Search

Motivation: Large Language Models (LLMs) have provided spectacular results across a wide variety of domains. However, persistent concerns about hallucination and fabrication of authoritative sources raise serious issues for their integral use in scientific research. Retrieval-augmented generation (RAG) is a technique for making data and documents, otherwise unavailable during training, available to the LLM for reasoning tasks. In addition to making dynamic and quantitative data available to the LLM, RAG provides the means by which to carefully control and trace source material, thereby ensuring results are accurate, complete and authoritative., Results: Here we introduce LmRaC, an LLM-based tool capable of answering complex scientific questions in the context of a user's own experimental results. LmRaC allows users to dynamically build domain specific knowledge-bases from PubMed sources (RAGdom). Answers are drawn solely from this RAG with citations to the paragraph level, virtually eliminating any chance of hallucination or fabrication. These answers can then be used to construct an experimental context (RAGexp) that, along with user supplied documents (e.g., design, protocols) and quantitative results, can be used to answer questions about the user's specific experiment. Questions about quantitative experimental data are integral to LmRaC and are supported by a user-defined and functionally extensible REST API server (RAGfun)., Availability and Implementation: Detailed documentation for LmRaC along with a sample REST API server for defining user functions can be found at https://github.com/dbcraig/LmRaC. The LmRaC web application image can be pulled from Docker Hub (https://hub.docker.com) as dbcraig/lmrac., (© The Author(s) 2024. Published by Oxford University Press.)

The Zika virus (ZIKV) epidemic in Latin America (2015-2016) has primarily been studied in urban centers, with less understanding of its impact on smaller rural communities. To address this gap, we analyzed ZIKV seroepidemiology in 6 rural Ecuadorian communities (2018-2019) with varying access to a commercial hub. Seroprevalence ranged from 19% to 54%, measured by nonstructural protein 1 blockade of binding enzyme-linked immunosorbent assay. We observed a decline in ZIKV seroprevalence between 2018 and 2019 that was greater among younger populations, suggesting that the attack rates in the 2015-2016 epidemic were significantly higher than our 2018 observations. These data indicate that the 2015-2016 epidemic included significant transmission in rural and more remote settings. Our observations of high seroprevalence in our area of study highlights the importance of surveillance and research in rural areas lacking robust health systems to manage future Zika outbreaks and vaccine initiatives., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: Even in the absence of inflammation, persistent symptoms in patients with Crohn's disease (CD) are prevalent and worsen quality of life. We previously demonstrated enrichment in sulfidogenic microbes in quiescent Crohn's disease patients with (qCD + S) vs without persistent GI symptoms (qCD-S). Thus, we hypothesized that sulfur metabolic pathways would be enriched in stool while differentially abundant microbes would be associated with important sulfur metabolic pathways in qCD + S., Methods: We performed a multicenter observational study nested within SPARC IBD. Quiescent inflammation was defined by fecal calprotectin level < 150 mcg/g. Persistent symptoms were defined by CD-PRO2. Active CD (aCD) and non-IBD diarrhea-predominant irritable bowel syndrome (IBS-D) were included as controls., Results: Thirty-nine patients with qCD + S, 274 qCD-S, 21 aCD, and 40 IBS-D underwent paired shotgun metagenomic sequencing and untargeted metabolomic profiling. The fecal metabolome in qCD + S was significantly different relative to qCD-S and IBS-D but not aCD. Patients with qCD + S were enriched in sulfur-containing amino acid pathways, including cysteine and methionine, as well as serine, glycine, and threonine. Glutathione and nicotinate/nicotinamide pathways were also enriched in qCD + S relative to qCD-S, suggestive of mitochondrial dysfunction, a downstream target of H2S signaling. Multi-omic integration demonstrated that enriched microbes in qCD + S were associated with important sulfur metabolic pathways. Bacterial sulfur metabolic genes, including CTH, isfD, sarD, and asrC, were dysregulated in qCD + S. Finally, sulfur metabolites with and without sulfidogenic microbes showed good accuracy in predicting the presence of qCD + S., Discussion: Microbial-derived sulfur pathways and downstream mitochondrial function are perturbed in qCD + S, which implicate H2S signaling in the pathogenesis