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BackgroundGlobal surgery research efforts have been criticized for failure to transition from problem identification to intervention implementation. We developed a context-appropriate trauma quality improvement (TQI) bundle to ameliorate care gaps at a regional referral hospital in Cameroon. We determined associations between bundle implementation and improvement in trauma resuscitation practices.MethodsWe implemented a TQI bundle consisting of a hospital-specific trauma protocol, staff training, a trauma checklist, provision of essential emergency trauma supplies in the resuscitation area, and monthly quality improvement meetings. We compared trends in target process measures (e.g., frequency and timing of vital sign collection and primary survey interventions) in the six-month period pre- and post-bundle implementation using Wilcoxon rank-sum and Fisher's exact tests.ResultsWe compared 246 pre-bundle patients with 203 post-bundle patients. Post-bundle patients experienced a greater proportion of all vital signs collected compared to the pre-intervention cohort (0 % pre-bundle vs. 69 % post-bundle, p < 0.001); specifically, the proportion of respiratory rate (0.8 % pre-bundle vs. 76 % post-bundle, p < 0.001) and temperature (7 % pre-bundle vs. 91 % post-bundle, p < 0.001) vital sign collection significantly increased. The post-bundle cohort had vital signs measured sooner (74 % vital signs measured within 15 min of arrival pre-bundle vs. 90 % post-bundle, p < 0.001) and more frequently per patient (7 % repeated vitals pre-bundle vs 52 % post-bundle, p < 0.001). Key primary survey interventions such as respiratory interventions (1 % pre-bundle vs. 8 % post-bundle, p < 0.001) and cervical collar placement (0 % pre-bundle vs. 7 % post-bundle, p < 0.001) also increased in the post-bundle cohort.ConclusionsThe implementation of a context-appropriate TQI bundle was associated with significant improvements in previously identified trauma care deficits at a single regional hospital. Data-derived interventions targeting frontline capacity at the local level can bridge the gap between identifying care limitations and improvement in resource-limited settings.

ImportanceBefore surgery, the best strategy for managing patients who are taking renin-angiotensin system inhibitors (RASIs) (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) is unknown. The lack of evidence leads to conflicting guidelines.ObjectiveTo evaluate whether a continuation strategy vs a discontinuation strategy of RASIs before major noncardiac surgery results in decreased complications at 28 days after surgery.Design, setting, and participantsRandomized clinical trial that included patients who were being treated with a RASI for at least 3 months and were scheduled to undergo a major noncardiac surgery between January 2018 and April 2023 at 40 hospitals in France.InterventionPatients were randomized to continue use of RASIs (n = 1107) until the day of surgery or to discontinue use of RASIs 48 hours prior to surgery (ie, they would take the last dose 3 days before surgery) (n = 1115).Main outcomes and measuresThe primary outcome was a composite of all-cause mortality and major postoperative complications within 28 days after surgery. The key secondary outcomes were episodes of hypotension during surgery, acute kidney injury, postoperative organ failure, and length of stay in the hospital and intensive care unit during the 28 days after surgery.ResultsOf the 2222 patients (mean age, 67 years [SD, 10 years]; 65% were male), 46% were being treated with angiotensin-converting enzyme inhibitors at baseline and 54% were being treated with angiotensin receptor blockers. The rate of all-cause mortality and major postoperative complications was 22% (245 of 1115 patients) in the RASI discontinuation group and 22% (247 of 1107 patients) in the RASI continuation group (risk ratio, 1.02 [95% CI, 0.87-1.19]; P = .85). Episodes of hypotension during surgery occurred in 41% of the patients in the RASI discontinuation group and in 54% of the patients in the RASI continuation group (risk ratio, 1.31 [95% CI, 1.19-1.44]). There were no other differences in the trial outcomes.Conclusions and relevanceAmong patients who underwent major noncardiac surgery, a continuation strategy of RASIs before surgery was not associated with a higher rate of postoperative complications than a discontinuation strategy.Trial registrationClinicalTrials.gov Identifier: NCT03374449.

PurposeLong COVID-19 syndrome occurs in 10-20 % of people after a confirmed/probable SARS-COV-2 infection; new symptoms begin within three months of COVID-19 diagnosis and last > 8 weeks. Little is known about risk factors for long COVID, particularly in older people who are at greater risk of COVID complications.MethodsData are from Women's Health Initiative (WHI) postmenopausal women who completed COVID surveys that included questions on whether they had ever been diagnosed with COVID and length and nature of symptoms. Long COVID was classified using standard consensus criteria. Using WHI demographic and health data collected at study enrollment (1993-98) through the present day, machine learning identified the top 20 risk factors for long COVID. These variables were tested in logistic regression models.ResultsOf n = 37,280 survey respondents, 1237 (mean age = 83 years) reported a positive COVID-19 test and 425 (30 %) reported long COVID. Symptoms included an array of neurological, cardio-pulmonary, musculoskeletal, and general fatigue, and malaise symptoms. Long COVID risk factors included weight loss, physical and mobility limitations, and specific heath conditions (e.g., history of heart valve procedure, rheumatoid arthritis).ConclusionsKnowledge of risk factors for long COVID may be the first step in understanding the etiology of this complex disease.

The presence of HIV in sequestered reservoirs is a central impediment to a functional cure, allowing HIV to persist despite life-long antiretroviral therapy (ART), and driving a variety of comorbid conditions. Our understanding of the latent HIV reservoir in the central nervous system is incomplete, because of difficulties in accessing human central nervous system tissues. Microglia contribute to HIV reservoirs, but the molecular phenotype of HIV-infected microglia is poorly understood. We leveraged the unique "Last Gift" rapid autopsy program, in which people with HIV are closely followed until days or even hours before death. Microglial populations were heterogeneous regarding their gene expression profiles but showed similar chromatin accessibility landscapes. Despite ART, we detected occasional microglia containing cell-associated HIV RNA and HIV DNA integrated into open regions of the host's genome (∼0.005%). Microglia with detectable HIV RNA showed an inflammatory phenotype. These results demonstrate a distinct myeloid cell reservoir in the brains of people with HIV despite suppressive ART. Strategies for curing HIV and neurocognitive impairment will need to consider the myeloid compartment to be successful.

In this study, we examine if observed line-level changes in OCTA bus boardings could be partly attributed to AB 60, while controlling for differences in transit supply, socioeconomic variables, gas prices, and the built environment. Using fixed effects panel data models, we analyzed monthly boardings on different OCTA route classifications—local, community, Express, and station link routes—one year before (2014) and two years after (2015 and 2016) AB 60’s implementation.

