Venous thromboembolism risk among pediatric patients with traumatic brain injury: a nationwide study of 44,128 patients.

Objective: Venous thromboembolism (VTE) chemoprophylaxis in pediatric patients with traumatic brain injury (TBI) requires balancing the risk of progression of intracranial bleeding versus the risk of VTE. The identification of VTE risk factors requires analysis of a very large data set. This case-control study aimed to identify VTE risk factors in pediatric patients with TBI in order to develop a TBI-specific association model that can be used for VTE risk stratification in this population.

Protocol for Development of American Association of Clinical Endocrinology Clinical Practice Guidelines and Consensus Statements: Summary of Methodology, Process, and Policy - 2023 Update.

Objective: This 2023 updated protocol summarizes the American Association of Clinical Endocrinology's (AACE's) new framework for the development of clinical practice guidelines and other guidance documents that includes changes to methodology, processes, and policies.

Methods: AACE has critically reviewed its development processes for guidance documents over the last several years against the National Academy of Medicine Standards for Developing Trustworthy Clinical Practice Guidelines and the Council of Medical Specialty Societies Principles for Development of Specialty Society Clinical Guidelines to determine areas for improvement.

Results: The new AACE framework for development of guidance documents incorporates many changes, including a revised conflicts of interest (COI) policy; strengthened commitment to collection of disclosures and management of relevant COI during development; open calls to membership for authors; new requirements for authors; new diversity, equity, and inclusion (DEI) policy; new empanelment process that incorporates consideration of DEI; and adoption of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to increase the quality of evidence assessment and standardize recommendation grades and statements, among other improvements.

Cytotoxic CD4 T cells eliminate senescent cells by targeting cytomegalovirus antigen.

Senescent cell accumulation has been implicated in the pathogenesis of aging-associated diseases, including cancer. The mechanism that prevents the accumulation of senescent cells in aging human organs is unclear. Here, we demonstrate that a virus-immune axis controls the senescent fibroblast accumulation in the human skin.

Single-cell atlas of the liver myeloid compartment before and after cure of chronic viral hepatitis.

Background & Aims: Chronic viral infections present serious public health challenges; however, direct-acting antivirals (DAAs) are now able to cure nearly all patients infected with hepatitis C virus (HCV), representing the only cure of a human chronic viral infection to date. DAAs provide a valuable opportunity to study immune pathways in the reversal of chronic immune failures in an in vivo human system.

Methods: To leverage this opportunity, we used plate-based single-cell RNA-seq to deeply profile myeloid cells from liver fine needle aspirates in patients with HCV before and after DAA treatment.

Combined PD-1, BRAF and MEK inhibition in BRAF colorectal cancer: a phase 2 trial.

While BRAF inhibitor combinations with EGFR and/or MEK inhibitors have improved clinical efficacy in BRAF colorectal cancer (CRC), response rates remain low and lack durability. Preclinical data suggest that BRAF/MAPK pathway inhibition may augment the tumor immune response. We performed a proof-of-concept single-arm phase 2 clinical trial of combined PD-1, BRAF and MEK inhibition with sparatlizumab (PDR001), dabrafenib and trametinib in 37 patients with BRAF CRC.

A Systematic Review Supporting the Endocrine Society Guidelines: Management of Diabetes and High Risk of Hypoglycemia.

Context: Interventions targeting hypoglycemia in people with diabetes are important for improving quality of life and reducing morbidity and mortality.

Objective: To support development of the Endocrine Society Clinical Practice Guideline for management of individuals with diabetes at high risk for hypoglycemia.

Methods: We searched several databases for studies addressing 10 questions provided by a guideline panel from the Endocrine Society.

Management of Individuals With Diabetes at High Risk for Hypoglycemia: An Endocrine Society Clinical Practice Guideline.