of this condition. Future studies will determine whether targeting H2S pathways results in improved quality of life in qCD + S., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Significant research interest has been focused on beige adipocytes, activation of which improves glucose and lipid homeostasis, therefore representing new therapeutic opportunities for metabolic diseases. Various Cre/Lox-based strategies have been used to investigate the developmental history of beige adipocytes and how these cells adapt to environmental changes. Despite the significant advancement of our understanding of beige adipocyte biology, much of the molecular insights of the beige adipocyte, including its origin, cell type specific function, remain to be further illustrated. It has previously been shown that Chrna2 (cholinergic receptor nicotinic alpha 2 subunit) has selective functionality in beige adipocytes. In this study, we explore the Chrna2-Cre-driven reporter expression in mouse beige adipocytes in vivo and in vitro. Our findings indicate that Chrna2-Cre expression is present selectively in multiple locular beige adipocytes in subcutaneous inguinal white adipose tissue (iWAT) and differentiated stromal vascular fraction from iWAT. Chrna2-Cre expression was detected in iWAT of young pups and mice after cold exposure where significant number of beige adipocytes are present. Chrna2-Cre driven reporter expression is permanent in iWAT post labeling and can be detected in iWAT of adult mice or mice that have been housed extensively at thermoneutrality after cold exposure, even though only "inactive dormant" beige adipocytes are present in these mice. Chrna2-Cre expression can also be increased by rosiglitazone treatment and β-adrenergic activation. This research, therefore, introduces the Chrna2-Cre line as a valuable tool for tracking the development of beige adipocytes and investigate beige fat function., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Lithium-ion batteries are used in many commercial products such as electronics, cell phones, and e-cigarettes. The use of these batteries has become widespread over recent years due to their chargeability and long-lasting performance. Though a rare occurrence, lithium-ion batteries can fail due to myriad battery defects, which can cause fires and burns. One particular concern is that of thermal runaway, a critical failure marked by a sudden exothermic reaction that occurs as a result of damage to the lithium battery. Thermal runaway can produce heat in excess of 1800 °F, causing severe burns to individuals in close proximity. A 39-year-old man presented to an emergency department (ED) with full-thickness burns to his right foot after an episode of lithium-ion battery thermal runaway in his footwarmer. The patient's boot suddenly and unexpectedly caught fire for several seconds prior to being successfully removed. The patient subsequently underwent several weeks of debridements, auto- and homografting, and wound care before eventually making a full recovery. This case highlights the rare, but serious, risk posed by lithium-ion batteries as a result of thermal runaway. This phenomenon can cause devastating full-thickness burns in a matter of seconds. As lithium-ion-powered appliances grow in popularity, stringent safety measures should be implemented to prevent catastrophic injuries. Furthermore, healthcare providers should be made aware of injuries caused by thermal runaway to appropriately treat patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Alternative splicing is a crucial cellular process in eukaryotes, enabling the generation of multiple protein isoforms with diverse functions from a single gene. To better understand the impact of alternative splicing on protein structures, protein-protein interaction and human diseases, we developed ASpdb (https://biodataai.uth.edu/ASpdb/), a comprehensive database integrating experimentally determined structures and AlphaFold 2-predicted models for human protein isoforms. ASpdb includes over 3400 canonical isoforms, each represented by both experimentally resolved and predicted structures, and >7200 alternative isoforms with AlphaFold 2 predictions. In addition to detailed splicing events, 3D structures, sequence variations and functional annotations, ASpdb uniquely offers comparative analyses and visualization of structural alterations among isoforms. This resource is invaluable for advancing research in alternative splicing, structural biology and disease mechanisms., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