BackgroundStandard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT), and temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that crosses the blood-brain barrier.MethodsEuropean Organisation for Research and Treatment of Cancer 1709/Canadian Cancer Trials Group CE.8 was a multicenter, randomized, controlled, open-label phase 3 superiority trial. Key eligibility criteria included newly diagnosed glioblastoma, age > 18 years and Karnofsky performance status > 70. Patients were randomized in a 1:1 ratio. The primary objective was to compare overall survival (OS) in patients receiving marizomib in addition to TMZ/RT→TMZ with patients receiving the only standard treatment in the whole population and in the subgroup of patients with MGMT promoter-unmethylated tumors.ResultsThe trial was opened at 82 institutions in Europe, Canada, and the U.S. A total of 749 patients (99.9% of the planned 750) were randomized. OS was not different between the standard and the marizomib arm (median 17 vs. 16.5 months; HR = 1.04; P = .64). PFS was not statistically different either (median 6.0 vs. 6.3 months; HR = 0.97; P = .67). In patients with MGMT promoter-unmethylated tumors, OS was also not different between standard therapy and marizomib (median 14.5 vs. 15.1 months, HR = 1.13; P = .27). More CTCAE grade 3/4 treatment-emergent adverse events were observed in the marizomib arm than in the standard arm.ConclusionsAdding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma.

Unlike the gender-based systems of noun categorization in many European languages, numerous semantic categories contribute to Bantu noun class systems. Kinyarwanda, the focus of our study, has a rich inventory of noun class prefixes, but it is unknown to what degree the semantic and morphological systems underlying these noun classes influence how speakers mentally categorize nominals in their language. To investigate this, speakers of Kinyarwanda (n = 46) were recruited to take part in an online triadic comparison experiment. Across 144 trials, participants were asked to identify the item most different from a written list of three nouns. These lists were constructed based on morphological similarity (from noun classes 3, 5, 7, or 9), semantic overlap (from the domains of ‘mammals’ and ‘tools’), or both. Results show an overall preference for semantic grouping in the triads, although the strength of these preferences differed across individuals. This variation turned out to be systematic and predictable: speakers of Kinyarwanda who spoke Kiswahili as an additional language generally preferred categorizing on the basis of noun class, while those who did not speak Kiswahili as an additional language were more likely to base their decisions on the shared semantic domains of the nouns. These data suggest that noun categorization choices in Kinyarwanda can be influenced by knowledge of other linguistic systems, highlighting the impact that learning additional languages may have on first-language lexical knowledge.

Inherited deficiency of the RNA lariat-debranching enzyme 1 (DBR1) is a rare etiology of brainstem viral encephalitis. The cellular basis of disease and the range of viral predisposition are unclear. We report inherited DBR1 deficiency in a 14-year-old boy who suffered from isolated SARS-CoV-2 brainstem encephalitis. The patient is homozygous for a previously reported hypomorphic and pathogenic DBR1 variant (I120T). Consistently, DBR1 I120T/I120T fibroblasts from affected individuals from this and another unrelated kindred have similarly low levels of DBR1 protein and high levels of RNA lariats. DBR1 I120T/I120T human pluripotent stem cell (hPSC)-derived hindbrain neurons are highly susceptible to SARS-CoV-2 infection. Exogenous WT DBR1 expression in DBR1 I120T/I120T fibroblasts and hindbrain neurons rescued the RNA lariat accumulation phenotype. Moreover, expression of exogenous RNA lariats, mimicking DBR1 deficiency, increased the susceptibility of WT hindbrain neurons to SARS-CoV-2 infection. Inborn errors of DBR1 impair hindbrain neuron-intrinsic antiviral immunity, predisposing to viral infections of the brainstem, including that by SARS-CoV-2.

Abstract: Faustini crater (41 km diameter) hosts a large (664 km2) permanently shadowed region (PSR) with a high potential to harbor water-ice deposits. One of the 13 candidate Artemis III landing areas contains a portion of the crater rim and proximal ejecta. The ShadowCam instrument aboard the Korea Pathfinder Lunar Orbiter provides detailed images of the PSR within Faustini. We characterize the terrain and thermal environment within the Faustini PSR from ShadowCam images, Lunar Reconnaissance Orbiter thermal measurements and laser ranging, and thermal modeling. Our mapping revealed three distinct areas of the floor of Faustini based on elevations, slopes, and surface roughness. These units broadly correlate with temperatures; thus, they may be influenced by variations in volatile sublimation. Crater retention and topographic diffusion rates appear to be asymmetric across the floor, likely due to differences in maximum and average temperatures. Several irregular depressions and a pronounced lobate-rim crater are consistent with subsurface ice. However, differences in the thicknesses of deposited materials on the floor may also explain the asymmetry. Additionally, zones of elevated surface roughness across Faustini appear to result from overprinted crater ray segments, possibly from Tycho and Jackson craters. Mass wasting deposits and pitting on opposite sides of the crater wall may have resulted from the low-angle delivery of material ejected by the Shackleton crater impact event, suggesting that the Artemis III candidate landing region named “Faustini Rim A” will contain material from Shackleton.

INTRODUCTION: Niraparib first-line maintenance (1LM) therapy has demonstrated clinical benefit for patients with ovarian cancer (OC) in clinical trial and real-world settings, but data on factors associated with real-world patient outcomes remain limited. This analysis identified patient characteristics associated with time to next treatment (TTNT), a proxy for real-world progression-free survival, in patients with OC treated with 1LM niraparib monotherapy. METHODS: This retrospective observational study used a USA nationwide electronic health record-derived deidentified database and included adult patients diagnosed with OC who initiated 1LM niraparib monotherapy after first-line platinum-based chemotherapy. Patients were followed until the earliest occurrence of last clinical activity, death, or end of study period. TTNT was measured from 1LM niraparib initiation to the start of second-line treatment or death. Cox proportional hazards models assessed univariable and multivariable associations between baseline characteristics and TTNT. RESULTS: Of 7872 patients diagnosed with OC, 526 met the eligibility criteria and were included in this analysis. Median (IQR) duration of follow-up was 14.1 (7.4-23.6) months. In univariable analyses, age, BRCA/homologous recombination deficiency (HRD) status, socioeconomic status, stage at initial diagnosis, cytoreductive surgery type, and residual disease status were significantly associated with observed TTNT and were introduced into the multivariable model with other clinically relevant variables. In the multivariable analysis, BRCA/HRD status, cytoreductive surgery type, and residual disease status were significantly associated with observed TTNT after covariate adjustment. Conversely, age, Eastern Cooperative Oncology Group performance status, disease stage, niraparib starting dose status, and first-line bevacizumab use were not associated with observed TTNT. CONCLUSION: This real-world, retrospective, observational analysis offers valuable insights on prognostic factors associated with TTNT in patients with OC treated with 1LM niraparib monotherapy after first-line platinum-based chemotherapy. Future studies are needed to examine how additional patient characteristics associated with clinical outcomes may guide treatment decisions and improve outcomes.

