocampal neuronal loss, and modulation of fear memory response. These data demonstrate that antibiotic-induced gut microbial dysbiosis after TBI impacts neuroinflammation, neurogenesis, and fear memory and implicate gut microbial modulation as a potential therapeutic intervention for TBI. Supplementary Information The online version contains supplementary material available at 10.1186/s40478-021-01137-2.

The output of text-to-image synthesis systems should be coherent, clear, photo-realistic scenes with high semantic fidelity to their conditioned text descriptions. Our Cross-Modal Contrastive Generative Adversarial Network (XMC-GAN) addresses this challenge by maximizing the mutual information between image and text. It does this via multiple contrastive losses which capture inter-modality and intra-modality correspondences. XMC-GAN uses an attentional self-modulation generator, which enforces strong text-image correspondence, and a contrastive discriminator, which acts as a critic as well as a feature encoder for contrastive learning. The quality of XMC-GAN's output is a major step up from previous models, as we show on three challenging datasets. On MS-COCO, not only does XMC-GAN improve state-of-the-art FID from 24.70 to 9.33, but--more importantly--people prefer XMC-GAN by 77.3 for image quality and 74.1 for image-text alignment, compared to three other recent models. XMC-GAN also generalizes to the challenging Localized Narratives dataset (which has longer, more detailed descriptions), improving state-of-the-art FID from 48.70 to 14.12. Lastly, we train and evaluate XMC-GAN on the challenging Open Images data, establishing a strong benchmark FID score of 26.91., CVPR 2021

By supporting multi-modal retrieval training and evaluation, image captioning datasets have spurred remarkable progress on representation learning. Unfortunately, datasets have limited cross-modal associations: images are not paired with other images, captions are only paired with other captions of the same image, there are no negative associations and there are missing positive cross-modal associations. This undermines research into how inter-modality learning impacts intra-modality tasks. We address this gap with Crisscrossed Captions (CxC), an extension of the MS-COCO dataset with human semantic similarity judgments for 267,095 intra- and inter-modality pairs. We report baseline results on CxC for strong existing unimodal and multimodal models. We also evaluate a multitask dual encoder trained on both image-caption and caption-caption pairs that crucially demonstrates CxC's value for measuring the influence of intra- and inter-modality learning., To be presented at EACL2021

Vision-and-Language Navigation wayfinding agents can be enhanced by exploiting automatically generated navigation instructions. However, existing instruction generators have not been comprehensively evaluated, and the automatic evaluation metrics used to develop them have not been validated. Using human wayfinders, we show that these generators perform on par with or only slightly better than a template-based generator and far worse than human instructors. Furthermore, we discover that BLEU, ROUGE, METEOR and CIDEr are ineffective for evaluating grounded navigation instructions. To improve instruction evaluation, we propose an instruction-trajectory compatibility model that operates without reference instructions. Our model shows the highest correlation with human wayfinding outcomes when scoring individual instructions. For ranking instruction generation systems, if reference instructions are available we recommend using SPICE., Accepted to EACL 2021

BACKGROUND: Although quality improvement interventions for acute heart failure have been studied in high-income countries, none have been studied in low- or middle-income country settings where quality of care can be lower. We evaluated the effect of a quality improvement toolkit on process of care measures and clinical outcomes in patients hospitalized for acute heart failure in 8 hospitals in Kerala, India utilizing an interrupted time series design from February 2018 to August 2018. METHODS: The quality improvement toolkit included checklists, audit-and-feedback reports, and patient education materials. The primary outcome was rate of discharge guideline-directed medical therapy for patients with heart failure with reduced ejection fraction. We used mixed effect logistic regression and interrupted time series models for analysis. RESULTS: Among 1400 participants, mean (SD) age was 66.6 (12.2) years, and 38% were female. Mean (SD) left ventricular ejection fraction was 35.2% (9.7%). The primary outcome was observed in 41.3% of participants in the intervention period and 28.1% of participants in the control period (difference 13.2%; 95% CI 6.8, 19.0; adjusted OR = 1.70; 95% CI 1.17, 2.48). Interrupted time series model demonstrated highest rate of guideline-directed medical therapy at discharge in the initial weeks following intervention delivery with a concomitant decline over time. Improvements were observed in discharge process of care measures, including diet counseling, weight monitoring instructions, and scheduling of outpatient clinic follow-up but not hospital length of stay nor inpatient mortality. CONCLUSIONS: Higher rates of guideline-directed medical therapy at discharge were observed in Kerala. Broader implementation of this quality improvement intervention may improve heart failure care in low- and middle-income countries. SUMMARY TWEET: QI toolkit in Kerala, India shows improvements in GDMT at discharge for patients with HFrEF. Centre for Chronic Disease Control, Cardiological Society of India, @DukeGHI, @Fogarty_NIH, @NMCardioVasc, @FSMGlobalHealth