In drug-resistant focal epilepsy, planning surgical resection may involve presurgical intracranial EEG recordings (iEEG) to detect seizures and other iEEG patterns to improve postsurgical seizure outcome. We hypothesized that resection of tissue generating interictal high frequency oscillations (HFOs, 80-500 Hz) in the iEEG predicts surgical outcome. Eight international epilepsy centres recorded iEEG during the patients' pre-surgical evaluation. The patients were of all ages, had epilepsy of all types, and underwent surgical resection of a single focus aiming at seizure freedom. In a prospective analysis we applied a fully automated definition of HFO which was independent of the dataset. Using an observational cohort design that was blinded to postsurgical seizure outcome, we analysed HFO rates during non-rapid-eye-movement sleep. If channels had consistently high rates over multiple epochs, they were labelled the "HFO area". After HFO analysis, centres provided the electrode contacts located in the resected volume and the seizure outcome at follow-up ≥24 months after surgery. The study was registered at www.clinicaltrials.gov (NCT05332990). We received 160 iEEG datasets. In 146 datasets (91%), the HFO area could be defined. The patients with completely resected HFO area were more likely to achieve seizure freedom compared to those without (OR 2.61 CI [1.15-5.91], P = 0.02). Among seizure free patients, the HFO area was completely resected in 31 and was not completely resected in 43. Among patients with recurrent seizures, the HFO area was completely resected in 14 and was not completely resected in 58. When predicting seizure freedom, the negative predictive value of the HFO area (68% CI [52-81]) was higher than that for the resected volume as predictor by itself (51% CI [42-59], P = 4e-5). The sensitivity and specificity for complete HFO area resection were 0.88 CI [0.72-0.98] and 0.39 CI [0.25-0.54] and the area under the curve was 0.83 CI [0.58-0.97], indicating good predictive performance. In a blinded cohort study from independent epilepsy centres, applying a previously validated algorithm for HFO marking without the need of adjusting to new datasets allowed us to validate the clinical relevance of HFOs to plan the surgical resection., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The essential Drosophila RNA-binding protein Brain Tumor (Brat) represses specific genes to control embryogenesis and differentiation of stem cells. In the brain, Brat functions as a tumor suppressor that diminishes neural stem cell proliferation while promoting differentiation. Though important Brat-regulated target mRNAs have been identified in these contexts, the full impact of Brat on gene expression remains to be discovered. Here, we identify the network of Brat-regulated mRNAs by performing RNA sequencing (RNA-seq) following depletion of Brat from cultured cells. We identify 158 mRNAs, with high confidence, that are repressed by Brat. De novo motif analysis identified a functionally enriched RNA motif in the 3' untranslated regions (UTRs) of Brat-repressed mRNAs that matches the biochemically defined Brat binding site. Integrative data analysis revealed a high-confidence list of Brat-repressed and Brat-bound mRNAs containing 3'UTR Brat binding motifs. Our RNA-seq and reporter assays show that multiple 3'UTR motifs promote the strength of Brat repression, whereas motifs in the 5'UTR are not functional. Strikingly, we find that Brat regulates expression of glycolytic enzymes and the vacuolar ATPase complex, providing new insight into its role as a tumor suppressor and the coordination of metabolism and intracellular pH., (Published by Oxford University Press on behalf of Nucleic Acids Research 2024.)

Disclaimer: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time., Purpose: A growing shortage of mental health providers and the increasing prevalence and severity of mental illness necessitate a qualified pharmacist workforce to increase access and care. Psychiatric learning experiences (PLEs) completed during pharmacy residency training are one way to address this need. The purpose of this study was to characterize PLEs offered by postgraduate year 1 (PGY1) programs and completed by PGY1 residents over a 5-year period., Methods: A retrospective review of data from PharmAcademic was conducted. All ASHP-accredited PGY1 programs from the 2016-2017 through 2020-2021 residency years were included in the descriptive analysis. PLE presence was identified using a keyword search of learning experience titles and descriptions. A post hoc analysis was conducted to compare yearly PLE completion rates during the study period and annual completion rates relative to presence or absence of a postgraduate year 2 psychiatric pharmacy residency., Results: Of 1,461 PGY1 programs, 511 programs (34.9%) offered a PLE. Most PLEs were elective (82%). During the study period, 20.8% of PGY1 residents completed