A multi-omics recovery factor predicts long COVID in the IMPACC study.

Background: Following SARS-CoV-2 infection, ~10-35% of COVID-19 patients experience long COVID (LC), in which debilitating symptoms persist for at least three months. Elucidating biologic underpinnings of LC could identify therapeutic opportunities.

Methods: We utilized machine learning methods on biologic analytes provided over 12-months after hospital discharge from >500 COVID-19 patients in the IMPACC cohort to identify a multi-omics "recovery factor", trained on patient-reported physical function survey scores.

Beta cell dysfunction occurs independently of insulitis in type 1 diabetes pathogenesis.

The loss of insulin secretory function associated with type 1 diabetes (T1D) is attributed to the immune-mediated destruction of beta cells. Yet, at onset of T1D, patients often retain a substantial beta cell mass, and T cell infiltration of pancreatic islets is typically sporadic. Here, we investigate the hypothesis that the remaining beta cells in T1D are dysfunctional, using live pancreas slices from organ donors recently diagnosed with T1D.

Protocol for processing and analyzing multiplexed images improves lymphatic cell identification and spatial architecture in human tissue.

Multiplexed images of human lymphatic tissue are extensively preprocessed before cell phenotyping and spatial analysis. Here, we present KINTSUGI (knowledge integration with new technologies: simplified user-guided image processing), a protocol designed to interactively engage the user in each processing step to ensure quality control. We describe steps for parameter tuning and batch processing of raw image data including illumination correction, stitching, deconvolution, 3D-2D conversion, registration, and autofluorescence subtraction.

Type 2 immune responses are associated with less severe COVID-19 in a hospitalized cohort.

Background: The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread rapidly after its identification in December 2019 to cause a global pandemic. The respiratory tract is the primary site of infection, and there is a large range in the severity of respiratory illnesses caused by the virus. Defining molecular and cellular factors for protection from severe disease and death has been a goal to better understand and to predict and mitigate the effects of SARS-CoV-2 and future coronaviruses.

Loss of Insulin-Positive Cell Clusters Precedes the Decrease in Islet Frequency and β-Cell Area in Type 1 Diabetes.

Unlabelled: In type 1 diabetes (T1D), insulin (INS) deficiency results from immune-mediated destruction of β-cells. The majority of functional β-cell mass is typically lost within months to years of disease diagnosis, but the timing and nature of this loss, particularly in early disease stages, remain unclear. We developed a whole-slide scanned image analysis pipeline for semiautomated quantitation of endocrine area, islet frequency, interislet distance, and endocrine object size distribution in 145 human pancreata from 60 donors without diabetes, 19 donors with single autoantibody positivity, 10 with multiple autoantibody positivity (mAAb+), and 16 with recent-onset (duration 0-1 year), 23 with medium-duration (1-7 years), and 17 with long-duration T1D (7+ years).

Baseline predictors for 28-day COVID-19 severity and mortality among hospitalized patients: results from the IMPACC study.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic threatened public health and placed a significant burden on medical resources. The Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study collected clinical, demographic, blood cytometry, serum receptor-binding domain (RBD) antibody titers, metabolomics, targeted proteomics, nasal metagenomics, Olink, nasal viral load, autoantibody, SARS-CoV-2 antibody titers, and nasal and peripheral blood mononuclear cell (PBMC) transcriptomics data from patients hospitalized with COVID-19. The aim of this study is to select baseline biomarkers and build predictive models for 28-day in-hospital COVID-19 severity and mortality with most predictive variables while prioritizing routinely collected variables.

MICBG406A polymorphism reduces risk of mechanical ventilation and death during viral acute lung injury.

MHC class I polypeptide-related sequence B (MICB) is a ligand for NKG2D. We have shown NK cells are central to lung transplant acute lung injury (ALI) via NKG2D activation, and increased MICB in bronchoalveolar lavage predicts ALI severity. Separately, we found a MICB polymorphism (MICBG406A) is associated with decreased ALI risk.

3D imaging of human pancreas suggests islet sizeand endocrine composition influence their loss intype 1 diabetes.

A high-definition description of pancreatic islets would prove beneficial for understanding the pathophysiology of type 1 diabetes (T1D), yet significant knowledge voids exist in terms of their size, endocrine cell composition, and number in both health and disease. Here, 3-dimensional (3D) analyses of pancreata from control persons without diabetes (ND) revealed heretofore underappreciated frequencies (approximately 50%) of insulin-positive (INS+) glucagon-negative (GCG-) islets. Non-diabetic individuals positive for a single Glutamic acid decarboxylase autoantibody (GADA+) yet at increased risk for disease consistently demonstrated endocrine features, including islet volume and cell composition, closely resembling the age-matched ND controls.

Spatial transcriptomics from pancreas and local draining lymph node tissue reveals a lymphotoxin-β signature in human type 1 diabetes.

