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BACKGROUND: We sought consensus among practising respiratory physicians on the prediction, identification and monitoring of progression in patients with fibrosing interstitial lung disease (ILD) using a modified Delphi process. METHODS: Following a literature review, statements on the prediction, identification and monitoring of progression of ILD were developed by a panel of physicians with specialist expertise. Practising respiratory physicians were sent a survey asking them to indicate their level of agreement with these statements on a binary scale or 7-point Likert scale (- 3 to 3), or to select answers from a list. Consensus was considered to be achieved if ≥ 70% of respondents selected the same answer, or, for responses on a Likert scale, the median score was ≤ -2 (disagree/not important) or ≥ 2 (agree/important) with an interquartile range ≤ 1. There were three rounds of the survey. RESULTS: Surveys 1, 2 and 3 were completed by 207, 131 and 94 physicians, respectively, between March 2022 and July 2023. Decline in forced vital capacity (FVC), decline in diffusing capacity of the lungs for carbon monoxide, and increased fibrosis on high-resolution computed tomography (HRCT) were ranked as the most important endpoints for determining progression. Consensus was reached that progression on HRCT or a decline in FVC ≥ 10% from baseline is sufficient to determine progression, and that small declines in multiple endpoints indicates progression. Consensus was reached that a histological pattern of usual interstitial pneumonia (UIP) is a risk factor for progression of ILD, but that a biopsy to look for a UIP pattern should not be performed solely for prognostic reasons. Consensus was not reached on the time period over which progression should be defined. There was consensus that appropriate management of ILD depends on the type of ILD, and that despite adequate management or despite usual management should be included in the definition of progression. CONCLUSIONS: This modified Delphi process provided consensus statements on the identification of ILD progression that were supported by a broad group of clinicians and may help to inform clinical practice until robust evidence-based guidelines are available.

During meiosis, each pair of homologous chromosomes becomes connected by at least one crossover, as required for accurate segregation, and adjacent crossovers are widely separated thereby limiting total numbers. In coarsening models, this crossover patterning results from nascent recombination sites competing to accrue a limiting pro-crossover RING-domain protein (COR) that diffuses between synapsed chromosomes. Here, we delineate the localization dynamics of three mammalian CORs in the mouse and determine their interdependencies. RNF212, HEI10, and the newest member RNF212B show divergent spatiotemporal dynamics along synapsed chromosomes, including profound differences in spermatocytes and oocytes, that are not easily reconciled by elementary coarsening models. Contrasting mutant phenotypes and genetic requirements indicate that RNF212B, RNF212, and HEI10 play distinct but interdependent functions in regulating meiotic recombination and coordinating the events of meiotic prophase-I by integrating signals from DNA breaks, homolog synapsis, the cell-cycle, and incipient crossover sites.

Patients with metastatic pancreatic ductal adenocarcinoma survive longer if disease spreads to the lung but not the liver. Here we generated overlapping, multi-omic datasets to identify molecular and cellular features that distinguish patients whose disease develops liver metastasis (liver cohort) from those whose disease develops lung metastasis without liver metastases (lung cohort). Lung cohort patients survived longer than liver cohort patients, despite sharing the same tumor subtype. We developed a primary organotropism (pORG) gene set enriched in liver cohort versus lung cohort primary tumors. We identified ongoing replication stress response pathways in high pORG/liver cohort tumors, whereas low pORG/lung cohort tumors had greater densities of lymphocytes and shared T cell clonal responses. Our study demonstrates that liver-avid pancreatic ductal adenocarcinoma is associated with tolerance to ongoing replication stress, limited tumor immunity and less-favorable outcomes, whereas low replication stress, lung-avid/liver-averse tumors are associated with active tumor immunity that may account for favorable outcomes.

PURPOSE: To assess outcomes of Descemet stripping endothelial keratoplasty (DSEK) in eyes with custom artificial iris (CAI) implantation. METHODS: This is a retrospective, interventional, consecutive, surgical case series of patients who underwent DSEK after CAI implantation between 2010 and 2021 at 2 referral centers. Primary safety measures were loss of corrected distance visual acuity (CDVA), increase in intraocular pressure (IOP), development or progression of glaucoma, and intraoperative and postoperative complications. Efficacy measures were graft survival at year 1 and improvement in cosmesis at postoperative month 3. In general, measures were compared between baseline and postoperative year 1 while any complication was reported for the full follow-up period. RESULTS: Thirty-nine eyes of 39 patients were identified. 64.1% of eyes had acquired aniridia from trauma. The mean follow-up interval was 27.7 months (range 12.2-117.4). Median CDVA improved from logMAR 1.0 to 0.7 at year 1 ( P = 0.0047). At the final follow-up, permanent loss of CDVA occurred in 25.6% of eyes, of which 90% was due to glaucoma. The most common postoperative complication was IOP elevation (66.7% of eyes). Graft survival at postoperative year 1 was 82.0% (95% confidence interval, 66.3-91.4). Secondary graft failure occurred in 28.2% of eyes at a mean duration of 39.7 months (SD 27.9 months) after DSEK. Cosmesis improved among 87.2% of eyes at postoperative month 3. CONCLUSIONS: DSEK is an effective procedure for addressing corneal edema in eyes with a CAI, but a majority develop elevated IOP and graft survival is shorter than in eyes without a CAI.

BACKGROUND: Condylar fractures are a major cause of morbidity and mortality in Thoroughbred racehorses. Condylar fractures have a variety of fracture configurations that suggest there may be differences in aetiopathogenesis. OBJECTIVE: To determine if exercise history differs with condylar fracture location in a population of Thoroughbred racehorses. STUDY DESIGN: Retrospective analysis of clinical and exercise data. METHODS: Exercise history of Thoroughbred racehorses that had condylar fracture repair between 1 January 2018 and 28 February 2021 was compared between racehorses that had fractures located radiographically either within the parasagittal groove (PSG) or abaxial to the PSG (non-PSG). Age, sex, and last event (race, timed work) matched control groups were compared between the PSG and non-PSG groups. Additionally, exercise history variables of both groups were each compared with a group-specific control population, each consisting of three control racehorses of equivalent age and sex matched to each affected racehorse by last event (race or official timed work) before fracture. RESULTS: Eighty-two horses with 84 fractures (45 PSG, 39 non-PSG) met inclusion criteria. Age was not different between groups (PSG: 3.4 ± 1.3 years [mean ± SD], non-PSG: 3.7 ± 1.3, p = 0.3). Number of races (PSG: 5.3 ± 7.1, non-PSG: 11.4 ± 8.9, p

BACKGROUND: Pretreatment computed tomography perfusion parameter relative cerebral blood volume (rCBV) lesion volume has been shown to predict 90-day modified Rankin Scale score in small-core strokes with Alberta Stroke Program Early Computed Tomography Score ≥5, including those with medium-vessel occlusions (mid and distal M2 segment occlusions). Hence, in this study we aim to assess the performance of different rCBV lesion volume thresholds (rCBV

The observation that the risk of developing Alzheimer's disease is reduced in individuals with high premorbid cognitive functioning, higher educational attainment, and occupational status has led to the 'cognitive reserve' hypothesis. This hypothesis suggests that individuals with greater cognitive reserve can tolerate a more significant burden of neuropathological changes before the onset of cognitive decline. The underpinnings of cognitive reserve remain poorly understood, although a shared genetic basis between measures of cognitive reserve and Alzheimer's disease has been suggested. Using the largest samples to date and novel statistical tools, we aimed to investigate shared genetic variants between Alzheimer's disease, and measures of cognitive reserve; cognition and educational attainment to identify molecular and neurobiological foundations. We applied the causal mixture model (MiXeR) to estimate the number of trait-influencing variants shared between Alzheimer's disease, cognition, and educational attainment, and condFDR/conjFDR to identify shared loci. To provide biological insights loci were functionally characterized. Subsequently, we constructed a Structural Equation Model (SEM) to determine if the polygenic foundation of cognition has a direct impact on Alzheimer's disease risk, or if its effect is mediated through established risk factors for the disease, using a case-control sample from the UK Biobank. Univariate MiXeR analysis (after excluding chromosome 19) revealed that Alzheimer's disease was substantially less polygenic (450 trait-influencing variants) compared to cognition (11,100 trait-influencing variants), and educational attainment (12,700 trait-influencing variants). Bivariate MiXeR analysis estimated that Alzheimer's disease shared approximately 70 % of trait-influencing variants with cognition, and approximately 40 % with educational attainment, with mixed effect directions. Using condFDR analysis, we identified 18 loci jointly associated with Alzheimer's disease and cognition and 6 loci jointly associated with Alzheimer's disease and educational attainment. Genes mapped to shared loci were associated with neurodevelopment, expressed in early life, and implicated the dendritic tree and phosphatidylinositol phosphate binding mechanisms. Spatiotemporal gene expression analysis of the identified genes showed that mapped genes were highly expressed during the mid-fetal period, further suggesting early neurodevelopmental stages as critical periods for establishing cognitive reserve which affect the risk of Alzheimer's disease in old age. Furthermore, our SEM analysis showed that genetic variants influencing cognition had a direct effect on the risk of developing Alzheimer's disease, providing evidence in support of the neurodevelopmental hypothesis of the disease.