a PLE despite 77% having access., Conclusion: PGY1 residents complete PLEs at low rates. The reasons for this are unclear and need to be further explored. The growing need for qualified pharmacists to care for patients with mental illness calls for strategies to increase mental health training, including greater completion of PLEs by PGY1 residents and an understanding of how PLEs are promoted to PGY1 residents., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Of 319 children with invasive candidiasis, 67 (21%) transitioned from intravenous to enteral antifungal therapy. Eight (12%) transitioned back to intravenous antifungal therapy, one due to perceived treatment failure defined by clinical progression or worsening. Global treatment response at study completion was success in 66 participants transitioned to enteral therapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Motivation: Microbiome differential abundance analysis remains a challenging problem despite multiple methods proposed in the literature. The excessive zeros and compositionality of metagenomics data are two main challenges for differential abundance analysis., Results: We propose a novel method called "Analysis of Differential Abundance by Pooling Tobit Models" (ADAPT) to overcome these two challenges. ADAPT interprets zero counts as left-censored observations to avoid unfounded assumptions and complex models. ADAPT also encompasses a theoretically justified way of selecting non-differentially abundant microbiome taxa as a reference to reveal differentially abundant taxa while avoiding false discoveries. We generate synthetic data using independent simulation frameworks to show that ADAPT has more consistent false discovery rate control and higher statistical power than competitors. We use ADAPT to analyze 16S rRNA sequencing of saliva samples and shotgun metagenomics sequencing of plaque samples collected from infants in the COHRA2 study. The results provide novel insights into the association between the oral microbiome and early childhood dental caries., Availability and Implementation: The R package ADAPT can be installed from Bioconductor at https://bioconductor.org/packages/release/bioc/html/ADAPT.html or from Github at https://github.com/mkbwang/ADAPT. The source codes for simulation studies and real data analysis are available at https://github.com/mkbwang/ADAPT&#95;example., Supplementary Information: The supplementary notes and figures are compiled together in a PDF document. The supplementary tables are combined in an excel file. Both the PDF document and the excel file are available online., (© The Author(s) 2024. Published by Oxford University Press.)

Objectives: To understand how health-related social needs (HRSN) data are collected at US hospitals and implications for use., Materials and Methods: Using 2023 nationally representative survey data on US hospitals (N = 2775), we described hospitals' routine and structured collection and use of HRSN data and examined the relationship between methods of data collection and specific uses. Multivariate logistic regression was used to identify characteristics associated with data collection and use and understand how methods of data collection relate to use., Results: In 2023, 88% of hospitals collected HRSN data (64% routinely, 72% structured). While hospitals commonly used data for internal purposes (eg, discharge planning, 79%), those that collected data routinely and in a structured format (58%) used data for purposes involving coordination or exchange with other organizations (eg, making referrals, 74%) at higher rates than hospitals that collected data but not routinely or in a non-structured format (eg, 93% vs 67% for referrals, P< .05). In multivariate regression, routine and structured data collection was positively associated with all uses of data examined. Hospital location, ownership, system-affiliation, value-based care participation, and critical access designation were associated with HRSN data collection, but only system-affiliation was consistently (positively) associated with use., Discussion: While most hospitals screen for social needs, fewer collect data routinely and in a structured format that would facilitate downstream use. Routine and structured data collection was associated with greater use, particularly for secondary purposes., Conclusion: Routine and structured screening may result in more actionable data that facilitates use for various purposes that support patient care and improve community and population health, indicating the importance of continuing efforts to increase routine screening and standardize HRSN data collection., (Published by Oxford University Press on behalf of the American Medical Informatics Association 2024.)