International audience; Purpose:CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype.Methods:We describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations.Results:Fourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism.Conclusion:We expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome.

SUMMARY STING modulates immunity by responding to bacterial and endogenous cyclic dinucleotides (CDNs). Humans and mice with STING gain-of-function mutations develop a syndrome known as STING-associated vasculopathy with onset in infancy (SAVI), which is characterized by inflammatory or fibrosing lung disease. We hypothesized that hyperresponsiveness of gain-of-function STING to bacterial CDNs might explain autoinflammatory lung disease in SAVI mice. We report that depletion of gut microbes with oral antibiotics (vancomycin, neomycin, and ampicillin [VNA]) nearly eliminates lung disease in SAVI mice, implying that gut microbes might promote STING-associated autoinflammation. However, we show that germ-free SAVI mice still develop severe autoinflammatory disease and that transferring gut microbiota from antibiotics-treated mice to germ-free animals eliminates lung inflammation. Depletion of anaerobes with metronidazole abolishes the protective effect of the VNA antibiotics cocktail, and recolonization with the metronidazole-sensitive anaerobe Bacteroides thetaiotaomicron prevents disease, confirming a protective role of a metronidazole-sensitive microbe in a model of SAVI., Graphical abstract, In brief Platt et al. report that oral antibiotics but not germ-free conditions prevent autoinflammatory lung disease in a mouse model of STING-associated vasculopathy with onset in infancy (SAVI). Recolonization of SAVI mice with either Bacteroidales-enriched stool or Bacteroides thetaiotaomicron is protective in this model of STING-associated autoinflammatory lung disease.

High sensitivity cardiac troponin T (hscTnT), soluble ST2 (sST2), N-terminal B-type natriuretic peptide (NT-proBNP), and galectin-3 are biomarkers of cardiac injury, stress, myocardial stretch, and fibrosis. Elevated levels are associated with poor outcomes. However, their association with cardiac mechanics in older persons is unknown. Associations between these biomarkers and cardiac mechanics derived from speckle tracking echocardiography, including left ventricular longitudinal strain (LVLS), early diastolic strain, and left atrial reservoir strain (LARS) were evaluated using standardized beta coefficients () in a cross sectional analysis with cardiac biomarkers in older patients without cardiovascular disease, low ejection fraction, or wall motion abnormalities. Biomarker associations with strain were attenuated by demographics and risk factors. In adjusted models, LVLS was associated with continuous measures of hscTnT (β∧−0.06, p = 0.020), sST2 (β∧ −0.05, p = 0.024) and NT-proBNP (β∧ −0.06, p = 0.007). “High” levels (i.e., greater than prognostic cutpoint) of hscTnT (>13 ng/ml), sST2 (>35 ng/ml), and NT-proBNP (>190 pg/ml) were also associated with worse LVLS. In risk factor adjusted models, LARS was associated with hscTnT (β∧ −0.08, p = 0.003) and NT-proBNP (β∧−0.18, p 13 ng/ml) and high NT-proBNP (>190 pg/ml) were also both associated with worse LARS. Gal-3 was not associated with any strain measure. In conclusion, in persons ≥ 65 years of age, without cardiovascular disease, low ejection fraction, or wall motion abnormalities, hscTnT, sST2, and NT-proBNP are associated with worse LVLS. HscTnT and NT-proBNP are associated with worse LARS. In conclusion, these subclinical increases in blood biomarkers, and their associations with subtle diastolic and systolic dysfunction, may represent pre-clinical heart failure.