We analyze both finite and infinite systems of Riccati equations derived from stochastic differential games on infinite networks. We discuss a connection to the Catalan numbers and the convergence of the Catalan functions by Fourier transforms.

UNLABELLED: Infections caused by antimicrobial-resistant Escherichia coli are the leading cause of death attributed to antimicrobial resistance (AMR) worldwide, and the known AMR mechanisms involve a range of functional proteins. Here, we employed a pan-genome wide association study (GWAS) approach on over 1,000 E. coli isolates from sick dogs collected across the US and Canada and identified a strong statistical association (empirical P < 0.01) of AMR, involving a range of antibiotics to a group 1 capsular (CPS) gene cluster. This cluster included genes under relaxed selection pressure, had several loci missing, and had pseudogenes for other key loci. Furthermore, this cluster is widespread in E. coli and Klebsiella clinical isolates across multiple host species. Earlier studies demonstrated that the octameric CPS polysaccharide export protein Wza can transmit macrolide antibiotics into the E. coli periplasm. We suggest that the CPS in question, and its highly divergent Wza, functions as an antibiotic trap, preventing antimicrobial penetration. We also highlight the high diversity of lineages circulating in dogs across all regions studied, the overlap with human lineages, and regional prevalence of resistance to multiple antimicrobial classes. IMPORTANCE: Much of the human genomic epidemiology data available for E. coli mechanism discovery studies has been heavily biased toward shiga-toxin producing strains from humans and livestock. E. coli occupies many niches and produces a wide variety of other significant pathotypes, including some implicated in chronic disease. We hypothesized that since dogs tend to share similar strains with their owners and are treated with similar antibiotics, their pathogenic isolates will harbor unexplored AMR mechanisms of importance to humans as well as animals. By comparing over 1,000 genomes with in vitro antimicrobial susceptibility data from sick dogs across the US and Canada, we identified a strong multidrug resistance association with an operon that appears to have once conferred a type 1 capsule production system.

With the growing popularity of cold brewed coffee comes a need for brewing efficiency while preserving the desirable flavor profile. Despite the wide use of full immersion brewing techniques, the effect of brew time on the dynamic sensory profiles of full immersion brewed coffee remains underexplored. Here, we investigated the relationship between coffee sensory quality and extraction dynamics, measured as Total Dissolved Solids (TDS) and Extraction (E) of full immersion brewed coffee at various roast levels, and brewing temperatures (4 °C, 22 °C and 92 °C), over brew time using a generic descriptive analysis method. Specifically, different brew time points were selected for different temperatures based on five targeted coffee extraction stages. Furthermore, the unique experimental design also explored a sensory-driven engineering research process. Roast level had the greatest impact on the sensory profile of the coffees, followed by brewing temperature, but brew time, especially the longer brew times as TDS plateaued, had subtler impacts than expected. Twenty-five of 28 sensory attributes were significantly different among the 30 coffee samples, indicating a single source green coffee blend can produce a wide range of complex sensory profiles using different combinations of roast level, temperature, and brew time. Specifically, the intensity of sweetness was negatively correlated with TDS, and 19 other attribute intensities were positively correlated with TDS. Interestingly, we found that certain long time cold brews had similar sensory profiles to those of some short time hot brews, suggesting the sensory profiles of certain hot brews and cold brews could possibly be matched through controlled preparation. Overall, our study demonstrated an approach of integrating food engineering and sensory analysis for product development, and our findings provide valuable insights into the extraction dynamics and sensory quality of full immersion brewed coffee and opens new brewing avenues for the coffee industry.

We analyze both finite and infinite systems of Riccati equations derived fromstochastic differential games on infinite networks. We discuss a connection tothe Catalan numbers and the convergence of the Catalan functions by Fouriertransforms.

The development of the retina is under tight temporal and spatial control. To gain insights into the molecular basis of this process, we generate a single-nuclei dual-omic atlas of the human developing retina with approximately 220,000 nuclei from 14 human embryos and fetuses aged between 8 and 23-weeks post-conception with matched macular and peripheral tissues. This atlas captures all major cell classes in the retina, along with a large proportion of progenitors and cell-type-specific precursors. Cell trajectory analysis reveals a transition from continuous progression in early progenitors to a hierarchical development during the later stages of cell type specification. Both known and unrecorded candidate transcription factors, along with gene regulatory networks that drive the transitions of various cell fates, are identified. Comparisons between the macular and peripheral retinae indicate a largely consistent yet distinct developmental pattern. This atlas offers unparalleled resolution into the transcriptional and chromatin accessibility landscapes during development, providing an invaluable resource for deeper insights into retinal development and associated diseases.

Laser-driven ion acceleration provides ultrashort, high-charge, low-emittance beams, which are desirable for a wide range of high-impact applications. Yet after decades of research, a significant increase in maximum ion energy is still needed. This paper introduces a quality-preserving staging concept for ultraintense ion bunches that is seamlessly applicable from the nonrelativistic plasma source to the relativistic regime. Full three-dimensional particle-in-cell simulations prove robustness and capture of a high-charge proton bunch, suitable for readily available and near-term laser facilities. Published by the American Physical Society 2024

The higher classification of termites requires substantial revision as the Neoisoptera, the most diverse termite lineage, comprise many paraphyletic and polyphyletic higher taxa. Here, we produce an updated termite classification using genomic-scale analyses. We reconstruct phylogenies under diverse substitution models with ultraconserved elements analyzed as concatenated matrices or within the multi-species coalescence framework. Our classification is further supported by analyses controlling for rogue loci and taxa, and topological tests. We show that the Neoisoptera are composed of seven family-level monophyletic lineages, including the Heterotermitidae Froggatt, Psammotermitidae Holmgren, and Termitogetonidae Holmgren, raised from subfamilial rank. The species-rich Termitidae are composed of 18 subfamily-level monophyletic lineages, including the new subfamilies Crepititermitinae, Cylindrotermitinae, Forficulitermitinae, Neocapritermitinae, Protohamitermitinae, and Promirotermitinae; and the revived Amitermitinae Kemner, Microcerotermitinae Holmgren, and Mirocapritermitinae Kemner. Building an updated taxonomic classification on the foundation of unambiguously supported monophyletic lineages makes it highly resilient to potential destabilization caused by the future availability of novel phylogenetic markers and methods. The taxonomic stability is further guaranteed by the modularity of the new termite classification, designed to accommodate as-yet undescribed species with uncertain affinities to the herein delimited monophyletic lineages in the form of new families or subfamilies.