BACKGROUND: Emotion-related impulsivity (ERI) describes the trait-like tendency toward poor self-control when experiencing strong emotions. ERI has been shown to be elevated across psychiatric disorders and predictive of the onset and worsening of psychiatric syndromes. Recent work has correlated ERI scores with the region-level neuroanatomical properties of the orbitofrontal cortex (OFC), but not posteromedial cortex (PMC). Informed by a growing body of research indicating that examining the morphology of specific cortical folds (sulci) can produce unique insights into behavioral outcomes, the present study modeled the association between ERI and the morphology of sulci within OFC and PMC, which is a finer scale than previously conducted. METHODS: Analyses were conducted in a transdiagnostic sample of 118 adult individuals with a broad range of psychiatric syndromes. First, we manually defined over 4,000 sulci across 236 cerebral hemispheres. Second, we implemented a model-based LASSO regression to relate OFC sulcal morphology to ERI. Third, we tested whether effects were specific to OFC sulci, sulcal depth, and ERI (as compared to PMC sulci, sulcal gray matter thickness, and non-emotion-related impulsivity). RESULTS: The LASSO regression revealed bilateral associations of ERI with the depths of eight OFC sulci. These effects were strongest for OFC sulci, sulcal depth, and ERI in comparison to PMC sulci, sulcal gray matter thickness, and non-emotion-related impulsivity. In addition, we identified a new transverse component of the olfactory sulcus in every hemisphere that is dissociable from the longitudinal component based on anatomical features and correlation with behavior, which could serve as a new transdiagnostic biomarker. CONCLUSIONS: The results of this data-driven investigation provide greater neuroanatomical and neurodevelopmental specificity on how OFC is related to ERI. As such, findings link neuroanatomical characteristics to a trait that is highly predictive of psychopathology.

AimsAnxiety disorders are prevalent and anxiety symptoms (ANX) co-occur with many psychiatric disorders. We aimed to identify genomic loci associated with ANX, characterize its genetic architecture, and genetic overlap with psychiatric disorders.MethodsWe included a genome-wide association study of ANX (meta-analysis of UK Biobank and Million Veterans Program, n = 301,732), schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD), and validated the findings in the Norwegian Mother, Father, and Child Cohort (n = 95,841). We employed the bivariate causal mixture model and local analysis of covariant association to characterize the genetic architecture including overlap between the phenotypes. Conditional and conjunctional false discovery rate analyses were performed to boost the identification of loci associated with anxiety and shared with psychiatric disorders.ResultsAnxiety was polygenic with 12.9k genetic variants and overlapped extensively with psychiatric disorders (4.1k-11.4k variants) with predominantly positive genetic correlations between anxiety and psychiatric disorders. We identified 119 novel loci for anxiety by conditioning on the psychiatric disorders, and loci shared between anxiety and MD n=47 , BIP n=33 , SCZ n=71 , ADHD n=20 , and ASD n=5 . Genes annotated to anxiety loci exhibit enrichment for a broader range of biological pathways including cell adhesion and neurofibrillary tangle compared with genes annotated to the shared loci.ConclusionsAnxiety is highly polygenic phenotype with extensive genetic overlap with psychiatric disorders, and we identified novel loci for anxiety implicating new molecular pathways. The shared genetic architecture may underlie the extensive cross-disorder comorbidity of anxiety, and the identified molecular underpinnings may lead to potential drug targets.

OBJECTIVE: To identify organizational service features associated with positive patient ratings of primary care within primary care clinics tailored to accommodate persons with ongoing and recent experiences of homelessness (PEH). DATA SOURCES AND STUDY SETTING: PEH receiving primary care in 29 United States Veterans Health Administration homeless-tailored clinics were surveyed about their primary care experience using the validated Primary Care Quality-Homeless (PCQ-H) survey. Characteristics of the clinics were assessed through surveys of clinic staff using a new organizational survey developed through literature review, site visits, statistical analysis, and consensus deliberation. STUDY DESIGN: Cross-sectional examination of patients ratings of care based on surveys of patients, and of clinic characteristics, analyzed with Classification and Regression Tree (CART) analysis, a form of machine learning. DATA COLLECTION METHODS: Patient surveys (n = 3394) were obtained from a random sample of enrolled patients by both mail and telephone by an external survey contractor. Staff (n = 52 from 29 clinics) were interviewed by telephone. PRINCIPAL FINDINGS: This analysis identified service features that impact patient experience favorably, including aspects of patient-centeredness, team identity, strong external leadership support, and service that reach beyond traditional primary care clinic confines. Results varied according to the patient experience scale analyzed. Individual characteristics of PEH, such as degree of social support, general health, and unsheltered status, were also correlated with how they rate care. CONCLUSIONS: Organizational characteristics correlate with ratings of primary care from patients with recent and ongoing homelessness. Primary care programs serving homeless individuals can assure better care based on who they hire, how they foster team identity, what services they provide, and the strength of leadership support to protect a homeless-focused mission.

BACKGROUND: Chronic pain and problematic substance use are prevalent among Veterans with homeless experience (VHE) and may contribute to a challenging primary care experience. OBJECTIVE: To examine the association of chronic pain and problematic substance use with unfavorable primary care experiences among VHE and to explore the association of pain treatment utilization and unfavorable care experiences in VHE with chronic pain. METHODS: We surveyed VHE (n = 3039) engaged in homeless-tailored primary care at 29 Veterans Affairs Medical Centers (VAMCs). We assessed unfavorable primary care experiences with four validated Primary Care Quality-Homeless (PCQ-H) scales: multivariable logistic regressions explored associations between unfavorable care experiences for VHE with chronic pain and problematic substance use, chronic pain alone, problematic substance use alone, or neither. We then examined the association between receipt of pain treatments and unfavorable experiences among VHE with chronic pain. Last, we identified PCQ-H items that had the greatest difference in unfavorable response rates between VHE with and without chronic pain. RESULTS: The prevalence of unfavorable primary care experience was higher on all four scales for patients reporting chronic pain (with or without problematic substance use) (all p

Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) that affects approximately 4% of males and 1% of females in the United States. While causes of ASD are multi-factorial, single rare genetic variants contribute to around 20% of cases. Here, we report a case series of seven unrelated probands (6 males, 1 female) with ASD or another variable NDD phenotype attributed to de novo heterozygous loss of function or missense variants in the gene LARP1 (La ribonucleoprotein 1). LARP1 encodes an RNA-binding protein that post-transcriptionally regulates the stability and translation of thousands of mRNAs, including those regulating cellular metabolism and metabolic plasticity. Using lymphocytes collected and immortalized from an index proband who carries a truncating variant in one allele of LARP1, we demonstrated that lower cellular levels of LARP1 protein cause reduced rates of aerobic respiration and glycolysis. As expression of LARP1 increases during neurodevelopment, with higher levels in neurons and astrocytes, we propose that LARP1 haploinsufficiency contributes to ASD or related NDDs through attenuated metabolic activity in the developing fetal brain.