Context: Hypoglycemia in people with diabetes is common, especially in those taking medications such as insulin and sulfonylureas (SU) that place them at higher risk. Hypoglycemia is associated with distress in those with diabetes and their families, medication nonadherence, and disruption of life and work, and it leads to costly emergency department visits and hospitalizations, morbidity, and mortality.

Objective: To review and update the diabetes-specific parts of the 2009 Evaluation and Management of Adult Hypoglycemic Disorders: Endocrine Society Clinical Practice Guideline and to address developing issues surrounding hypoglycemia in both adults and children living with diabetes.

Incidental Appendiceal Tumors During Appendectomy: A Nineteen-Year Retrospective Review at a Municipal Hospital.

Non-operative management of appendicitis (NOMA) has recently gained popularity, but a concern is that NOMA might miss appendiceal neoplasms. We conducted a retrospective review of 1694 appendectomies done for acute appendicitis at our institution between January 2001 and December 2019 to study the incidence and distribution of appendiceal tumors. We identified 24 appendiceal neoplasms (1.

An Assessment of Diversity, Inclusion, and Health Equity Training in Endocrinology Fellowship Programs in the United States.

Context: The Accreditation Council for Graduate Medical Education has instituted common program requirements related to diversity, equity, and inclusion (DEI) for postgraduate trainees in the United States; however, the extent to which DEI training is being incorporated across endocrinology fellowship programs is unknown.

Objectives: To describe the sociodemographic representation and DEI training experiences within endocrinology fellowship programs.

Design, Setting, And Participants: National cross-sectional survey study of fellows and fellowship program leaders in the United States whose fellowships were members of the Association of Program Directors in Endocrinology and Metabolism.

Enhancing the Trustworthiness of the Endocrine Society's Clinical Practice Guidelines.

In an effort to enhance the trustworthiness of its clinical practice guidelines, the Endocrine Society has recently adopted new policies and more rigorous methodologies for its guideline program. In this Clinical Practice Guideline Communication, we describe these recent enhancements-many of which reflect greater adherence to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to guideline development-in addition to the rationale for such changes. Improvements to the Society's guideline development practices include, but are not limited to, enhanced inclusion of nonendocrinologist experts, including patient representatives, on guideline development panels; implementation of a more rigorous conflict/duality of interest policy; a requirement that all formal recommendations must be demonstrably underpinned by systematic evidence review; the explicit use of GRADE Evidence-to-Decision frameworks; greater use and explanation of standardized guideline language; and a more intentional approach to guideline updating.

Radiation therapy enhances immunotherapy response in microsatellite stable colorectal and pancreatic adenocarcinoma in a phase II trial.

Overcoming intrinsic resistance to immune checkpoint blockade for microsatellite stable (MSS) colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) remains challenging. We conducted a single-arm, non-randomized, phase II trial (NCT03104439) combining radiation, ipilimumab and nivolumab to treat patients with metastatic MSS CRC (n = 40) and PDAC (n = 25) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The primary endpoint was disease control rate (DCR) by intention to treat.

Systematic identification of genomic elements that regulate FCGR2A expression and harbor variants linked with autoimmune disease.

Background: FCGR2A binds antibody-antigen complexes to regulate the abundance of circulating and deposited complexes along with downstream immune and autoimmune responses. Although the abundance of FCRG2A may be critical in immune-mediated diseases, little is known about whether its surface expression is regulated through cis genomic elements and non-coding variants. In the current study, we aimed to characterize the regulation of FCGR2A expression, the impact of genetic variation and its association with autoimmune disease.

Spatially organized multicellular immune hubs in human colorectal cancer.

Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors.

Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory.

T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Here we confirmed pervasive phenotypic, functional and transcriptional differences between memory and exhausted antigen-specific CD8 T cells in human hepatitis C virus (HCV) infection before and after treatment.

Investigation of the Relationship Between Frequency of Blast Exposure, mTBI History, and Post-traumatic Stress Symptoms.