BACKGROUND: The group-I metabotropic glutamate receptor subtype 5 (mGlu5) has been implicated in methamphetamine exposure in animals and in human cognition. Because people with methamphetamine use disorder (MUD) exhibit cognitive deficits, we evaluated mGlu5 in people with MUD and controls and tested its association with cognitive performance. METHODS: Positron emission tomography was performed to measure the total VT of [18F]FPEB, a radiotracer for mGlu5, in brains of participants with MUD (abstinent from methamphetamine for at least 2 weeks, N = 14) and a control group (N = 14). Drug use history questionnaires and tests of verbal learning, spatial working memory, and executive function were administered. Associations of VT with methamphetamine use, tobacco use, and cognitive performance were tested. RESULTS: MUD participants did not differ from controls in global or regional VT, and measures of methamphetamine use were not correlated with VT. VT was significantly higher globally in nonsmoking vs smoking participants (main effect, P = .0041). MUD participants showed nonsignificant weakness on the Rey Auditory Verbal Learning Task and the Stroop test vs controls (P = .08 and P = .13, respectively) with moderate to large effect sizes, and significantly underperformed controls on the Spatial Capacity Delayed Response Test (P = .015). Across groups, Rey Auditory Verbal Learning Task performance correlated with VT in the dorsolateral prefrontal cortex and superior frontal gyrus. CONCLUSION: Abstinent MUD patients show no evidence of mGlu5 downregulation in brain, but association of VT in dorsolateral prefrontal cortex with verbal learning suggests that medications that target mGlu5 may improve cognitive performance.

Mutations in five canonical Ras pathway genes (NF1, NRAS, KRAS, PTPN11 and CBL) are detected in nearly 90% of patients with juvenile myelomonocytic leukemia (JMML), a frequently fatal malignant neoplasm of early childhood. In this report, we describe seven patients diagnosed with SH2B3-mutated JMML, including five patients who were found to have initiating, loss-of-function mutations in the gene. SH2B3 encodes the adaptor protein LNK, a negative regulator of normal hematopoiesis upstream of the Ras pathway. These mutations were identified to be germline, somatic or a combination of both. Loss of function of LNK, which has been observed in other myeloid malignancies, results in abnormal proliferation of hematopoietic cells due to cytokine hypersensitivity and activation of the JAK/STAT signaling pathway. In vitro studies of induced pluripotent stem cell-derived JMML-like hematopoietic progenitor cells also demonstrated sensitivity of SH2B3-mutated hematopoietic progenitor cells to JAK inhibition. Lastly, we describe two patients with JMML and SH2B3 mutations who were treated with the JAK1/2 inhibitor ruxolitinib. This report expands the spectrum of initiating mutations in JMML and raises the possibility of targeting the JAK/STAT pathway in patients with SH2B3 mutations.

Much has been written about the potential benefits of electric and connected vehicles. However, one important, but often overlooked, implication of electrifying trucks is that if they are powerful enough (such as the Tesla semi), they can eliminate the moving bottleneck or queuing effect created by slow-moving conventional heavy-duty trucks because electric trucks are much more responsive compared to conventional diesel trucks because electric motors provide maximum torque from a standstill. This could substantially increase road capacity in areas with high commercial truck traffic, especially around major ports or logistics complexes, thus alleviating the need to add new lanes to local freeways.

Health concerns and government restrictions during the COVID-19 pandemic caused a sharp increase in telecommuting (i.e., doing paid work at home or possibly an alternate worksite). In addition to reducing vehicle miles traveled (VMT), decreasing energy use, and lowering emissions of air pollutants and greenhouse gases (GHG), telecommuting may offer numerous other co-benefits, including increasing the worker pool, decreasing time and costs associated with travel, improving work-life balance, and decreasing stress. It may also stimulate greater use of non-motorized and active modes of travel (e.g., walking, biking, taking transit).

The ODYSSEY OUTCOMES trial, comprising over 47 000 patient-years of placebo-controlled observation, demonstrated important reductions in the risk of recurrent ischaemic cardiovascular events with the monoclonal antibody to proprotein convertase subtilisin/kexin type 9 alirocumab, as well as lower all-cause death. These benefits were observed in the context of substantial and persistent lowering of low-density lipoprotein cholesterol with alirocumab compared with that achieved with placebo. The safety profile of alirocumab was indistinguishable from matching placebo except for a ∼1.7% absolute increase in local injection site reactions. Further, the safety of alirocumab compared with placebo was evident in vulnerable groups identified before randomization, such as the elderly and those with diabetes mellitus, previous ischaemic stroke, or chronic kidney disease. The frequency of adverse events and laboratory-based abnormalities was generally similar to that in placebo-treated patients. Thus, alirocumab appears to be a safe and effective lipid-modifying treatment over a duration of at least 5 years.

The biomedical research community addresses reproducibility challenges in animal studies through standardized nomenclature, improved experimental design, transparent reporting, data sharing, and centralized repositories. The ARRIVE guidelines outline documentation standards for laboratory animals in experiments, but genetic information is often incomplete. To remedy this, we propose the Laboratory Animal Genetic Reporting (LAG-R) framework. LAG-R aims to document animals genetic makeup in scientific publications, providing essential details for replication and appropriate model use. While verifying complete genetic compositions may be impractical, better reporting and validation efforts enhance reliability of research. LAG-R standardization will bolster reproducibility, peer review, and overall scientific rigor.