Children with autism and other neurodevelopmental concerns (NDC) frequently exhibit an array of sensory processing dysfunction phenotypes, posing a significant challenge their adaptive development. Additionally, these children often encounter difficulties with self-regulation, including emotion dysregulation, anxiety, and symptoms associated with attention and hyperactivity. However, further research is required to comprehend how patterns of sensory processing differences across neurodevelopmental conditions may contribute to regulatory control problems. Adopting a transdiagnostic perspective within the Research Domain Criteria (RDoC) framework, this study examined the relationship between clusters of sensory processing phenotypes and differential patterns of self-regulation behaviors. We recruited a sample of 117 participants (8-12 years) with a diverse range of neurodevelopmental concerns including autism, ADHD, anxiety, and sensory processing differences. This study aimed to (1) establish the prevalence of self-regulation problems in a community-recruited cohort of children with diverse NDCs; (2) construct data-driven sensory processing latent subtypes; (3) investigate group differences in emotion dysregulation, anxiety, and ADHD symptoms. Results showed that 39% of NDC children met clinically concerning thresholds for emotion dysregulation, 19% for anxiety, and 62% for ADHD. Second, latent profile analysis identified five sensory processing subtypes categorized by modality: Typical Processing, Intermediate/Mixed, Sensory Over-Responsive, Sensory Seeking, and Sensory Under-Responsive. Notably, the Sensory Over-Responsive group exhibited distinctively elevated anxiety scores, while the Sensory Seeking and Sensory Under-Responsive groups showed heightened ADHD scores. Intriguingly, the Sensory Over-Responsive, Sensory Under-Responsive, and Sensory Seeking subgroups all demonstrated elevated emotion dysregulation scores, suggesting a potential shared mechanism of emotion dysregulation that might elucidate the connection between sensory processing differences and increased anxiety and ADHD behaviors in children with autism and other NDCs.

Despite their beneficial actions as immunosuppressants, glucocorticoids (GC) have devastating effects on the musculoskeletal and cardiac systems, as long-term treated patients exhibit high incidence of falls, bone fractures, and cardiovascular events. Herein, we show that GC upregulate simultaneously in bone, skeletal muscle, and the heart the expression of E3 ubiquitin ligases (atrogenes), known to stimulate the proteasomal degradation of proteins. Activation of vitamin D receptor (VDR) signaling with the VDR ligands calcitriol or eldecalcitol prevented GC-induced atrogene upregulation in vivo and ex vivo in bone/muscle organ cultures and preserved tissue structure/mass and function of the 3 tissues in vivo. Direct pharmacologic inhibition of the proteasome with carfilzomib also conferred musculoskeletal protection. Genetic loss of the atrogene MuRF1-mediated protein ubiquitination in ΔRING mice afforded temporary or sustained protection from GC excess in bone or skeletal and heart muscle. We concluded that the atrogene pathway downstream of MuRF1 underlies GC action in bone, muscle, and the heart, and it can be pharmacologically or genetically targeted to confer protection against the damaging actions of GC simultaneously in the 3 tissues.

Cancer transcriptional patterns reflect both unique features and shared hallmarks across diverse cancer types, but whether differences in these patterns are sufficient to characterize the full breadth of tumor phenotype heterogeneity remains an open question. We hypothesized that these shared transcriptomic signatures reflect repurposed versions of functional tasks performed by normal tissues. Starting with normal tissue transcriptomic profiles, we use non-negative matrix factorization to derive six distinct transcriptomic phenotypes, called archetypes, which combine to describe both normal tissue patterns and variations across a broad spectrum of malignancies. We show that differential enrichment of these signatures correlates with key tumor characteristics, including overall patient survival and drug sensitivity, independent of clinically actionable DNA alterations. Additionally, we show that in HR+/HER2- breast cancers, metastatic tumors adopt transcriptomic signatures consistent with the invaded tissue. Broadly, our findings suggest that cancer often arrogates normal tissue transcriptomic characteristics as a component of both malignant progression and drug response. This quantitative framework provides a strategy for connecting the diversity of cancer phenotypes and could potentially help manage individual patients.

Individuals befriend others who are similar to them. One important source of similarity in relationships is similarity in felt emotion. In the present study, we used novel methods to assess whether greater similarity in the multivoxel brain representation of affective stimuli was associated with adolescents proximity within real-world school-based social networks. We examined dyad-level neural similarity within a set of brain regions associated with the representation of affect including the ventromedial prefrontal cortex (vmPFC), amygdala, insula, and temporal pole. Greater proximity was associated with greater vmPFC neural similarity during pleasant and neutral experiences. Moreover, we used unsupervised clustering on social networks to identify groups of friends and observed that individuals from the same (versus different) friend groups were more likely to have greater vmPFC neural similarity during pleasant and negative experiences. These findings suggest that similarity in the multivoxel brain representation of affect may play an important role in adolescent friendships.

BACKGROUND: Despite advances in cancer care and detection, >65% of patients with squamous cell cancer of the head and neck (HNSCC) will develop recurrent and/or metastatic disease. The prognosis for these patients is poor with a 5-year overall survival of 39%. Recent treatment advances in immunotherapy, including immune checkpoint inhibitors like pembrolizumab and nivolumab, have resulted in clinical benefit in a subset of patients. There is a critical clinical need to identify patients who benefit from these antiprogrammed cell death protein 1 (anti-PD-1) immune checkpoint inhibitors. METHODS: Here, we report findings from a multicenter observational study, PREDicting immunotherapy efficacy from Analysis of Pre-treatment Tumor biopsies (PREDAPT), conducted across 17 US healthcare systems. PREDAPT aimed to validate OncoPrism-HNSCC, a clinical biomarker assay predictive of disease control in patients with recurrent or metastatic HNSCC treated with anti-PD-1 immune checkpoint inhibitors as a single agent (monotherapy) and in combination with chemotherapy (chemo-immunotherapy). The test used RNA-sequencing data and machine learning models to score each patient and place them into groups of low, medium, or high. RESULTS: The OncoPrism-HNSCC prediction significantly correlated with disease control in both the monotherapy cohort (n=62, p=0.004) and the chemo-immunotherapy cohort (n=50, p=0.01). OncoPrism-HNSCC also significantly predicted progression-free survival in both cohorts (p=0.015 and p=0.037, respectively). OncoPrism-HNSCC had more than threefold higher specificity than programmed death-ligand 1 combined positive score and nearly fourfold higher sensitivity than tumor mutational burden for predicting disease control. CONCLUSIONS: Here, we demonstrate the clinical validity of the OncoPrism-HNSCC assay in identifying patients with disease control in response to anti-PD-1 immune checkpoint inhibitors. TRIAL REGISTRATION NUMBER: NCT04510129.

PurposeCognitive impairment is prevalent among individuals with epilepsy, and increasing evidence indicates that genetic factors can underlie this relationship. However, the extent to which epilepsy subtypes differ in their genetic relationship with cognitive function, and information about the specific genetic variants involved remain largely unknown.MethodsWe investigated the genetic relationship between epilepsies and general cognitive ability (COG) using complementary statistical tools, including linkage disequilibrium score (LDSC) regression, MiXeR and conjunctional false discovery rate (conjFDR). We analyzed genome-wide association study data on COG (n = 269,867) and common epilepsies (n = 27,559 cases, 42,436 controls), including the broad phenotypes 'all epilepsy', focal epilepsies and genetic generalized epilepsies (GGE), as well as specific subtypes. We functionally annotated the identified loci using several biological resources and validated the results in independent samples.ResultsUsing MiXeR, COG (11.2k variants) was estimated to be almost four times more polygenic than 'all epilepsy', GGE, juvenile myoclonic epilepsy (JME), and childhood absence epilepsy (CAE) (2.5k - 2.9k variants). The other epilepsy phenotypes were insufficiently powered for MiXeR analysis. We quantified extensive genetic overlap between COG and epilepsy types, but with varying negative genetic correlations (-0.23 to -0.04). COG was estimated to share 2.9k variants with both GGE and 'all epilepsy', and 2.3k variants with both JME and CAE. Using conjFDR, we identified 66 distinct loci shared between COG and epilepsies, including novel associations for GGE (27), 'all epilepsy' (5), JME (5) and CAE (5). The implicated genes were significantly expressed in multiple brain regions. The results were validated in independent samples (COG: p = 3.62 × 10-7; 'all epilepsy': p = 2.58 × 10-3).ConclusionOur study further dissects the substantial genetic basis shared between epilepsies and COG and identifies novel shared loci. An improved understanding of the genetic relationship between epilepsies and COG may lead to the development of novel comorbidity-targeted epilepsy treatments.