The indiscriminate administration of broad-spectrum antibiotics is a primary contributor to the increasing prevalence of antibiotic resistance. Unfortunately, culture, the gold standard for bacterial identification is a time intensive process. Due to this extended diagnostic period, broad-spectrum antibiotics are generally prescribed to prevent poor outcomes. To overcome the deficits of culture-based methods, we have developed a rapid universal bacterial identification system. The platform utilizes a unique universal polymerase chain reaction (PCR) primer set that targets the internal transcribed spacer (ITS) regions between conserved bacterial genes, creating a distinguishable amplicon signature for every bacterial species. Bioinformatic simulation demonstrates that at least 45 commonly isolated pathogenic species can be uniquely identified using this approach. We experimentally confirmed these predictions on a representative set of pathogenic bacterial species. We also show that the system can determine the corresponding concentration of each pathogen. Finally, we validated performance in clinical urinary tract infection samples., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Genome-wide association studies typically evaluate the autosomes and sometimes the X Chromosome, but seldom consider the Y or mitochondrial (MT) Chromosomes. We genotyped the Y and MT Chromosomes in heterogeneous stock (HS) rats (Rattus norvegicus), an outbred population created from 8 inbred strains. We identified 8 distinct Y and 4 distinct MT Chromosomes among the 8 founders. However, only 2 types of each nonrecombinant chromosome were observed in our modern HS rat population (generations 81-97). Despite the relatively large sample size, there were virtually no significant associations for behavioral, physiological, metabolome, or microbiome traits after correcting for multiple comparisons. However, both Y and MT Chromosomes were strongly associated with the expression of a few genes located on those chromosomes, which provided a positive control. Our results suggest that within modern HS rats there are no Y and MT Chromosomes differences that strongly influence behavioral or physiological traits. These results do not address other ancestral Y and MT Chromosomes that do not appear in modern HS rats, nor do they address effects that may exist in other rat populations, or in other species., Competing Interests: Conflicts of interest RK is a scientific advisory board member, and consultant for BiomeSense, Inc., has equity and receives income. He is a scientific advisory board member and has equity in GenCirq. He is a consultant for DayTwo, and receives income. He has equity in and acts as a consultant for Cybele. He is a co-founder of Biota, Inc., and has equity. He is a cofounder of Micronoma, and has equity and is a scientific advisory board member. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)

Objectives: Concerns persist regarding pulmonary regurgitation after transannular patch repair (TAP) for Tetralogy of Fallot. Despite various architectural preservation techniques being introduced, the optimal strategy remains controversial. We aimed to compare different right ventricular outlet tract reconstruction techniques., Methods: PubMed, EMBASE and Cochrane Central were searched through March 2024 to identify comparative studies on right ventricular outlet tract reconstruction techniques (PROSPERO ID: CRD42024519404). The primary outcome was mid-term pulmonary regurgitation, with secondary outcomes including postoperative mortality, postoperative pulmonary regurgitation, length of intensive care unit stays, postoperative right ventricular outlet tract pressure gradient, and mid-term mortality. We performed a network meta-analysis to compare outcomes among TAP, valve-repairing (VR), TAP with neo-valve creation (TAPN), and valve-sparing (VS)., Results: Two randomized controlled studies and 32 observational studies were identified with 8,890 patients. TAP carried a higher risk of mid-term pulmonary regurgitation compared to TAPN (HR, 0.53; 95％CI [0.33; 0.85]) and VS (HR, 0.27; 95% CI [0.19; 0.39]), with no significant difference compared to VR. VS was also associated with reduced postoperative mortality compared to TAP (RR, 0.31; 95% CI [0.18; 0.56]), in addition to reduced ventilation time. TAP also carried an increased risk of postoperative pulmonary regurgitation compared to the other groups. The groups were comparable in terms of length of intensive care unit stay, right ventricular outlet tract pressure gradient, and mid-term mortality., Conclusions: VR was associated with a reduced risk of postoperative pulmonary regurgitation, while TAPN was associated with reduced risks of both postoperative and mid-term pulmonary regurgitation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Many components of long-term cancer follow-up and survivorship care are managed in the primary care context. Given the important role that primary care has in survivorship care, it is critical to ensure that teams in these settings are prepared to address long-term needs. Evidence-based strategies to deliver survivorship care in primary care settings in the US remain limited. The National Cancer Institute (NCI) Office of Cancer Survivorship (OCS) conducted a day-long virtual event, Enhancing Capacity for Primary Care Research in Cancer Survivorship: A Workshop for Action, on February 28, 2024, to discuss research needs addressing the intersection between primary care and cancer survivorship. Topics discussed to advance this area of research included: system-level interventions, methods and measurement, and mentorship and research team building, especially for early career researchers. The purpose of this report is to provide a summary of the key findings. Gaps and opportunities include: (1) health systems-level research that investigates primary care practice-level capacity, (2) identification and characterization of the targeted cancer survivor populations for primary care research; (3) leveraging electronic medical records to track relevant patient outcomes throughout survivorship; and (4) development/creation of communities of practice to support and build research capacity. Team science approaches were identified as a core strategy to advance survivorship research. The meeting closed with a reflection and call to action focused on building collaborations that span different research areas, disciplines, and organizations and building a broad network of a primary care practice focused research., (Published by Oxford University Press 2024.)