The coronary angiogram is the gold standard for evaluating the severity of coronary artery disease stenoses. Presently, the assessment is conducted visually by cardiologists, a method that lacks standardization. This study introduces DeepCoro, a ground-breaking AI-driven pipeline that integrates advanced vessel tracking and a video-based Swin3D model that was trained and validated on a dataset comprised of 182,418 coronary angiography videos spanning 5 years. DeepCoro achieved a notable precision of 71.89% in identifying coronary artery segments and demonstrated a mean absolute error of 20.15% (95% CI: 19.88-20.40) and a classification AUROC of 0.8294 (95% CI: 0.8215-0.8373) in stenosis percentage prediction compared to traditional cardiologist assessments. When compared to two expert interventional cardiologists, DeepCoro achieved lower variability than the clinical reports (19.09%; 95% CI: 18.55-19.58 vs 21.00%; 95% CI: 20.20-21.76, respectively). In addition, DeepCoro can be fine-tuned to a different modality type. When fine-tuned on quantitative coronary angiography assessments, DeepCoro attained an even lower mean absolute error of 7.75% (95% CI: 7.37-8.07), underscoring the reduced variability inherent to this method. This study establishes DeepCoro as an innovative video-based, adaptable tool in coronary artery disease analysis, significantly enhancing the precision and reliability of stenosis assessment.

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.

Rationale: Oral appliances are second-line treatments after continuous positive airway pressure for obstructive sleep apnea (OSA) management. However, the need for oral appliance titration limits their use as a result of monitoring challenges to assess the treatment effect on OSA. Objectives: To assess the validity of mandibular jaw movement (MJM) automated analysis compared with polysomnography (PSG) and polygraphy (PG) in evaluating the effect of oral appliance treatment and the effectiveness of MJM monitoring for oral appliance titration at home in patients with OSA. Methods: This observational, prospective study included 135 patients with OSA eligible for oral appliance therapy. The primary outcome was the apnea-hypopnea index (AHI), measured through in-laboratory PSG/PG and MJM-based technology. Additionally, MJM monitoring at home was conducted at regular intervals during the titration process. The agreement between PSG/PG and MJM automated analysis was revaluated using Bland-Altman analysis. Changes in AHI during the home-based oral appliance titration process were evaluated using a generalized linear mixed model and a generalized estimating equation model. Results: The automated MJM analysis demonstrated strong agreement with PG in assessing AHI at the end of titration, with a median bias of 0.24/h (limits of agreement, -11.2 to 12.8/h). The improvement of AHI from baseline in response to oral appliance treatment was consistent across three evaluation conditions: in-laboratory PG (-59.6%; 95% confidence interval, -59.8% to -59.5%), in-laboratory automated MJM analysis (-59.2%; -65.2% to -52.2%), and at-home automated MJM analysis (-59.7%; -67.4% to -50.2%). Conclusions: Incorporating MJM automated analysis into the oral appliance titration process has the potential to optimize oral appliance therapy outcomes for OSA.

Authorship and dissemination policies vary across NIH research consortia. We aimed to describe elements of real-life policies in use by eligible U01 clinical research consortia. Principal investigators of eligible, active U01 clinical research projects identified in the NIH Research Portfolio Online Reporting Tools database shared relevant policies. The characteristics of key policy elements, determined a priori, were reviewed and quantified, when appropriate. Twenty one of 81 research projects met search criteria and provided policies. K elements (e.g., in quotations): manuscript proposals reviewed and approved by committee (90%); guidelines for acknowledgements (86%); writing team formation (71%); process for final manuscript review and approval (71%), responsibilities for lead author (67%), guidelines for other types of publications (67%); draft manuscript review and approval (62%); recommendation for number of members per consortium site (57%); and requirement to identify individual contributions in the manuscript (19%). Authorship/dissemination policies for large team science research projects are highly variable. Creation of an NIH policies repository and accompanying toolkit with model language and recommended key elements could improve comprehensiveness, ethical integrity, and efficiency in team science work while reducing burden and cost on newly funded consortia and directing time and resources to scientific endeavors.

Hospitals within the Veterans Affairs (VA) health care system exhibited growing use of observation care. It is unknown how this affected VA hospital performance since observation care is not included in acute inpatient measures. To examine changes in VA hospitalization outcomes and whether it was affected by shifting acute inpatient care to observation care. Longitudinal analysis of 986,355 acute hospitalizations and observation stays in 11 states 2011 to 2017. We estimated temporal changes in 30-day mortality, 30-day readmissions, costs, and length of stay (LOS) for all hospitalizations and 6 conditions in adjusted models. Changes in mortality and readmissions were compared including and excluding observation care. A 9% drop in acute hospitalizations was offset by a 157% increase in observation stays 2011 to 2017. A 30-day mortality decreased but readmissions did not when observation stays were included (all P

Parallel I/O is a critical technique for moving data between compute and storage subsystems of supercomputers. With massive amounts of data produced or consumed by compute nodes, high-performant parallel I/O is essential. I/O benchmarks play an important role in this process; however, there is a scarcity of I/O benchmarks representative of current workloads on HPC systems. Toward creating representative I/O kernels from real-world applications, we have created h5bench, a set of I/O kernels that exercise hierarchical data format version 5 (HDF5) I/O on parallel file systems in numerous dimensions. Our focus on HDF5 is due to the parallel I/O library's heavy usage in various scientific applications running on supercomputing systems. The various tests benchmarked in the h5bench suite include I/O operations (read and write), data locality (arrays of basic data types and arrays of structures), array dimensionality (one-dimensional arrays, two-dimensional meshes, three-dimensional cubes), I/O modes (synchronous and asynchronous). In this paper, we present the observed performance of h5bench executed along several of these dimensions on existing supercomputers (Cori and Summit) and pre-exascale platforms (Perlmutter, Theta, and Polaris). h5bench measurements can be used to identify performance bottlenecks and their root causes and evaluate I/O optimizations. As the I/O patterns of h5bench are diverse and capture the I/O behaviors of various HPC applications, this study will be helpful to the broader supercomputing and I/O community.

In the modern "omics" era, measurement of the human exposome is a critical missing link between genetic drivers and disease outcomes. High-resolution mass spectrometry (HRMS), routinely used in proteomics and metabolomics, has emerged as a leading technology to broadly profile chemical exposure agents and related biomolecules for accurate mass measurement, high sensitivity, rapid data acquisition, and increased resolution of chemical space. Non-targeted approaches are increasingly accessible, supporting a shift from conventional hypothesis-driven, quantitation-centric targeted analyses toward data-driven, hypothesis-generating chemical exposome-wide profiling. However, HRMS-based exposomics encounters unique challenges. New analytical and computational infrastructures are needed to expand the analysis coverage through streamlined, scalable, and harmonized workflows and data pipelines that permit longitudinal chemical exposome tracking, retrospective validation, and multi-omics integration for meaningful health-oriented inferences. In this article, we survey the literature on state-of-the-art HRMS-based technologies, review current analytical workflows and informatic pipelines, and provide an up-to-date reference on exposomic approaches for chemists, toxicologists, epidemiologists, care providers, and stakeholders in health sciences and medicine. We propose efforts to benchmark fit-for-purpose platforms for expanding coverage of chemical space, including gas/liquid chromatography-HRMS (GC-HRMS and LC-HRMS), and discuss opportunities, challenges, and strategies to advance the burgeoning field of the exposome.