Localized Narratives is a dataset with detailed natural language descriptions of images paired with mouse traces that provide a sparse, fine-grained visual grounding for phrases. We propose TReCS, a sequential model that exploits this grounding to generate images. TReCS uses descriptions to retrieve segmentation masks and predict object labels aligned with mouse traces. These alignments are used to select and position masks to generate a fully covered segmentation canvas; the final image is produced by a segmentation-to-image generator using this canvas. This multi-step, retrieval-based approach outperforms existing direct text-to-image generation models on both automatic metrics and human evaluations: overall, its generated images are more photo-realistic and better match descriptions., Comment: To appear in WACV 2021

The influence of the gut microbiota on traumatic brain injury (TBI) is presently unknown. This knowledge gap is of paramount clinical significance as TBI patients are highly susceptible to alterations in the gut microbiota by antibiotic exposure. Antibiotic-induced gut microbial dysbiosis established prior to TBI significantly worsened neuronal loss and reduced microglia activation in the injured hippocampus with concomitant changes in fear memory response. Importantly, microbial dysbiosis after TBI reduced hippocampal infiltration of Ly6Chigh monocytes followed by a decreased presence of CD4+ and CD8+ T cells that persisted through 1 month post-injury, and increase of microglial pro-inflammatory markers. By 3 months, these mice had a larger percentage of microglia with a persistent amoeboid morphology, increased neuronal loss, and a maladaptive fear memory response. These data demonstrate the important role the gut microbiota plays in neuroinflammation and recovery after TBI and implicate gut microbial modulation as a potential therapeutic intervention.

This chapter examines the case of the National Technical Institute for the Deaf (NTID) at the Rochester Institute of Technology (RIT) in the context of research on breaking barriers to organizational inclusion for persons with disabilities. The goal of this chapter is to help bridge existing research and real-world practices to offer insights into best practices for leaders seeking to tap talent from underutilized groups. NTID is the first and largest technological college in the world for students who are deaf or hard of hearing. We outline what we refer to as NTID’s three pillars for bolstering employment success: employment readiness (i.e., skill building initiatives), employability showcasing (i.e., sensitizing stakeholders to this talent base), and post-employment support (i.e., for accessibility, inclusion, and sustained performance).

Objectives This study aims to characterize caregivers of patients considering destination therapy left ventricular assist device (DT-LVAD) and evaluate the effectiveness of a shared decision-making (SDM) intervention. Background Caregivers play an integral role in the care of patients with chronic illness. At the extreme, pursuing a DT-LVAD is a major preference-sensitive decision that requires high-level caregiver engagement. Yet, little is known about caregivers of patients considering DT-LVAD, and there is a paucity of research on the involvement of caregivers in medical decision-making. Methods A 6-center, stepped-wedge trial was conducted. After varying time in usual care (control), sites were transitioned to an SDM intervention consisting of staff education and pamphlet and video decision aids (DAs). The primary outcome was decision quality, measured by knowledge and values-choice concordance. Results From 2015 to 2017, 182 caregivers of patients considering DT-LVAD were enrolled (control group, n = 111; intervention group, n = 71). The median age was 61 years, 86.5% were female, and 75.8% were spouses. Caregiver knowledge (0% to 100%) improved from baseline to post-education in both groups: in the control group it improved from 64.2% to 73.3%; in the intervention group it improved from 62.6% to 76.4% (adjusted difference of difference: 4.8%; p = 0.08). At 1 month, correlation between stated values and caregiver-reported treatment choice was stronger in the intervention group (difference in Kendall’s tau: 0.36, 95% confidence interval: 0.04 to 0.71; p = 0.03). Caregivers reported decisional conflict (0 to 100) at baseline (control group: 19.0 ± 2.1; intervention group: 21.4 ± 2.6), which decreased post-education more in the control group (control group: 9.0 ± 1.9, intervention group: 18.8 ± 2.4; p = 0.009). Caregivers in the control group were more likely to “definitely recommend” the educational materials than those in the intervention group (93.5% vs. 74.5%, respectively; p = 0.004). Conclusions An SDM intervention improved concordance between caregiver values and treatment choice for their loved ones but did not significantly impact knowledge. Caregivers found the DAs less acceptable than more biased educational materials and exposure to DAs led to higher conflict initially. These findings highlight the complexity of SDM involving caregivers of patients with chronic illness. (PCORI-1310-06998 Trial of a Decision Support Intervention for Patients and Caregivers Offered Destination Therapy Heart Assist Device [DECIDE-LVAD]; NCT02344576 )