This study explores the inflammatory response observed in pancreata and pancreatic lymph node (pLN) samples obtained throughout the natural history of type 1 diabetes (T1D) including non-diabetic individuals and non-diabetic autoantibody positive individuals with high susceptibility using spatial transcriptomics (ST). Integration of ST with public single-cell RNA sequencing data enabled interrogation of transcriptional alterations in T1D pathogenesis across both tissues and cellular scales. In the T1D pancreas, we observed global upregulation of multiple inflammation-associated transcripts, including regenerating islet-derived () family genes, complement factor 3 (), , and , and highlighted cellular candidates potentially contributing to these signatures.

3D imaging of human pancreas suggests islet size and endocrine composition influence their loss in type 1 diabetes.

A high-definition description of pancreatic islets would prove beneficial for understanding the pathophysiology of type 1 diabetes (T1D), yet significant knowledge voids exist in terms of their size, endocrine cell composition, and number in both health and disease. Here, 3-dimensional (3D) analyses of pancreata from control persons without diabetes (ND) revealed heretofore underappreciated frequencies (approximately 50%) of insulin-positive (INS+) glucagon-negative (GCG-) islets. Non-diabetic individuals positive for a single Glutamic acid decarboxylase autoantibody (GADA+) yet at increased risk for disease consistently demonstrated endocrine features, including islet volume and cell composition, closely resembling the age-matched ND controls.

Etiologic Determinants and Characteristics of Diabetes in Haitian Youth (EDDHY Study).

Published information on youth-onset diabetes in Haiti is scarce, with limited data available on diabetes autoimmunity and genetic susceptibility to the disease. We determined the anthropometric, metabolic, and immunological characteristics and human leukocyte antigen (HLA)-associated risks in patients with youth-onset diabetes. One hundred and ten subjects with type 1 diabetes (T1D) aged <22 years and diagnosed for < 2 years were evaluated.

Increased inflammation as well as decreased endoplasmic reticulum stress and translation differentiate pancreatic islets from donors with pre-symptomatic stage 1 type 1 diabetes and non-diabetic donors.

Aims/hypothesis: Progression to type 1 diabetes is associated with genetic factors, the presence of autoantibodies and a decline in beta cell insulin secretion in response to glucose. Very little is known regarding the molecular changes that occur in human insulin-secreting beta cells prior to the onset of type 1 diabetes. Herein, we applied an unbiased proteomics approach to identify changes in proteins and potential mechanisms of islet dysfunction in islet-autoantibody-positive organ donors with pre-symptomatic stage 1 type 1 diabetes (HbA ≤42 mmol/mol [6.

High-affinity CD16A polymorphism associated with reduced risk ofsevere COVID-19.

CD16A is an activating Fc receptor on NK cells that mediates antibody-dependent cellular cytotoxicity (ADCC), a key mechanism in antiviral immunity. However, the role of NK cell-mediated ADCC in SARS-CoV-2 infection remains unclear, particularly whether it limits viral spread and disease severity or contributes to the immunopathogenesis of COVID-19. We hypothesized that the high-affinity CD16AV176 polymorphism influences these outcomes.

Immune perturbations in human pancreas lymphatic tissues prior to and after type 1 diabetes onset.

Autoimmune destruction of pancreatic β cells results in type 1 diabetes (T1D), with pancreatic immune infiltrate representing a key feature in this process. However, characterization of the immunological processes occurring in human pancreatic lymphatic tissues is lacking. Here, we conduct a comprehensive study of immune cells from pancreatic, mesenteric, and splenic lymphatic tissues of non-diabetic control (ND), β cell autoantibody-positive non-diabetic (AAb+), and T1D donors using flow cytometry and CITEseq.

Effect of Oral Insulin on Early Combined Glucose and C-Peptide Endpoints in Individuals at High-Risk for Type 1 Diabetes.

The TrialNet Oral Insulin (OI) prevention trial showed no overall treatment effect, using the diagnosis of type 1 diabetes as an endpoint. A significant delay in onset was only found in a high-risk stratum (termed secondary stratum 1) of participants with low first-phase insulin release (FPIR). Since trials with an endpoint of type 1 diabetes take years to complete, in this post hoc analysis, we assessed whether a novel combination of glucose and C-peptide markers could identify a therapeutic benefit after 1 year of follow-up (trial participants followed for a median 2.

Closing the Gap Between Vision and Victory in Type 1 Diabetes: The NIDDK Human Islet Research Network (HIRN) Initiative.

Unlabelled: The identification of a "rundlichen Häuflein" by Paul Langerhans more than 150 years ago marked the initiation of a global effort to unravel the mysteries of pancreatic islets, an intricate system of nutrient-sensing, hormone-secreting, and signaling cells. In type 1 diabetes, this interconnected network is vulnerable to malfunction and immune attack, with strategies to prevent or repair islet damage still in their infancy. In 2014, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) established the Human Islet Research Network (HIRN) to accelerate our understanding of the molecular and cellular basis of type 1 diabetes development.

The Cardiovascular Repository for Type 1 Diabetes (CaRe-T1D): An NIDDK Initiative to Advance Understanding of Mechanisms Underlying Cardiovascular Disease in Type 1 Versus Type 2 Diabetes.