SUMMARY: perox-per-cell automates cumbersome, image-based data collection tasks often encountered in peroxisome research. The software processes microscopy images to quantify peroxisome features in yeast cells. It uses off-the-shelf image processing tools to automatically segment cells and peroxisomes and then outputs quantitative metrics including peroxisome counts per cell and spatial areas. In validation tests, we found that perox-per-cell output agrees well with manually quantified peroxisomal counts and cell instances, thereby enabling high-throughput quantification of peroxisomal characteristics. AVAILABILITY AND IMPLEMENTATION: The software is coded in Python. Compiled executables and source code are available at https://github.com/AitchisonLab/perox-per-cell. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Garbage In Garbage Out is a universally agreed quote by computer scientists from various domains, including Artificial Intelligence (AI). As data is the fuel for AI, models trained on low-quality, biased data are often ineffective. Computer scientists who use AI invest a considerable amount of time and effort in preparing the data for AI. However, there are no standard methods or frameworks for assessing the “readiness” of data for AI. To provide a quantifiable assessment of the readiness of data for AI processes, we define parameters of AI data readiness and introduce AIDRIN (AI Data Readiness INspector). AIDRIN is a framework covering a broad range of readiness dimensions available in the literature that aid in evaluating the readiness of data quantitatively and qualitatively. AIDRIN uses metrics in traditional data quality assessment such as completeness, outliers, and duplicates for data evaluation. Furthermore, AIDRIN uses metrics specific to assess data for AI, such as feature importance, feature correlations, class imbalance, fairness, privacy, and FAIR (Findability, Accessibility, Interoperability, and Reusability) principle compliance. AIDRIN provides visualizations and reports to assist data scientists in further investigating the readiness of data. The AIDRIN framework enhances the efficiency of the machine learning pipeline to make informed decisions on data readiness for AI applications.

While the #LandBack movement has captured popular imagination, it remains unconvincing to many settlers who are the primary landowners in settler states. This article seeks to expand Indigenous studies understandings of the LandBack movement by looking at the strategic relations the Osage Nation used to get back 43,000 acres of land in 2016. Such strategic relations are mired in colonial and capitalist systems, but they are also how many Native nations, such as the Osage, are rebuilding their homelands. This article thus seeks to tell fuller stories of Indigenous strategies for survival and, ultimately, relationality.

Beyond Bias was an intervention introduced in Burkina Faso, Pakistan and Tanzania, with the aim of reducing health worker bias toward young, unmarried and nulliparous women seeking family planning services. This study used qualitative methods - based on interviews with health workers who participated in the intervention, managers at health facilities that participated in the intervention, and policy and program stakeholders at the national level - to understand implementation experiences with the intervention. The results offer insights for organizations or countries seeking to implement Beyond Bias or similar programs, and point to some other key implementation challenges for multi-component interventions in lower-resource settings. The intervention, developed using a human-centered design approach, was seen as key for successful implementation but there were logistical challenges. The digital intervention was disruptive and distracting to many. In addition, the non-financial rewards intervention was perceived as complex, and some participants expressed feeling discouraged when they did not receive a reward. Beyond Bias did not sufficiently attend to the outer setting, and this was perceived as a major implementation barrier as it limited individuals capacity to fully achieve the desired behavior change; for example, space constraints meant that some health facilities could not ensure private services for all clients. There were scalability concerns related to cost, and there is uncertainty whether diversity of contexts (within and across countries) might constrain implementation of Beyond Bias at scale.

There has been an increase in volume as well as an improvement in overall survival (OS) after hematopoietic cell transplantation (HCT) for hematologic disorders. It is unknown if these changes have affected racial/ethnic minorities equally. In this observational study from the Center for International Blood and Marrow Transplant Research of 79 904 autologous (auto) and 65 662 allogeneic (allo) HCTs, we examined the volume and rates of change of autoHCT and alloHCT over time and trends in OS in 4 racial/ethnic groups: non-Hispanic Whites (NHWs), non-Hispanic African Americans (NHAAs), and Hispanics across 5 2-year cohorts from 2009 to 2018. Rates of change were compared using Poisson model. Adjusted and unadjusted Cox proportional hazards models examined trends in mortality in the 4 racial/ethnic groups over 5 study time periods. The rates of increase in volume were significantly higher for Hispanics and NHAAs vs NHW for both autoHCT and alloHCT. Adjusted overall mortality after autoHCT was comparable across all racial/ethnic groups. NHAA adults (hazard ratio [HR] 1.13; 95% confidence interval [CI] 1.04-1.22; P = .004) and pediatric patients (HR 1.62; 95% CI 1.3-2.03; P < .001) had a higher risk of mortality after alloHCT than NHWs. Improvement in OS over time was seen in all 4 groups after both autoHCT and alloHCT. Our study shows the rate of change for the use of autoHCT and alloHCT is higher in NHAAs and Hispanics than in NHWs. Survival after autoHCT and alloHCT improved over time; however, NHAAs have worse OS after alloHCT, which has persisted. Continued efforts are needed to mitigate disparities for patients requiring alloHCT.

Effectively leveraging the complex software and hardware I/O stacks of HPC systems to deliver needed I/O performance has been a challenging task for domain scientists. To identify and address I/O issues in their applications, scientists largely rely on I/O experts to analyze the recorded I/O traces of their applications and provide insights into the potential issues. However, due to the limited number of I/O experts and the growing demand for data-intensive applications across the wide spectrum of sciences, inaccessibility has become a major bottleneck hindering scientists from maximizing their productivity. Inspired by the recent rapid progress of large language models (LLMs), in this work we propose IO Navigator (ION), an LLM-based framework that takes a recorded I/O trace of an application as input and leverages the in-context learning, chain-of-thought, and code generation capabilities of LLMs to comprehensively analyze the I/O trace and provide diagnosis of potential I/O issues. Similar to an I/O expert, ION provides detailed justifications for the diagnosis and an interactive interface for scientists to ask detailed questions about the diagnosis. We illustrate ION's applicability by assessing it on a set of controlled I/O traces generated with different I/O issues. We also demonstrate that ION can match state-of-the-art I/O optimization tools and provide more insightful and adaptive diagnoses for real applications. We believe ION, with its full capabilities, has the potential to become a powerful tool for scientists to navigate through complex I/O subsystems in the future.