Students are challenged in transitioning from acquiring knowledge and understanding through reading textbooks to their learning to select, read, evaluate, and synthesize the primary literature. A customary approach to teaching this transition to beginning graduate students is for a faculty member to assign “readings” from the recent literature that promise to become key publications; such assignments generally underscore recent, novel scientific content. We advocate here an alternative approach for coaching students very early in their training: first, to read, analyze, and discuss a paper that highlights critically important features of effective and valid experimental design; and, second, to study a paper that can be shown historically to have fundamentally changed the way in which physiological function is understood. We consider as an example of the first goal a study that purports to demonstrate a principle of thermoregulation, but that interaction between students and instructor reveals the study’s lack of an essential control. The second goal requires sufficient time for the publication to concretely validate its contribution(s). The purpose is to identify those essential properties of the selected paper that contributed to its having become a truly exemplary study. We present a 1957 paper by Dr. A. C. Burton ( Am Heart J 54: 801–810, 1957) as an illustration and analyze the study with respect to those attributes that contributed to its lasting importance. These alternative approaches to introduce inexperienced students to the original literature can produce critical insight into the process and can help students inculcate essential practices, guiding them to more productive careers.

Fructosamine and glycated albumin are potentially useful alternatives to hemoglobin A1c (HbA1c) as diabetes biomarkers. The genetic determinants of fructosamine and glycated albumin, however, are unknown. We performed genome-wide association studies of fructosamine and glycated albumin among 2,104 black and 7,647 white participants without diabetes in the Atherosclerosis Risk in Communities (ARIC) Study and replicated findings in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Among whites, rs34459162, a novel missense single nucleotide polymorphism (SNP) in RCN3, was associated with fructosamine (P = 5.3 × 10−9) and rs1260236, a known diabetes-related missense mutation in GCKR, was associated with percent glycated albumin (P = 5.9 × 10−9) and replicated in CARDIA. We also found two novel associations among blacks: an intergenic SNP, rs2438321, associated with fructosamine (P = 6.2 × 10−9), and an intronic variant in PRKCA, rs59443763, associated with percent glycated albumin (P = 4.1 × 10−9), but these results did not replicate. Few established fasting glucose or HbA1c SNPs were also associated with fructosamine or glycated albumin. Overall, we found genetic variants associated with the glycemic information captured by fructosamine and glycated albumin as well as with their nonglycemic component. This highlights the importance of examining the genetics of hyperglycemia biomarkers to understand the information they capture, including potential glucose-independent factors.

Background/ContextThe current educational market nestled in neoliberal and market-based reform efforts has shifted the nature of public education. Community-based educational spaces are also shaped within this context. As such, given the political and educational climate youth workers are situated in, their role as advocates, cultural workers, and pedagogues warrants greater exploration within educational scholarship. Although previous scholarship captures the significance of community-based youth workers in the lives of marginalized youth, their voices and experiences are absent from broader educational discourse. Subsequently, community-based youth workers’ relationship with schools, engagement with youth, and their pedagogical practices remain underutilized and undervalued.PurposeThe purpose of this article is to highlight the critical space youth workers occupy in the academic, social, and cultural lives of Black youth within community-based educational spaces. This article critically examines the intricate roles that youth workers play in the academic and social lives of youth and proposes deeper inquiry into the practices of youth workers and implications for broader education discourse.SettingThe study takes place at Educational Excellence (EE), a community-based educational program operating after school in the Northeastern part of the United States.Research DesignThis study employed a critical qualitative design with ethnographic methods. Participant observations occurred at program events for youth and their families over 13 months, events during the holidays (2), middle and high school retreats (2), staff retreats (2), parent orientation meetings (4), curriculum planning meetings (13), and staff-development trainings (10). In order to triangulate participant observation data, every youth worker was interviewed individually (n = 20) and observed during (or in) staff meetings, organizational events, and interaction with coworkers and students in the program. A total of three focus groups, lasting between 60 minutes and 90 minutes were held with participants.Findings/ResultsFindings indicate that a combination of factors contributes to the important role that youth workers play in the lives of students. From their vantage point, youth workers are community members that have extensive knowledge of the current educational landscape and the ways in which it shapes the experiences, opportunities, and outcomes of youth in their program. As former school administrators, teachers, and life-long community-based educators, youth workers’ understanding and analysis of students’ experiences in schools is extremely significant to their understanding of educational problems and the needs of their students. As such, youth workers were able to revive students through culturally responsive and relevant curricula and engagement that gave students an opportunity to think critically about the world around them and to also think more deeply about their social, academic, and political identities.Conclusions/RecommendationsYouth workers within community-based educational spaces serve as essential actors in the lives of young people. Recognizing and validating these educators and community-based spaces as distinct, equally important, and complimentary spaces to schools and classroom teachers is an essential step in the process of reimagining the possibilities of youth work in community-based settings and in broader conceptions of educational opportunity. Further research and practice should recognize community-based spaces as vital sites of learning and growth for young people. In addition, education research and policy should acknowledge the distinct value and pedagogical practices of community-based educational spaces from traditional school spaces.