BACKGROUND: Finerenone, a selective non-steroidal mineralocorticoid receptor antagonist, improves kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D). The FINE-REAL study (NCT05348733) aims to evaluate the characteristics and treatment patterns of participants treated with finerenone in clinical practice. METHODS: FINE-REAL is a prospective, single-arm, non-interventional study of patients initiated on finerenone as part of their routine care in accordance with country-approved labels. The study, initiated in June 2022, is expected to be completed by January 2028. The cutoff for this pre-specified interim analysis was June 13, 2023. RESULTS: Participants were recruited across nephrology, endocrinology, cardiology, and primary care settings. Of 556 participants enrolled in the study by the cut-off date, 504 were included in this analysis (median follow-up duration of 7 months [finerenone treatment initiation to last recorded observation]). At baseline, 76.1% of participants were in the high or very high (KDIGO) CKD risk categories. Angiotensin converting enzyme inhibitors/angiotensin receptor blockers and sodium-glucose cotransporter 2 inhibitors were prescribed to 71.8% and 46.6% of participants, respectively. Based on prescribing information, 87.9% and 12.1% of participants initiated finerenone at doses of 10 and 20 mg, respectively. Finerenone treatment was uninterrupted in 92.3% of participants after 7 months median follow-up. Treatment-emergent adverse events occurred in 110 (21.8%) participants. Hyperkalemia occurred in 25 (5.0%) participants, with no cases leading to death, dialysis, or hospitalization. CONCLUSION: At this interim analysis, finerenone was initiated in patients with CKD and T2D across various clinical practices participating in the study. Treatment discontinuation and hyperkalemia occurred infrequently.

OBJECTIVE: The potential for choline metabolism to influence the development of diabetes has received increased attention. Previous studies on circulating choline metabolites and incident diabetes have been conducted in samples of older adults, often with a high prevalence of risk factors. RESEARCH DESIGN AND METHODS: Participants were from year 15 of follow-up (2000-2001) in the Coronary Artery Risk Development in Young Adults (CARDIA) Study (n = 3,133, aged 33-45 years) with plasma choline metabolite (choline, betaine, and trimethylamine N-oxide [TMAO]) data. We quantified associations between choline metabolites and 15-year risk of incident diabetes (n = 387) among participants free of diabetes at baseline using Cox proportional hazards regression models adjusted for sociodemographics, health behaviors, and clinical variables. RESULTS: Betaine was inversely associated with 15-year risk of incident diabetes (hazard ratio 0.76 [95% CI 0.67, 0.88] per 1-SD unit betaine), and TMAO was positively associated with 15-year risk of incident diabetes (1.11 [1.01, 1.22] per 1-SD unit). Choline was not significantly associated with 15-year risk of incident diabetes (1.05 [0.94, 1.16] per 1-SD). CONCLUSIONS: Our findings are consistent with other published literature supporting a role for choline metabolism in diabetes. Our study extends the current literature by analyzing a racially diverse population-based cohort of early middle-aged individuals in whom preventive activities may be most relevant.

BACKGROUND: The Get With The Guidelines-Stroke program is a quality improvement initiative designed to enhance adherence to evidence-based stroke care. Since its inception in 2003, over 2800 hospitals in the United States have participated in the program. METHODS: We examined patient characteristics, adherence to performance measures, and in-hospital outcomes in patients hospitalized for acute ischemic stroke, subarachnoid hemorrhage, intracerebral hemorrhage, and transient ischemic attack in The Get With The Guidelines-Stroke hospitals from 2003 through 2022. We quantified temporal changes in performance measure adherence and clinical outcomes over time. Performance measure denominators consisted of patients who were eligible, excluding those with contraindications. RESULTS: Over the 20 years of the program, a total of 7837 849 stroke cases (median age 71 years, 51.0% female; 69.2% ischemic strokes, 3.9% SAHs, 11.5% ICHs, and 15.3% TIAs) were entered into the registry. Except for antithrombotics at discharge, in which the baseline performance was >92%, there was sustained improvement in all performance metrics regardless of type of cerebrovascular event (P

BACKGROUND: Motion Tape (MT) is a low-profile, disposable, self-adhesive wearable sensor that measures skin strain. Preliminary studies have validated MT for measuring lower back movement. However, further analysis is needed to determine if MT can be used to measure lower back muscle engagement. The purpose of this study was to measure differences in MT strain between conditions in which the lower back muscles were relaxed versus maximally activated. METHODS: Ten participants without low back pain were tested. A matrix of six MTs was placed on the lower back, and strain data were captured under a series of conditions. The first condition was a baseline trial, in which participants lay prone and the muscles of the lower back were relaxed. The subsequent trials were maximum voluntary isometric contractions (MVICs), in which participants did not move, but resisted the examiner force in extension or rotational directions to maximally engage their lower back muscles. The mean MT strain was calculated for each condition. A repeated measures ANOVA was conducted to analyze the effects of conditions (baseline, extension, right rotation, and left rotation) and MT position (1-6) on the MT strain. Post hoc analyses were conducted for significant effects from the overall analysis. RESULTS: The results of the ANOVA revealed a significant main effect of condition (p < 0.001) and a significant interaction effect of sensor and condition (p = 0.01). There were significant differences in MT strain between the baseline condition and the extension and rotation MVIC conditions, respectively, for sensors 4, 5, and 6 (p = 0.01-0.04). The largest differences in MT strain were observed between baseline and rotation conditions for sensors 4, 5, and 6. CONCLUSIONS: MT can capture maximal lower back muscle engagement while the trunk remains in a stationary position. Lower sensors are better able to capture muscle engagement than upper sensors. Furthermore, MT captured muscle engagement during rotation conditions better than during extension.

BIVV003 is a gene-edited autologous cell therapy in clinical development for the potential treatment of sickle cell disease (SCD). Hematopoietic stem cells (HSC) are genetically modified with mRNA encoding zinc finger nucleases (ZFN) that target and disrupt a specific regulatory GATAA motif in the BCL11A erythroid enhancer to reactivate fetal hemoglobin (HbF). We characterized ZFN-edited HSC from healthy donors and donors with SCD. Results of preclinical studies show that ZFN-mediated editing is highly efficient, with enriched biallelic editing and high frequency of on-target indels, producing HSC capable of long-term multilineage engraftment in vivo, and express HbF in erythroid progeny. Interim results from the Phase 1/2 PRECIZN-1 study demonstrated that BIVV003 was well-tolerated in seven participants with SCD, of whom five of the six with more than 3 months of follow-up displayed increased total hemoglobin and HbF, and no severe vaso-occlusive crises. Our data suggest BIVV003 represents a compelling and novel cell therapy for the potential treatment of SCD.