Introduction: In ensuring the timely delivery of emergency care to Veterans, Veterans Affairs (VA) offers both emergency care services in its own facilities and, increasingly, purchases care for Veterans in non-VA (community) emergency department (ED) settings. Although in recent years emergency care coverage has become the single largest contributor to VA community care spending, no study to date has examined Veteran decision-making as it relates to ED setting choice. The purpose of this study is to identify and describe reasons why Veterans choose VA versus non-VA emergency care settings., Materials and Methods: Veterans Health Administration data were used to identify geographically diverse Veterans who recently used emergency care. We conducted semi-structured telephone interviews from December 2018 through March 2020 with 50 Veterans to understand the factors Veterans consider when deciding where to obtain ED care. Interviews were audio-recorded and transcribed verbatim. We conducted a directed content analysis of interview transcripts and developed a matrix to summarize and categorize each Veteran's decision-making process to compare participants and to identify common patterns., Results: When choosing between VA and non-VA-EDs, Veterans described 3 distinct patterns of decision-making: (1) choosing the closest ED (often community) for acute conditions; (2) traveling farther for VA care due to preference and financial coverage; and (3) selecting VA when both types of ED care were equidistant. Perceptions of community resources, condition-specific needs, financial considerations, and personal preferences dominated the decision-making. For example, most Veterans (74%) rated their acuity as high, and self-perceived severity/urgency of their condition was the most cited factor influencing where Veterans decided to go for ED care., Conclusions: Our qualitative results help provide insight into how and why Veterans choose to seek emergency care. As the number of Veterans treated in non-VA EDs continues to rise, VA and non-VA ED providers as well as policy makers may benefit from understanding the challenges Veterans face when making this decision., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2024. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Least absolute shrinkage and selection operator (LASSO) regression is widely used for large-scale propensity score (PS) estimation in health-care database studies. In these settings, previous work has shown that undersmoothing (overfitting) LASSO PS models can improve confounding control, but it can also cause problems of nonoverlap in covariate distributions. It remains unclear how to select the degree of undersmoothing when fitting large-scale LASSO PS models to improve confounding control while avoiding issues that can result from reduced covariate overlap. Here, we used simulations to evaluate the performance of using collaborative-controlled targeted learning to data-adaptively select the degree of undersmoothing when fitting large-scale PS models within both singly and doubly robust frameworks to reduce bias in causal estimators. Simulations showed that collaborative learning can data-adaptively select the degree of undersmoothing to reduce bias in estimated treatment effects. Results further showed that when fitting undersmoothed LASSO PS models, the use of cross-fitting was important for avoiding nonoverlap in covariate distributions and reducing bias in causal estimates., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2024.)

Objectives: Ceftazidime/avibactam is a key antibiotic for carbapenemase-producing Enterobacterales (CPE) Gram-negative infections, but current dosing may be suboptimal to grant activity. This study explores the population pharmacokinetics/pharmacodynamics (PK/PD) of continuous infusion (CI) ceftazidime/avibactam for maximizing treatment efficacy in critically ill patients., Methods: A retrospective analysis of adult patients receiving CI ceftazidime/avibactam and therapeutic drug monitoring (TDM) of both compounds was performed. Population PK/PD modelling identified the most accurate method for estimating ceftazidime/avibactam clearance based on kidney function and Monte Carlo simulations investigated the relationship between various CI dosing regimens and aggressive joint PK/PD target attainment of ceftazidime/avibactam., Results: The European Kidney Function Consortium (EKFC) equation best described kidney function for ceftazidime/avibactam clearance. The findings challenge the current approach of only reducing the ceftazidime/avibactam dose based on kidney function by identifying dose adjustments in patients with augmented kidney function. Our CI ceftazidime/avibactam dosing strategies, adjusted by TDM, showed promise for achieving optimal aggressive joint PK/PD targets and potentially improving clinical/microbiological outcomes against KPC- and OXA-48-producing Enterobacterales. The risk of neurotoxicity associated with these strategies appears acceptable., Conclusions: This study suggests that adjusting ceftazidime/avibactam dosing regimen based solely on eCLcr might be suboptimal