Current prognostic indicators are ineffective for identifying advanced-stage colorectal cancer (CRC) patients with high risk of recurrence after surgical resection. We investigated the prognostic value of p53, Ki-67, and programmed death ligand 1 (PD-L1) in 254 patients with stage II and III CRC. The expression of p53 was positive in 63% of cases. Up-regulation of p53 was associated with smaller tumor size (P=.001) and higher Ki-67 labeling index (LI) (P=.031). The tumor Ki-67 LI was high (≥20%) in 197 (78%) of the patients. High Ki-67 LI was associated with higher TNM stage (P=.031), positive p53 expression (P=.031), and negative PD-L1 expression (P=.003). The 5-year relapse-free survivals (RFS) were 53% and 89%, respectively, for the p53-positive and Ki-67 LI-high patients and the p53-negative and Ki-67 LI-low patients (P

Importance Whole-genome sequencing (WGS) shows promise as a first-line genetic test for acutely ill infants, but widespread adoption and implementation requires evidence of an effect on clinical management. Objective To determine the effect of WGS on clinical management in a racially and ethnically diverse and geographically distributed population of acutely ill infants in the US. Design, setting, and participants This randomized, time-delayed clinical trial enrolled participants from September 11, 2017, to April 30, 2019, with an observation period extending to July 2, 2019. The study was conducted at 5 US academic medical centers and affiliated children's hospitals. Participants included infants aged between 0 and 120 days who were admitted to an intensive care unit with a suspected genetic disease. Data were analyzed from January 14 to August 20, 2020. Interventions Patients were randomized to receive clinical WGS results 15 days (early) or 60 days (delayed) after enrollment, with the observation period extending to 90 days. Usual care was continued throughout the study. Main outcomes and measures The main outcome was the difference in the proportion of infants in the early and delayed groups who received a change of management (COM) 60 days after enrollment. Additional outcome measures included WGS diagnostic efficacy, within-group COM at 90 days, length of hospital stay, and mortality. Results A total of 354 infants were randomized to the early (n = 176) or delayed (n = 178) arms. The mean participant age was 15 days (IQR, 7-32 days); 201 participants (56.8%) were boys; 19 (5.4%) were Asian; 47 (13.3%) were Black; 250 (70.6%) were White; and 38 (10.7%) were of other race. At 60 days, twice as many infants in the early group vs the delayed group received a COM (34 of 161 [21.1%; 95% CI, 15.1%-28.2%] vs 17 of 165 [10.3%; 95% CI, 6.1%-16.0%]; P = .009; odds ratio, 2.3; 95% CI, 1.22-4.32) and a molecular diagnosis (55 of 176 [31.0%; 95% CI, 24.5%-38.7%] vs 27 of 178 [15.0%; 95% CI, 10.2%-21.3%]; P Conclusions and relevance In this randomized clinical trial, for acutely ill infants in an intensive care unit, introduction of WGS was associated with a significant increase in focused clinical management compared with usual care. Access to first-line WGS may reduce health care disparities by enabling diagnostic equity. These data support WGS adoption and implementation in this population. Trail registration ClinicalTrials.gov Identifier: NCT03290469.