The basal ganglia are subcortical brain structures involved in motor control, cognition, and emotion regulation. We conducted univariate and multivariate genome-wide association analyses (GWAS) to explore the genetic architecture of basal ganglia volumes using brain scans obtained from 34,794 Europeans with replication in 4,808 white and generalization in 5,220 non-white Europeans. Our multivariate GWAS identified 72 genetic loci associated with basal ganglia volumes with a replication rate of 55.6% at P

BACKGROUND: The inflammatory response in patients with traumatic brain injury (TBI) offers opportunities for stratification and intervention. Previous unselected approaches to immunomodulation in patients with TBI have not improved patient outcomes. METHODS: Serum and plasma samples from two prospective, multi-centre observational studies of patients with TBI were used to discover (Collaborative European NeuroTrauma Effectiveness Research [CENTER-TBI], Europe) and validate (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI] Pilot, USA) individual variations in the immune response using a multiplex panel of 30 inflammatory mediators. Mediators that were associated with unfavourable outcomes (Glasgow outcome score-extended [GOS-E] ≤ 4) were used for hierarchical clustering to identify patients with similar signatures. FINDINGS: Two clusters were identified in both the discovery and validation cohorts, termed early-inflammatory and pauci-inflammatory. The early-inflammatory phenotype had higher concentrations of interleukin-6 (IL-6), IL-15, and monocyte chemoattractant protein 1 (MCP1). Patients with the early-inflammatory phenotype were older and more likely to have an unfavourable GOS-E at 6 months. There were no differences in the baseline injury severity scores between patients in each phenotype. A combined IL-15 and MCP1 signature identified patients with the early-inflammatory phenotype in both cohorts. Inflammatory processes mediated outcomes in older patients with moderate-severe TBI. INTERPRETATION: Our findings offer a precision medicine approach for future clinical trials of immunomodulation in patients with TBI, by using inflammatory signatures to stratify patients. FUNDING: CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.

Key HIV cure strategies involve reversing immune dysfunction and limiting the proliferation of infected T cells. We evaluate the safety of sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, in people with HIV (PWH) and study the impact of sirolimus on HIV-1 reservoir size and HIV-1-specific immunity in a single-arm study of 20 weeks of treatment in PWH on antiretroviral therapy (ART). Sirolimus treatment does not impact HIV-1-specific CD8 T cell responses but leads to a significant decrease in CD4+ T cell-associated HIV-1 DNA levels at 20 weeks of therapy in the primary efficacy population (n = 16; 31% decline, p = 0.008). This decline persists for at least 12 weeks following cessation of the study drug. Sirolimus treatment also leads to a significant reduction in CD4+ T cell cycling and PD-1 expression on CD8+ lymphocytes. These data suggest that homeostatic proliferation of infected cells, an important mechanism for HIV persistence, is an intriguing therapeutic target.

Crohn's disease (CD) is a complex and heterogeneous condition with no perfect preclinical model or cure. To address this, we explore adult stem cell-derived organoids that retain their tissue identity and disease-driving traits. We prospectively create a biobank of CD patient-derived organoid cultures (PDOs) from colonic biopsies of 53 subjects across all clinical subtypes and healthy subjects. Gene expression analyses enabled benchmarking of PDOs as tools for modeling the colonic epithelium in active disease and identified two major molecular subtypes: immune-deficient infectious CD (IDICD) and stress and senescence-induced fibrostenotic CD (S2FCD). Each subtype shows internal consistency in the transcriptome, genome, and phenome. The spectrum of morphometric, phenotypic, and functional changes within the "living biobank" reveals distinct differences between the molecular subtypes. Drug screens reverse subtype-specific phenotypes, suggesting phenotyped-genotyped CD PDOs can bridge basic biology and patient trials by enabling preclinical phase "0" human trials for personalized therapeutics.

This post hoc analysis of the randomized, placebo-controlled N-MOmentum study (NCT02200770) of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD) evaluated relationships between circulating B-cell subsets and aquaporin-4 immunoglobulin G (AQP4-lgG) titers and attacks. Among participants receiving placebo, CD20+ and CD27+ B-cell counts were modestly increased from the pre-attack visit to attack; plasmablast/plasma cell gene signature was increased from baseline to the pre-attack visit (p = 0.016) and from baseline to attack (p = 0.009). With inebilizumab treatment, B-cell subset counts decreased and did not increase with attacks. No difference in change of AQP4-IgG titers from baseline to time of attack was observed.

BACKGROUND: Provisional Tic Disorder (PTD) is common in childhood. The received wisdom among clinicians is that PTD is short-lived and mild, with at most a few tics, and rarely includes complex tics, premonitory phenomena or comorbid illnesses. However, such conclusions come from clinical experience, with biased ascertainment and limited follow-up. METHODS: Prospective study of 89 children with tics starting 0-9 months ago (median 4 months), fewer than half from clinical sources. Follow-up at 12 (± 24, 36, 48) months after the first tic. RESULTS: At study entry, many children had ADHD (39), an anxiety disorder (27), OCD (9) or enuresis (17). All had at least two current tics, with a mean total since onset of 6.9 motor and 2.0 phonic tics. Forty-one had experienced a complex tic, and 69 could suppress some tics. Tics were clinically meaningful: 64 had tics severe enough for a clinical trial, and 76 families sought medical attention for the tics. At 12 months, 79 returned, and 78 still had tics. Of these, 29 manifested no tics during history and extended examination, but only via audio-visual monitoring when the child was seated alone. Only 12/70 now had plans to see a doctor for tics. Most who returned at 2-4 years still had tics known to the child and family, but medical impact was low. CONCLUSIONS: Our results do not contradict previous data, but overturn clinical lore. The data strongly argue against the longstanding but arbitrary tradition of separating tic disorders into recent-onset versus chronic.

PurposeTraumatic brain injury (TBI) and potentially traumatic events (PTEs) contribute to increased substance use, mental health issues, and cognitive impairments. However, there's not enough research on how TBI and PTEs combined impact mental heath, substance use, and neurocognition.MethodsThis study leverages a subset of The National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) multi-site dataset with 551 adolescents to assess the combined and distinctive impacts of TBI, PTEs, and TBI+PTEs (prior to age 18) on substance use, mental health, and neurocognitive outcomes at age 18.ResultsTBI, PTEs, and TBI+PTEs predicted greater lifetime substance use and past-year alcohol and cannabis use. PTEs predicted greater internalizing symptoms, while TBI+PTEs predicted greater externalizing symptoms. Varying effects on neurocognitive outcomes included PTEs influencing attention accuracy and TBI+PTEs predicting faster speed in emotion tasks. PTEs predicted greater accuracy in abstraction-related tasks. Associations with working memory were not detected.ConclusionThis exploratory study contributes to the growing literature on the complex interplay between TBI, PTEs, and adolescent mental health, substance use, and neurocognition. The developmental implications of trauma via TBIs and/or PTEs during adolescence are considerable and worthy of further investigation.

BACKGROUND: Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their contribution to understanding antiviral efficacy in the multicenter Adaptive COVID-19 Treatment Trial 1, which randomized patients to remdesivir or placebo. METHODS: Longitudinal specimens collected during hospitalization from a substudy of 642 patients with COVID-19 were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers. Associations with clinical outcomes and response to therapy were assessed. RESULTS: Higher baseline plasma viral loads were associated with poorer clinical outcomes, and decreases in viral RNA and antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95% CI, 1.40-2.71) for levels >245 pg/mL vs 1.04 (95% CI, .76-1.42) for levels

Infectious keratitis is a leading cause of corneal blindness worldwide with little information known about causative etiologies in Malawi, Africa. This area is resource-limited with ophthalmologist and microbiology services. The Department of Ophthalmology at the Kamuzu College of Health Sciences in Blantyre, Malawi, is a participating site of an international corneal ulcer consortium, capriCORN (Comprehensive Analysis of Pathogens, Resistomes, and Inflammatory-markers in the CORNea). In this study, 50 patients with corneal ulcers were swabbed for pathogen identification using RNA-sequencing. Corneal trauma was reported in 41% and 19% of the patients worked in agriculture. A pathogen was identified in 58% of the cases. Fungal pathogens predominated, followed by viruses and bacteria. Aspergillus, Fusarium, HSV-1, and Gardnerella were the most common pathogens detected. 50% of patients reported treatment with an antibiotic before presentation. Pathogens unusual for infectious keratitis, such as Subramaniula asteroids, Aureobasidium pullulans, and Gardnerella vaginalis, were also detected.