Unlabelled: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in individuals with diabetes. Individuals with type 1 diabetes have a two- to fourfold higher risk of CVD in comparison with the general population, driven by an earlier onset and increased lifetime incidence of CVD events and mortality. Similarly, type 2 diabetes confers two- to threefold increased CVD risk, usually alongside metabolic syndrome, obesity, and hypertension.

Enterovirus VP1 protein and HLA class I hyperexpression in pancreatic islet cells of organ donors with type 1 diabetes.

Aims/hypothesis: Earlier studies of pancreases from donors with type 1 diabetes demonstrated enteroviral capsid protein VP1 in beta cells. In the context of a multidisciplinary approach undertaken by the nPOD-Virus group, we assessed VP1 positivity in pancreas and other tissues (spleen, duodenum and pancreatic lymph nodes) from 188 organ donors, including donors with type 1 diabetes and donors expressing autoantibody risk markers. We also investigated whether VP1 positivity is linked to the hyperexpression of HLA class I (HLA-I) molecules in islet cells.

Joint analysis of the nPOD-Virus Group data: the association of enterovirus with type 1 diabetes is supported by multiple markers of infection in pancreas tissue.

Aims/hypothesis: Previous pathology studies have associated enterovirus infections with type 1 diabetes by examining the enterovirus capsid protein 1 (VP1) in autopsy pancreases obtained near diabetes diagnosis. The Network for Pancreatic Organ Donors with Diabetes (nPOD) has since obtained pancreases from organ donors with type 1 diabetes (with broad age and disease duration) and donors with disease-associated autoantibodies (AAbs), the latter representing preclinical disease. Two accompanying manuscripts from the nPOD-Virus Group report primary data from a coordinated analysis of multiple enterovirus indices.

Machine learning models predict long COVID outcomes based on baseline clinical and immunologic factors.

The post-acute sequelae of SARS-CoV-2 (PASC), also known as long COVID, remain a significant health issue that is incompletely understood. Predicting which acutely infected individuals will go on to develop long COVID is challenging due to the lack of established biomarkers, clear disease mechanisms, or well-defined sub-phenotypes. Machine learning (ML) models offer the potential to address this by leveraging clinical data to enhance diagnostic precision.

Identification of a multi-omics factor predictive of long COVID in the IMPACC study.

Following SARS-CoV-2 infection, ~10-35% of COVID-19 patients experience long COVID (LC), in which often debilitating symptoms persist for at least three months. Elucidating the biologic underpinnings of LC could identify therapeutic opportunities. We utilized machine learning methods on biologic analytes and patient reported outcome surveys provided over 12 months after hospital discharge from >500 hospitalized COVID-19 patients in the IMPACC cohort to identify a multi-omics "recovery factor".

Host-microbe multiomic profiling identifies distinct COVID-19 immune dysregulation in solid organ transplant recipients.

Coronavirus disease 2019 (COVID-19) poses significant risks for solid organ transplant recipients, who have atypical but poorly characterized immune responses to infection. We aim to understand the host immunologic and microbial features of COVID-19 in transplant recipients by leveraging a prospective multicenter cohort of 86 transplant recipients age- and sex-matched with 172 non-transplant controls. We find that transplant recipients have higher nasal SARS-CoV-2 viral abundance and impaired viral clearance, and lower anti-spike IgG levels.

Beta cell dysfunction occurs independently of insulitis in type 1 diabetes pathogenesis.

The loss of insulin secretory function associated with type 1 diabetes (T1D) is attributed to the immune-mediated destruction of beta cells. Yet, at onset of T1D, patients often have a significant beta cell mass remaining while T cell infiltration of pancreatic islets is sporadic. Thus, we investigated the hypothesis that the remaining beta cells in T1D are largely dysfunctional using live human pancreas tissue slices prepared from organ donors with recently diagnosed T1D.

Mapping histological and functional maturation of human endocrine pancreas across early postnatal periods.

Human endocrine cell differentiation and islet morphogenesis play critical roles in determining islet cell mass and function, but the events and timeline of these processes are incompletely defined. To better understand early human islet cell development and maturation, we collected 115 pediatric pancreata and mapped morphological and spatiotemporal changes from birth through the first ten years of life. Using quantitative analyses and a combination of complementary tissue imaging approaches, including confocal microscopy and whole-slide imaging, we developed an integrated model for endocrine cell formation and islet architecture, including endocrine cell type heterogeneity and abundance, endocrine cell proliferation, and islet vascularization and innervation.

Characterizing cell-type spatial relationships across length scales in spatially resolved omics data.

Spatially resolved omics (SRO) technologies enable the identification of cell types while preserving their organization within tissues. Application of such technologies offers the opportunity to delineate cell-type spatial relationships, particularly across different length scales, and enhance our understanding of tissue organization and function. To quantify such multi-scale cell-type spatial relationships, we present CRAWDAD, Cell-type Relationship Analysis Workflow Done Across Distances, as an open-source R package.