Introduction: Post-traumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) are common conditions among military personnel that frequently co-occur. This study investigated relationships between self-reported blast exposure, mTBI history, and current post-traumatic stress (PTS) symptoms in a population of active duty service members (n = 202) from the Intensive Outpatient Program at the National Intrepid Center of Excellence.

Materials And Methods: Participants were divided into four mTBI groups (0, 1, 2, and 3+) and four blast exposure groups (0-10, 11-100, 101-1,000, and 1,000+).

Longitudinal proteomic analysis of severe COVID-19 reveals survival-associated signatures, tissue-specific cell death, and cell-cell interactions.

Mechanisms underlying severe coronavirus disease 2019 (COVID-19) disease remain poorly understood. We analyze several thousand plasma proteins longitudinally in 306 COVID-19 patients and 78 symptomatic controls, uncovering immune and non-immune proteins linked to COVID-19. Deconvolution of our plasma proteome data using published scRNA-seq datasets reveals contributions from circulating immune and tissue cells.

Epitope spreading toward wild-type melanocyte-lineage antigens rescues suboptimal immune checkpoint blockade responses.

Although immune checkpoint inhibitors (ICIs), such as anti-programmed cell death protein-1 (PD-1), can deliver durable antitumor effects, most patients with cancer fail to respond. Recent studies suggest that ICI efficacy correlates with a higher load of tumor-specific neoantigens and development of vitiligo in patients with melanoma. Here, we report that patients with low melanoma neoantigen burdens who responded to ICI had tumors with higher expression of pigmentation-related genes.

Plasma proteomics reveals tissue-specific cell death and mediators of cell-cell interactions in severe COVID-19 patients.

COVID-19 has caused over 1 million deaths globally, yet the cellular mechanisms underlying severe disease remain poorly understood. By analyzing several thousand plasma proteins in 306 COVID-19 patients and 78 symptomatic controls over serial timepoints using two complementary approaches, we uncover COVID-19 host immune and non-immune proteins not previously linked to this disease. Integration of plasma proteomics with nine published scRNAseq datasets shows that SARS-CoV-2 infection upregulates monocyte/macrophage, plasmablast, and T cell effector proteins.

Loss of the Nuclear Protein RTF2 Enhances Influenza Virus Replication.

While hundreds of genes are induced by type I interferons, their roles in restricting the influenza virus life cycle remain mostly unknown. Using a loss-of-function CRISPR screen in cells prestimulated with interferon beta (IFN-β), we identified a small number of factors required for restricting influenza A virus replication. In addition to known components of the interferon signaling pathway, we found that replication termination factor 2 (RTF2) restricts influenza virus at the nuclear stage (and perhaps other stages) of the viral life cycle, based on several lines of evidence.

Temporal and Spatial Heterogeneity of Host Response to SARS-CoV-2 Pulmonary Infection.

The relationship of SARS-CoV-2 lung infection and severity of pulmonary disease is not fully understood. We analyzed autopsy specimens from 24 patients who succumbed to SARS-CoV-2 infection using a combination of different RNA and protein analytical platforms to characterize inter- and intra- patient heterogeneity of pulmonary virus infection. There was a spectrum of high and low virus cases that was associated with duration of disease and activation of interferon pathway genes.

Disabled Homolog 2 Controls Prometastatic Activity of Tumor-Associated Macrophages.

Tumor-associated macrophages (TAM) are regulators of extracellular matrix (ECM) remodeling and metastatic progression, the main cause of cancer-associated death. We found that disabled homolog 2 mitogen-responsive phosphoprotein (DAB2) is highly expressed in tumor-infiltrating TAMs and that its genetic ablation significantly impairs lung metastasis formation. DAB2-expressing TAMs, mainly localized along the tumor-invasive front, participate in integrin recycling, ECM remodeling, and directional migration in a tridimensional matrix.

Publisher Correction: The immune cell landscape in kidneys of patients with lupus nephritis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.