Political partisanship is often conceived as a lens through which people view politics. Behavioral research has distinguished two types of "partisan lenses"-policy-based and identity-based-that may influence peoples' perception of political events. Little is known, however, about the mechanisms through which partisan discourse appealing to policy beliefs or targeting partisan identities operate within individuals. We addressed this question by collecting neuroimaging data while participants watched videos of speakers expressing partisan views. A "partisan lens effect" was identified as the difference in neural synchrony between each participant's brain response and that of their partisan ingroup vs. outgroup. When processing policy-based messaging, a partisan lens effect was observed in socio-political reasoning and affective responding brain regions. When processing negative identity-based attacks, a partisan lens effect was observed in mentalizing and affective responding brain regions. These data suggest that the processing of political discourse that appeals to different forms of partisanship is supported by related but distinguishable neural-and therefore psychological-mechanisms, which may have implications for how we characterize partisanship and ameliorate its deleterious impacts.

BackgroundPrenatal folate supplementation has been consistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Previous germline genetic studies examining the one carbon (folate) metabolism pathway were limited in sample size, scope, and population diversity and led to inconclusive results.MethodsWe evaluated whether ∼2,900 single-nucleotide polymorphisms (SNP) within 46 candidate genes involved in the folate metabolism pathway influence the risk of childhood ALL, using genome-wide data from nine case-control studies in the Childhood Cancer and Leukemia International Consortium (n = 9,058 cases including 4,510 children of European ancestry, 3,018 Latinx, and 1,406 Asians, and 92,364 controls). Each study followed a standardized protocol for quality control and imputation of genome-wide data and summary statistics were meta-analyzed for all children combined and by major ancestry group using METAL software.ResultsNone of the selected SNPs reached statistical significance, overall and for major ancestry groups (using adjusted Bonferroni P-value of 5 × 10-6 and less-stringent P-value of 3.5 × 10-5 accounting for the number of "independent" SNPs). None of the 10 top (nonsignificant) SNPs and corresponding genes overlapped across ancestry groups.ConclusionsThis large meta-analysis of original data does not reveal associations between many common genetic variants in the folate metabolism pathway and childhood ALL in various ancestry groups.ImpactGenetic variants in the folate pathway alone do not appear to substantially influence childhood acute lymphoblastic leukemia risk. Other mechanisms such as gene-folate interaction, DNA methylation, or maternal genetic effects may explain the observed associations with self-reported prenatal folate intake.

In this study, we describe a comprehensive 3D magnetic resonance imaging (MRI) protocol designed to assess major tissue and fluid components in the brain. The protocol comprises four different sequences: 1) magnetization transfer prepared Cones (MT-Cones) for two-pool MT modeling to quantify macromolecular content; 2) short-TR adiabatic inversion-recovery prepared Cones (STAIR-Cones) for myelin water imaging; 3) proton-density weighted Cones (PDw-Cones) for total water imaging; and 4) highly T2 weighted Cones (T2w-Cones) for free water imaging. By integrating these techniques, we successfully mapped key brain components-namely macromolecules, myelin water, intra/extracellular water, and free water-in ten healthy volunteers and five patients with multiple sclerosis (MS) using a 3T clinical scanner. Brain macromolecular proton fraction (MMPF), myelin water proton fraction (MWPF), intra/extracellular water proton fraction (IEWPF), and free water proton fraction (FWPF) values were generated in white matter (WM), grey matter (GM), and MS lesions. Excellent repeatability of the protocol was demonstrated with high intra-class correlation coefficient (ICC) values. In MS patients, the MMPF and MWPF values of the lesions and normal-appearing WM (NAWM) were significantly lower than those in normal WM (NWM) in healthy volunteers. Moreover, we observed significantly higher FWPF values in MS lesions compared to those in NWM and NAWM regions. This study demonstrates the capability of our technique to volumetrically map major brain components. The technique may have particular value in providing a comprehensive assessment of neuroinflammatory and neurodegenerative diseases of the brain.

Physical activity, including structured exercise, is associated with favorable health-related chronic disease outcomes. Although there is evidence of various molecular pathways that affect these responses, a comprehensive molecular map of these molecular responses to exercise has not been developed. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) is a multicenter study designed to isolate the effects of structured exercise training on the molecular mechanisms underlying the health benefits of exercise and physical activity. MoTrPAC contains both a preclinical and human component. The details of the human studies component of MoTrPAC that include the design and methods are presented here. The human studies contain both an adult and pediatric component. In the adult component, sedentary participants are randomized to 12 wk of Control, Endurance Exercise Training, or Resistance Exercise Training with outcomes measures completed before and following the 12 wk. The adult component also includes recruitment of highly active endurance-trained or resistance-trained participants who only complete measures once. A similar design is used for the pediatric component; however, only endurance exercise is examined. Phenotyping measures include weight, body composition, vital signs, cardiorespiratory fitness, muscular strength, physical activity and diet, and other questionnaires. Participants also complete an acute rest period (adults only) or exercise session (adults, pediatrics) with collection of biospecimens (blood only for pediatrics) to allow for examination of the molecular responses. The design and methods of MoTrPAC may inform other studies. Moreover, MoTrPAC will provide a repository of data that can be used broadly across the scientific community.NEW & NOTEWORTHY The Molecular Transducers of Physical Activity Consortium (MoTrPAC) will be the first large trial to isolate the effects of structured exercise training on the molecular mechanisms underlying the health benefits of exercise and physical activity. By generating a compendium of the molecular responses to exercise, MoTrPAC will lay the foundation for a new era of biomedical research on Precision Exercise Medicine. Presented here is the design, protocols, and procedures for the MoTrPAC human studies.

Here we conducted wireless electrophysiological recording of hippocampal neurons from Egyptian fruit bats in the presence of human experimenters. In flying bats, many neurons modulated their activity depending on the identity of the human at the landing target. In stationary bats, many neurons carried significant spatial information about the position and identity of humans traversing the environment. Our results reveal that hippocampal activity is robustly modulated by the presence, movement and identity of human experimenters.

IntroductionRecent technology has enabled researchers to collect ecological momentary assessments (EMA) to examine within-person correlates of suicidal thoughts. Prior studies examined generalized temporal dynamics of emotions and suicidal thinking over brief periods, but it is not yet known how variable these processes are across people.MethodWe use data EMA data delivered over two weeks with youth/young adults (N = 60) who reported past year self-injurious thoughts/behaviors. We used group iterative multiple model estimation (GIMME) to model group- and person-specific associations of negative emotions (i.e., fear, sadness, shame, guilt, and anger) and suicidal thoughts.Results29 participants (48.33%) reported at least one instance of a suicidal thought and were included in GIMME models. In group level models, we consistently observed autoregressive effects for suicidal thoughts (e.g., earlier thoughts predicting later thoughts), although the magnitude and direction of this link varied from person-to-person. Among emotions, sadness was most frequently associated with contemporaneous suicidal thoughts, but this was evident for less than half of the sample, while other emotional correlates of suicidal thoughts broadly differed across people. No emotion variable was linked to future suicidal thoughts in >14% of the sample, CONCLUSIONS: Emotion-based correlates of suicidal thoughts are heterogeneous across people. Better understanding of the individual-level pathways maintaining suicidal thoughts/behaviors may lead to more effective, personalized interventions.