Dense gas in minihalos with masses of 106−108 M ⊙ can shield themselves from reionization for ∼100 Myr after being exposed to the UV background. These self-shielded systems, often unresolved in cosmological simulations, can introduce strong absorption in quasar spectra. This paper is the first systematic study on the impact of these systems on the Lyα forest. We first derive the H i column density profile of photoevaporating minihalos by conducting 1D radiation-hydrodynamics simulations. We utilize these results to estimate the Lyα opacity from minihalos in a large-scale simulation that cannot resolve self-shielding. When the ionization rate of the background radiation is 0.03 × 10−12 s−1, as expected near the end of reionization at z ∼ 5.5, we find that the incidence rate of damped Lyα absorbers increases by a factor of ∼2−4 compared to at z = 4.5. The Lyα flux is, on average, suppressed by ∼3% of its mean due to minihalos. The absorption features enhance the 1D power spectrum up to ∼5% at k ∼ 0.1 h Mpc−1 (or 10−3 km−1 s), which is comparable to the enhancement caused by inhomogeneous reionization. The flux is particularly suppressed in the vicinity of large halos along the line-of-sight direction at separations of up to 10 h −1 Mpc at r ⊥ ≲ 2 h −1 Mpc. However, these effects become much smaller for higher ionizing rates (≳0.3 × 10−12 s−1) expected in the post-reionization Universe. Our findings highlight the need to consider minihalo absorption when interpreting the Lyα forest at z ≳ 5.5. Moreover, the sensitivity of these quantities to the ionizing background intensity can be exploited to constrain the intensity itself.

Purpose To assess the performance of a local open-source large language model (LLM) in various information extraction tasks from real-life emergency brain MRI reports. Materials and Methods All consecutive emergency brain MRI reports written in 2022 from a French quaternary center were retrospectively reviewed. Two radiologists identified MRI scans that were performed in the emergency department for headaches. Four radiologists scored the reports conclusions as either normal or abnormal. Abnormalities were labeled as either headache-causing or incidental. Vicuna (LMSYS Org), an open-source LLM, performed the same tasks. Vicunas performance metrics were evaluated using the radiologists consensus as the reference standard. Results Among the 2398 reports during the study period, radiologists identified 595 that included headaches in the indication (median age of patients, 35 years [IQR, 26-51 years]; 68% [403 of 595] women). A positive finding was reported in 227 of 595 (38%) cases, 136 of which could explain the headache. The LLM had a sensitivity of 98.0% (95% CI: 96.5, 99.0) and specificity of 99.3% (95% CI: 98.8, 99.7) for detecting the presence of headache in the clinical context, a sensitivity of 99.4% (95% CI: 98.3, 99.9) and specificity of 98.6% (95% CI: 92.2, 100.0) for the use of contrast medium injection, a sensitivity of 96.0% (95% CI: 92.5, 98.2) and specificity of 98.9% (95% CI: 97.2, 99.7) for study categorization as either normal or abnormal, and a sensitivity of 88.2% (95% CI: 81.6, 93.1) and specificity of 73% (95% CI: 62, 81) for causal inference between MRI findings and headache. Conclusion An open-source LLM was able to extract information from free-text radiology reports with excellent accuracy without requiring further training. Keywords: Large Language Model (LLM), Generative Pretrained Transformers (GPT), Open Source, Information Extraction, Report, Brain, MRI Supplemental material is available for this article. Published under a CC BY 4.0 license. See also the commentary by Akinci DAntonoli and Bluethgen in this issue.

INTRODUCTION AND HYPOTHESIS: We evaluated a pilot multi-component reintegration intervention to improve womens physical and psychosocial quality of life after genital fistula surgery. METHODS: Twelve women undergoing fistula repair at Mulago Specialized Women and Neonatal Hospital (Kampala, Uganda) anticipated in a 2-week multi-component intervention including health education, psychosocial therapy, physiotherapy, and economic investment. We assessed feasibility through recruitment, retention, and adherence, acceptability through intervention satisfaction, and preliminary effectiveness through reintegration, mental health, physical health, and economic status. We collected quantitative data at enrollment, 6 weeks, 3 months, and 6 months. We conducted in-depth interviews with six participants. Quantitative data are presented descriptively, and qualitative data analyzed thematically. RESULTS: Participants had a median age of 34.5 years (25.5-38.0), 50% were married/partnered, 42% were separated, 50$ had completed less than primary education, and 67% were unemployed. Mean number of sessions received was 12 for health education (range 5-15), 8 for counseling (range 8-9), and 6 for physiotherapy (range 4-8). Feasibility was demonstrated by study acceptance among all those eligible (100%); comfort with study measures, data collection frequency and approach; and procedural fidelity. Acceptability was high; all participants reported being very satisfied with the intervention and each of the components. Participant narratives echoed quantitative findings and contributed nuanced perspectives to understanding approach and content. CONCLUSIONS: Our results suggest that the intervention and associated research were both feasible and acceptable, and suggested certain modifications to the intervention protocol to reduce participant burden. Further research to determine the effectiveness of the intervention above and beyond surgery alone with regard to the health and well-being of women with fistulas is warranted.

BACKGROUND: Few studies have investigated the relationship between the food and physical activity environment and odds of gestational diabetes mellitus (GDM). This study quantifies the association between densities of several types of food establishments and fitness centers with the odds of having GDM. METHODS: The density of supermarkets, fast-food restaurants, full-service restaurants, convenience stores and fitness centers at 500, 1000 and 1500 m (m) buffers was counted at residential addresses of 68,779 pregnant individuals from Eastern Massachusetts during 2000-2016. The healthy food index assessed the relative availability of healthy (supermarkets) vs unhealthy (fast-food restaurants, convenience stores) food retailers. Multivariable logistic regression quantified the cross-sectional association between exposure variables and the odds of having GDM, adjusting for individual and area-level characteristics. Effect modification by area-level socioeconomic status (SES) was assessed. FINDINGS: In fully adjusted models, pregnant individuals living in the highest density tertile of fast-food restaurants had higher GDM odds compared to those living in the lowest density tertile (500 m: odds ratio (OR):1.17 95% CI: [1.04, 1.31]; 1000 m: 1.33 95% CI: [1.15, 1.53]); 1500 m: 1.18 95% CI: [1.01, 1.38]). Greater residential density of supermarkets was associated with lower odds of GDM (1000 m: 0.86 95% CI: [0.74, 0.99]; 1500 m: 0.86 95% CI: [0.72, 1.01]). Similarly, living in the highest fitness center density tertile was associated with decreased GDM odds (500 m:0.87 95% CI: [0.76, 0.99]; 1500 m: 0.89 95% CI: [0.79, 1.01]). There was no evidence of effect modification by SES and no association found between the healthy food index and GDM odds. INTERPRETATION: In Eastern Massachusetts, living near a greater density of fast-food establishments was associated with higher GDM odds. Greater residential access to supermarkets and fitness centers was associated with lower the odds of having GDM. FUNDING: NIH.