Importance There is limited evidence on the benefits of sacubitril/valsartan vs broader renin angiotensin system inhibitor background therapy on surrogate outcome markers, 6-minute walk distance, and quality of life in patients with heart failure and mildly reduced or preserved left ventricular ejection fraction (LVEF >40%). Objective To evaluate the effect of sacubitril/valsartan on N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, 6-minute walk distance, and quality of life vs background medication-based individualized comparators in patients with chronic heart failure and LVEF of more than 40%. Design, Setting, and Participants A 24-week, randomized, double-blind, parallel group clinical trial (August 2017-October 2019). Of 4632 patients screened at 396 centers in 32 countries, 2572 patients with heart failure, LVEF of more than 40%, elevated NT-proBNP levels, structural heart disease, and reduced quality of life were enrolled (last follow-up, October 28, 2019). Interventions Patients were randomized 1:1 either to sacubitril/valsartan (n = 1286) or to background medication-based individualized comparator (n = 1286), ie, enalapril, valsartan, or placebo stratified by prior use of a renin angiotensin system inhibitor. Main Outcomes and Measures Primary end points were change from baseline in plasma NT-proBNP level at week 12 and in the 6-minute walk distance at week 24. Secondary end points were change from baseline in quality of life measures and New York Heart Association (NYHA) class at 24 weeks. Results Among 2572 randomized patients (mean age, 72.6 years [SD, 8.5 years]; 1301 women [50.7%]), 2240 (87.1%) completed the trial. At baseline, the median NT-proBNP levels were 786 pg/mL in the sacubitril/valsartan group and 760 pg/mL in the comparator group. After 12 weeks, patients in the sacubitril/valsartan group (adjusted geometric mean ratio to baseline, 0.82 pg/mL) had a significantly greater reduction in NT-proBNP levels than did those in the comparator group (adjusted geometric mean ratio to baseline, 0.98 pg/mL) with an adjusted geometric mean ratio of 0.84 (95% CI, 0.80 to 0.88; P

Importance Cardiac fibrosis is exceedingly rare in young adults. Identification of genetic variants that cause early-onset cardiomyopathy may inform novel biological pathways. Experimental models and a single case report have linked genetic deficiency of plasminogen activator inhibitor-1 (PAI-1), a downstream target of cardiac transforming growth factor β, with cardiac fibrosis. Objective To perform detailed cardiovascular phenotyping and genotyping in young adults from an Amish family with a frameshift variant (c.699_700dupTA) inSERPINE1, the gene that codes for PAI-1. Design, Setting, and Participants This observational study included participants from 3 related nuclear families from an Amish community in the primary analysis and participants from the extended family in the secondary analysis. Participants were recruited from May 2015 to December 2016, and analysis took place from June 2015 to June 2020. Main Outcomes and Measures (1) Multimodality cardiovascular imaging (transthoracic echocardiography and cardiac magnetic resonance imaging), (2) whole-exome sequencing, and (3) induced pluripotent stem cell–derived cardiomyocytes. Results Among 17 participants included in the primary analysis, the mean (interquartile range) age was 23.7 (20.9-29.9) years and 9 individuals (52.9%) were confirmed to be homozygous for theSERPINE1c.699_700dupTA variant. Late gadolinium enhancement was present in 6 of 9 homozygous participants (67%) with absolute PAI-1 deficiency vs 0 of 8 in the control group (P = .001). Late gadolinium enhancement patterns tended to be dense and linear, usually subepicardial but also midmyocardial and transmural with noncoronary distributions. Targeted whole-exome sequencing analysis identified that homozygosity for c.699_700dupTASERPINE1was the only shared pathogenic variant or variant of uncertain significance after examination of cardiomyopathy genes among those with late gadolinium enhancement. Induced pluripotent stem cell–derived cardiomyocytes from participants homozygous for theSERPINE1c.699_700dupTA variant exhibited susceptibility to cardiomyocyte injury in response to angiotensin II (increased transforming growth factor β1 secretion and release of lactate dehydrogenase) compared with control induced pluripotent stem cell–derived cardiomyocytes. In a secondary analysis based on echocardiography in 155 individuals across 3 generations in the extended family, no difference in global longitudinal strain was observed in carriers for theSERPINE1c.699_700dupTA variant compared with wild-type participants, supporting an autosomal recessive inheritance pattern. Conclusions and Relevance In this study, a highly penetrant, autosomal recessive, cardiac fibrosis phenotype among young adults with homozygous frameshift variant forSERPINE1was identified, suggesting an optimal range of PAI-1 levels are needed for cardiac homeostasis.