BackgroundWe evaluated associations between antepartum weight change and adverse pregnancy outcomes and between antiretroviral therapy (ART) regimens and week 50 postpartum body mass index in IMPAACT 2010.MethodsWomen with human immunodeficiency virus (HIV)-1 in 9 countries were randomized 1:1:1 at 14-28 weeks' gestational age (GA) to start dolutegravir (DTG) + emtricitabine (FTC)/tenofovir alafenamide fumarate (TAF) versus DTG + FTC/tenofovir disoproxil fumarate (TDF) versus efavirenz (EFV)/FTC/TDF. Insufficient antepartum weight gain was defined using Institute of Medicine guidelines. Cox-proportional hazards regression models were used to evaluate the association between antepartum weight change and adverse pregnancy outcomes: stillbirth (≥20 weeks' GA), preterm delivery (

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Sacituzumab govitecan (SG), a first-in-class anti-trophoblast cell surface antigen 2 (Trop-2) antibody-drug conjugate, demonstrated superior efficacy over single-agent chemotherapy (treatment of physicians choice [TPC]) in patients with metastatic triple-negative breast cancer (mTNBC) in the international, multicenter, phase III ASCENT study.Patients were randomly assigned 1:1 to receive SG or TPC until unacceptable toxicity/progression. Final efficacy secondary end point analyses and post hoc analyses of outcomes stratified by Trop-2 expression and human epidermal growth factor receptor 2 status are reported. Updated safety analyses are provided.In this final analysis, SG (n = 267) improved median progression-free survival (PFS; 4.8 v 1.7 months; hazard ratio (HR), 0.41 [95% CI, 0.33 to 0.52]) and median overall survival (OS; 11.8 v 6.9 months; HR, 0.51 [95% CI, 0.42 to 0.63]) over TPC (n = 262). SG improved PFS over TPC in each Trop-2 expression quartile (n = 168); a trend was observed for improved OS across quartiles. Overall, SG had a manageable safety profile, with ≤5% of treatment-related discontinuations because of adverse events and no treatment-related deaths. The safety profile was consistent across all subgroups.These data confirm the clinical benefit of SG over chemotherapy, reinforcing SG as an effective treatment option in patients with mTNBC in the second line or later.

To understand the roles of acute-phase viral dynamics and host immune responses in post-acute sequelae of SARS-CoV-2 infection (PASC), we enrolled 136 participants within 5 days of their first positive SARS-CoV-2 real-time PCR test. Participants self-collected up to 21 nasal specimens within the first 28 days post-symptom onset; interviewer-administered questionnaires and blood samples were collected at enrollment, days 9, 14, 21, 28, and month 4 and 8 post-symptom onset. Defining PASC as the presence of any COVID-associated symptom at their 4-month visit, we compared viral markers (quantity and duration of nasal viral RNA load, infectious viral load, and plasma N-antigen level) and host immune markers (IL-6, IL-10, TNF-α, IFN-α, IFN-γ, MCP, IP-10, and Spike IgG) over the acute period. Compared to those who fully recovered, those reporting PASC demonstrated significantly higher maximum levels of SARS-CoV-2 RNA and N-antigen, burden of RNA and infectious viral shedding, and lower Spike-specific IgG levels within 9 days post-illness onset. No significant differences were identified among a panel of host immune markers. Our results suggest early viral dynamics and the associated host immune responses play a role in the pathogenesis of PASC, highlighting the importance of understanding early biological markers in the natural history of PASC.

BACKGROUND: Schistosomiasis is a parasitic infection that can cause pulmonary hypertension (PH). Th2 CD4 T cells are necessary for experimental Schistosoma-PH. However, if T cells migrate to the lung to initiate, the localized inflammation that drives vascular remodeling and PH is unknown. METHODS: Mice were sensitized to Schistosoma mansoni eggs intraperitoneally and then challenged using tail vein injection. FTY720 was administered, which blocks lymphocyte egress from lymph nodes. T cells were quantified using flow cytometry, PH severity via heart catheterization, and cytokine concentration through ELISA. RESULTS: FTY720 decreased T cells in the peripheral blood, and increased T cells in the mediastinal lymph nodes. However, FTY720 treatment resulted in no change in PH or type 2 inflammation severity in mice sensitized and challenged with S. mansoni eggs, and the number of memory and effector CD4 T cells in the lung parenchyma was also unchanged. Notably, intraperitoneal Schistosoma egg sensitization alone resulted in a significant increase in intravascular lymphocytes and T cells, including memory T cells, although there was no significant change in parenchymal cell density, IL-4 or IL-13 expression, or PH. CONCLUSION: Blocking T cell migration did not suppress PH following Schistosoma egg challenge. Memory CD4 T cells, located in the lung intravascular space following egg sensitization, appear sufficient to cause type 2 inflammation and PH.

Fecal microbial transplantation (FMT) offers promise for treating ulcerative colitis (UC), though the mechanisms underlying treatment failure are unknown. This study harnessed longitudinally collected colonic biopsies (n = 38) and fecal samples (n = 179) from 19 adults with mild-to-moderate UC undergoing serial FMT in which antimicrobial pre-treatment and delivery mode (capsules versus enema) were assessed for clinical response (≥ 3 points decrease from the pre-treatment Mayo score). Colonic biopsies underwent dual RNA-Seq; fecal samples underwent parallel 16S rRNA and shotgun metagenomic sequencing as well as untargeted metabolomic analyses. Pre-FMT, the colonic mucosa of non-responsive (NR) patients harbored an increased burden of bacteria, including Bacteroides, that expressed more antimicrobial resistance genes compared to responsive (R) patients. NR patients also exhibited muted mucosal expression of innate immune antimicrobial response genes. Post-FMT, NR and R fecal microbiomes and metabolomes exhibited significant divergence. NR metabolomes had elevated concentrations of immunostimulatory compounds including sphingomyelins, lysophospholipids and taurine. NR fecal microbiomes were enriched for Bacteroides fragilis and Bacteroides salyersiae strains that encoded genes capable of taurine production. These findings suggest that both effective mucosal microbial clearance and reintroduction of bacteria that reshape luminal metabolism associate with FMT success and that persistent mucosal and fecal colonization by antimicrobial-resistant Bacteroides species may contribute to FMT failure.

BACKGROUND: Automated analysis of lung computed tomography (CT) scans may help characterize subphenotypes of acute respiratory illness. We integrated lung CT features measured via deep learning with clinical and laboratory data in spontaneously breathing subjects to enhance the identification of COVID-19 subphenotypes. METHODS: This is a multicenter observational cohort study in spontaneously breathing patients with COVID-19 respiratory failure exposed to early lung CT within 7 days of admission. We explored lung CT images using deep learning approaches to quantitative and qualitative analyses; latent class analysis (LCA) by using clinical, laboratory and lung CT variables; regional differences between subphenotypes following 3D spatial trajectories. RESULTS: Complete datasets were available in 559 patients. LCA identified two subphenotypes (subphenotype 1 and 2). As compared with subphenotype 2 (n = 403), subphenotype 1 patients (n = 156) were older, had higher inflammatory biomarkers, and were more hypoxemic. Lungs in subphenotype 1 had a higher density gravitational gradient with a greater proportion of consolidated lungs as compared with subphenotype 2. In contrast, subphenotype 2 had a higher density submantellar-hilar gradient with a greater proportion of ground glass opacities as compared with subphenotype 1. Subphenotype 1 showed higher prevalence of comorbidities associated with endothelial dysfunction and higher 90-day mortality than subphenotype 2, even after adjustment for clinically meaningful variables. CONCLUSIONS: Integrating lung-CT data in a LCA allowed us to identify two subphenotypes of COVID-19, with different clinical trajectories. These exploratory findings suggest a role of automated imaging characterization guided by machine learning in subphenotyping patients with respiratory failure. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04395482. Registration date: 19/05/2020.

HER2, encoded by the ERBB2 gene, is an important druggable driver of human cancer gaining increasing importance as a therapeutic target in urothelial carcinoma (UC). The genomic underpinnings of HER2 overexpression in ERBB2 nonamplified UC are poorly defined. To address this knowledge gap, we investigated 172 UC tumors from patients treated at the University of California San Francisco, using immunohistochemistry and next-generation sequencing. We found that GATA3 and PPARG copy number gains individually predicted HER2 protein expression independently of ERBB2 amplification. To validate these findings, we interrogated the Memorial Sloan Kettering/The Cancer Genome Atlas (MSK/TCGA) dataset and found that GATA3 and PPARG copy number gains individually predicted ERBB2 mRNA expression independently of ERBB2 amplification. Our findings reveal a potential link between the luminal marker HER2 and the key transcription factors GATA3 and PPARG in UC and highlight the utility of examining GATA3 and PPARG copy number states to identify UC tumors that overexpress HER2 in the absence of ERBB2 amplification. In summary, we found that an increase in copy number of GATA3 and PPARG was independently associated with higher ERBB2 expression in patient samples of UC. This finding provides a potential explanation for HER2 overexpression in UC tumors without ERBB2 amplification and a way to identify these tumors for HER2-targeted therapies.