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15-90. The effects of dementia, mild cognitive impairment, Parkinsons disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia (p < 0.001), while neither depression nor ADHD showed consistent associations with VLM scores (p > 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders.

Horses revolutionized human history with fast mobility1. However, the timeline between their domestication and their widespread integration as a means of transport remains contentious2-4. Here we assemble a collection of 475 ancient horse genomes to assess the period when these animals were first reshaped by human agency in Eurasia. We find that reproductive control of the modern domestic lineage emerged around 2200 BCE, through close-kin mating and shortened generation times. Reproductive control emerged following a severe domestication bottleneck starting no earlier than approximately 2700 BCE, and coincided with a sudden expansion across Eurasia that ultimately resulted in the replacement of nearly every local horse lineage. This expansion marked the rise of widespread horse-based mobility in human history, which refutes the commonly held narrative of large horse herds accompanying the massive migration of steppe peoples across Europe around 3000 BCE and earlier3,5. Finally, we detect significantly shortened generation times at Botai around 3500 BCE, a settlement from central Asia associated with corrals and a subsistence economy centred on horses6,7. This supports local horse husbandry before the rise of modern domestic bloodlines.

Despite efforts to increase childhood vaccination coverage in the Democratic Republic of the Congo (DRC), approximately 20% of infants have not started their routine immunization schedule (zero-dose). The present study aims to evaluate the relative influence of geospatial access to health facilities and caregiver perceptions of vaccines on the vaccination status of children in rural DRC. Pooled data from two consecutive nationwide immunization surveys conducted in 2022 and 2023 were used. Geographic accessibility was assessed based on travel time from households to their nearest health facility using the AccessMod 5 model. Caregiver attitudes to vaccination were assessed using the survey question How good do you think vaccines are for your child? We used logistic regression to assess the relationship between geographic accessibility, caregiver attitudes toward vaccination, and their childs vaccination status. Geographic accessibility to health facilities was high in rural DRC, with 88% of the population living within an hours walk to a health facility. Responding that vaccines are Bad, Very Bad, or Dont Know relative to Very Good for children was associated with a many-fold increased odds of a zero-dose status (ORs 69.3 [95%CI: 63.4-75.8]) compared to the odds for those living 60+ min from a health facility, relative to

We previously reported two siblings with inherited PD-1 deficiency who died from autoimmune pneumonitis at 3 and 11 years of age after developing other autoimmune manifestations, including type 1 diabetes (T1D). We report here two siblings, aged 10 and 11 years, with neonatal-onset T1D (diagnosed at the ages of 1 day and 7 wk), who are homozygous for a splice-site variant of CD274 (encoding PD-L1). This variant results in the exclusive expression of an alternative, loss-of-function PD-L1 protein isoform in overexpression experiments and in the patients primary leukocytes. Surprisingly, cytometric immunophenotyping and single-cell RNA sequencing analysis on blood leukocytes showed largely normal development and transcriptional profiles across lymphoid and myeloid subsets in the PD-L1-deficient siblings, contrasting with the extensive dysregulation of both lymphoid and myeloid leukocyte compartments in PD-1 deficiency. Our findings suggest that PD-1 and PD-L1 are essential for preventing early-onset T1D but that, unlike PD-1 deficiency, PD-L1 deficiency does not lead to fatal autoimmunity with extensive leukocytic dysregulation.

The inability to scalably and precisely measure the activity of developmental cis-regulatory elements (CREs) in multicellular systems is a bottleneck in genomics. Here we develop a dual RNA cassette that decouples the detection and quantification tasks inherent to multiplex single-cell reporter assays. The resulting measurement of reporter expression is accurate over multiple orders of magnitude, with a precision approaching the limit set by Poisson counting noise. Together with RNA barcode stabilization via circularization, these scalable single-cell quantitative expression reporters provide high-contrast readouts, analogous to classic in situ assays but entirely from sequencing. Screening >200 regions of accessible chromatin in a multicellular in vitro model of early mammalian development, we identify 13 (8 previously uncharacterized) autonomous and cell-type-specific developmental CREs. We further demonstrate that chimeric CRE pairs generate cognate two-cell-type activity profiles and assess gain- and loss-of-function multicellular expression phenotypes from CRE variants with perturbed transcription factor binding sites. Single-cell quantitative expression reporters can be applied in developmental and multicellular systems to quantitatively characterize native, perturbed and synthetic CREs at scale, with high sensitivity and at single-cell resolution.

PURPOSE: To examine changes in rural and urban Veterans utilization of acute inpatient care in Veterans Health Administration (VHA) and non-VHA hospitals following access expansion from the Veterans Choice Act, which expanded eligibility for VHA-paid community hospitalization. METHODS: Using repeated cross-sectional data of VHA enrollees hospitalizations in 9 states (AZ, CA, CT, FL, LA, MA, NY, PA, and SC) between 2012 and 2017, we compared rural and urban Veterans probability of admission in VHA and non-VHA hospitals by payer over time for elective and nonelective hospitalizations using multinomial logistic regression to adjust for patient-level sociodemographic features. We also used generalized linear models to compare rural and urban Veterans travel distances to hospitals. FINDINGS: Over time, the probability of VHA-paid community hospitalization increased more for rural Veterans than urban Veterans. For elective inpatient care, rural Veterans probability of VHA-paid admission increased from 2.9% (95% CI 2.6%-3.2%) in 2012 to 6.5% (95% CI 5.8%-7.1%) in 2017. These changes were associated with a temporal trend that preceded and continued after the implementation of the Veterans Choice Act. Overall travel distances to hospitalizations were similar over time; however, the mean distance traveled decreased from 39.2 miles (95% CI 35.1-43.3) in 2012 to 32.3 miles (95% CI 30.2-34.4) in 2017 for rural Veterans receiving elective inpatient care in VHA-paid hospitals. CONCLUSIONS: Despite limited access to rural hospitals, these data demonstrate an increase in rural Veterans use of non-VHA hospitals for acute inpatient care and a small reduction in distance traveled to elective inpatient services.