BACKGROUND AND OBJECTIVE: Congenital heart defects are known to be associated with increased odds of severe COVID-19. Congenital anomalies affecting other body systems may also be associated with poor outcomes. This study is an exhaustive assessment of congenital anomalies and odds of severe COVID-19 in pediatric patients. METHODS: Data were retrieved from the COVID-19 dataset of Cerner® Real-World Data for encounters from March 2020 to February 2022. Prior to matching, the data consisted of 664,523 patients less than 18 years old and 927,805 corresponding encounters with COVID-19 from 117 health systems across the United States. One-to-one propensity score matching was performed, and a cumulative link mixed-effects model with random intercepts for health system and patients was built to assess corresponding associations. RESULTS: All congenital anomalies were associated with worse COVID-19 outcomes, with the strongest association observed for cardiovascular anomalies (odds ratio [OR], 3.84; 95% CI, 3.63-4.06) and the weakest association observed for anomalies affecting the eye/ear/face/neck (OR, 1.16; 95% CI, 1.03-1.31). CONCLUSIONS AND RELEVANCE: Congenital anomalies are associated with greater odds of experiencing severe symptoms of COVID-19. In addition to congenital heart defects, all other birth defects may increase the odds for more severe COVID-19. IMPACT: All congenital anomalies are associated with increased odds of severe COVID-19. This study is the largest and among the first to investigate birth defects across all body systems. The multicenter large data and analysis demonstrate the increased odds of severe COVID19 in pediatric patients with congenital anomalies affecting any body system. These data demonstrate that all children with birth defects are at increased odds of more severe COVID-19, not only those with heart defects. This should be taken into consideration when optimizing prevention and intervention resources within a hospital.

IMPORTANCE: There are consistent data demonstrating that socioeconomic disadvantage is associated with risk of premature mortality, but research on the relationship between neighborhood socioeconomic factors and premature mortality is limited. Most studies evaluating the association between neighborhood socioeconomic status (SES) and mortality have used a single assessment of SES during middle to older adulthood, thereby not considering the contribution of early life neighborhood SES. OBJECTIVE: To investigate the association of life course neighborhood SES and premature mortality. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included Black and White participants of the multicenter Atherosclerosis Risk in Communities Study, a multicenter study conducted in 4 US communities: Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and the northwestern suburbs of Minneapolis, Minnesota. Participants were followed up for a mean (SD) of 18.8 (5.7) years (1996-2020). Statistical analysis was performed from March 2023 through May 2024. EXPOSURE: Participants residential addresses during childhood, young adulthood, and middle adulthood were linked with US Census-based socioeconomic indicators to create summary neighborhood SES scores for each of these life epochs. Neighborhood SES scores were categorized into distribution-based tertiles. MAIN OUTCOMES AND MEASURES: Premature death was defined as all-cause mortality occurring before age 75 years. Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: Among 12 610 study participants, the mean (SD) age at baseline was 62.6 (5.6) years; 3181 (25.2%) were Black and 9429 (74.8%) were White; and 7222 (57.3%) were women. The lowest, compared with the highest tertile, of neighborhood SES score in middle adulthood was associated with higher risk of premature mortality (HR, 1.28; 95% CI, 1.07-1.54). Similar associations were observed for neighborhood SES in young adulthood among women (HR, 1.25; 95% CI, 1.00-1.56) and neighborhood SES in childhood among White participants (HR, 1.25; 95% CI, 1.01-1.56). Participants whose neighborhood SES remained low from young to middle adulthood had an increased premature mortality risk compared with those whose neighborhood SES remained high (HR, 1.25; 95% CI, 1.05-1.49). CONCLUSIONS AND RELEVANCE: In this study, low neighborhood SES was associated with premature mortality. The risk of premature mortality was greatest among individuals experiencing persistently low neighborhood SES from young to middle adulthood. Place-based interventions that target neighborhood social determinants of health should be designed from a life course perspective that accounts for early-life socioeconomic inequality.

BACKGROUND: Travel time can be used to assess health services accessibility by reflecting the proximity of services to the people they serve. We aimed to demonstrate an indicator of physical access to cataract surgery and identify subnational locations where people were more at risk of not accessing cataract surgery. METHODS: We used an open-access inventory of public health facilities plus key informants in Kenya, Malawi and Rwanda to compile a geocoded inventory of cataract facilities. For each country, gridded estimates of the population aged ≥ 50 years and a travel-time friction surface were combined and a least-cost-path algorithm applied to estimate the shortest travel time between each grid and the nearest cataract facility. We categorised continuous travel time by 1-, 2- and 3 h thresholds and calculated the proportion of the population in each category. RESULTS: At the national level, the proportion of the population aged ≥ 50 years within 2 h travel time to permanent cataract surgical services was 97.2% in Rwanda (n = 10 facilities), 93.5% in Kenya (n = 74 facilities) and 92.0% in Malawi (n = 6 facilities); this reduced to 77.5%, 84.1% and 52.4% within 1 h, respectively. The least densely populated subnational regions had the poorest access to cataract facilities in Malawi (0.0%) and Kenya (1.9%). CONCLUSION: We demonstrated an indicator of access that reflects the distribution of the population at risk of age-related cataract and identifies regions that could benefit from more accessible services. This indicator provides additional demand-side context for eye health planning and supports WHOs goal of advancing integrated people-centred eye care.

Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain-age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain-age has highlighted the need for robust and publicly available brain-age models pre-trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain-age model. Here we expand this work to develop, empirically validate, and disseminate a pre-trained brain-age model to cover most of the human lifespan. To achieve this, we selected the best-performing model after systematically examining the impact of seven site harmonization strategies, age range, and sample size on brain-age prediction in a discovery sample of brain morphometric measures from 35,683 healthy individuals (age range: 5-90 years; 53.59% female). The pre-trained models were tested for cross-dataset generalizability in an independent sample comprising 2101 healthy individuals (age range: 8-80 years; 55.35% female) and for longitudinal consistency in a further sample comprising 377 healthy individuals (age range: 9-25 years; 49.87% female). This empirical examination yielded the following findings: (1) the accuracy of age prediction from morphometry data was higher when no site harmonization was applied; (2) dividing the discovery sample into two age-bins (5-40 and 40-90 years) provided a better balance between model accuracy and explained age variance than other alternatives; (3) model accuracy for brain-age prediction plateaued at a sample size exceeding 1600 participants. These findings have been incorporated into CentileBrain (https://centilebrain.org/#/brainAGE2), an open-science, web-based platform for individualized neuroimaging metrics.

ObjectivePatients with relapsed or metastatic head and neck squamous cell carcinoma (HNSCC) after primary local therapy have low response rates with cetuximab, systemic chemotherapy or check point inhibitor therapy. Novel combination therapies with the potential to improve outcomes for patients with HNSCC is an area of high unmet need.MethodsThis is a phase II single-arm clinical trial of locally advanced or metastatic HNSCC patients treated with a combination of soluble EphB4-human serum albumin (sEphB4-HSA) fusion protein and pembrolizumab after platinum-based chemotherapy with up to 2 prior lines of treatment. The primary endpoints were safety and tolerability and the primary efficacy endpoint was overall response rate (ORR). Secondary endpoints included progression free survival (PFS) and overall survival (OS). HPV status and EphrinB2 expression were evaluated for outcome.ResultsTwenty-five patients were enrolled. Median follow up was 40.4 months (range 9.8 - 40.4). There were 6 responders (ORR 24%). There were 5 responders in the 11 HPV-negative and EphrinB2 positive patients, (ORR 45%) with 2 of these patients achieving a complete response (CR). The median PFS in HPV-negative/EphrinB2 positive patients was 3.2 months (95% CI 1.1, 7.3). Median OS in HPV-negative/EphrinB2 positive patients was 10.9 months (95% CI 2.0, 13.7). Hypertension, transaminitis and fatigue were the most common toxicities.DiscussionThe combination of sEphB4-HSA and pembrolizumab has a favorable toxicity profile and favorable activity particularly among HPV-negative EphrinB2 positive patients with HNSCC.