for critically ill patients. Higher daily doses delivered by CI and adjusted based on TDM have the potential to improve aggressive joint PK/PD target attainment and potentially clinical/microbiological outcomes. Further investigations are warranted to confirm these findings and establish optimal TDM-guided dosing strategies for ceftazidime/avibactam in clinical practice., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Despite advances in medical therapy, many children and adults with ileal Crohn's disease (CD) progress to fibrostenosis requiring surgery. We aimed to identify MRI and circulating biomarkers associated with the need for surgical management., Methods: This prospective, multicenter study included pediatric and adult CD cases undergoing ileal resection and CD controls receiving medical therapy. Noncontrast research MRI examinations measured bowel wall 3-dimensional magnetization transfer ratio normalized to skeletal muscle (normalized 3D MTR), modified Look-Locker inversion recovery (MOLLI) T1 relaxation, intravoxel incoherent motion (IVIM) diffusion-weighted imaging metrics, and the simplified magnetic resonance index of activity (sMaRIA). Circulating biomarkers were measured on the same day as the research MRI and included CD64, extracellular matrix protein 1 (ECM1), and granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies (Ab). Associations between MRI and circulating biomarkers and need for ileal resection were tested using univariate and multivariable LASSO regression., Results: Our study sample included 50 patients with CD undergoing ileal resection and 83 patients with CD receiving medical therapy; mean participant age was 23.9 ± 13.1 years. Disease duration and treatment exposures did not vary between the groups. Univariate biomarker associations with ileal resection included log GM-CSF Ab (odds ratio [OR], 2.87; P = .0009), normalized 3D MTR (OR, 1.05; P = .002), log MOLLI T1 (OR, 0.01; P = .02), log IVIM perfusion fraction (f; OR, 0.38; P = .04), and IVIM apparent diffusion coefficient (ADC; OR, 0.3; P = .001). The multivariable model for surgery based upon corrected Akaike information criterion included age (OR, 1.03; P = .29), BMI (OR, 0.91; P = .09), log GM-CSF Ab (OR, 3.37; P = .01), normalized 3D MTR (OR, 1.07; P = .007), sMaRIA (OR, 1.14; P = .61), luminal narrowing (OR, 10.19; P = .003), log C-reactive protein (normalized; OR, 2.75; P = .10), and hematocrit (OR, 0.90; P = .13)., Conclusion: After accounting for clinical and MRI measures of severity, normalized 3D MTR and GM-CSF Ab are associated with the need for surgery in ileal CD., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: The purpose of this quality improvement (QI) project was to evaluate outcomes across Veterans Health Administration (VHA) hospital facilities engaged in an enterprise-wide implementation of a high-reliability organization (HRO) framework., Materials and Methods: This QI project relied on primary data drawn from 139 facilities nationwide from 2019 to 2023. Data sources included the All Employee Survey Patient Safety Culture (PSC) Module and patient safety reporting data derived from the Joint Patient Safety Reporting system. The project design applied a pre-post quasi-experimental design that examined within-cohort changes at pre-intervention, intervention, and 2 post-intervention follow-up timepoints. HRO interventions included a combination of training, leadership coaching, site assessments, and experiential learning. HRO interventions were initiated at 18 facilities beginning in 2019 (Cohort 1), 54 facilities in 2020 (Cohort 2), and 67 facilities in 2021 (Cohort 3). For between-cohort analyses, the relative degree of change within Cohort 1 sites was compared with all other sites., Results: There were broad positive within-group trends for PSC scores across all sites, and domain-specific between-group differences in PSC Dimension 2-Risk Identification and Just Culture-and Dimension 4-Error Transparency and Risk Mitigation. For patient safety reporting, total events reported, and close calls increased for Cohort 1. The ratio of close calls to adverse events also increased for both Cohort 1 and all other VHA sites at post-intervention year 2., Conclusions: The results of this QI project will inform further refinements to VHA's efforts to implement HRO principles and practices in the nation's largest integrated health system. In addition, the implementation practices may inform other large-scale, multi-level efforts to improve quality and patient safety., (© The Association of Military Surgeons of the United States 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Motivation: Accurate protein function prediction is crucial for understanding biological processes and advancing biomedical research. However, the rapid growth of protein sequences far outpaces the experimental characterization of their functions, necessitating the development of automated computational methods., Results: We present InterLabelGO+, a hybrid approach that integrates a deep learning-based method with an alignment-based method for improved protein function prediction. InterLabelGO+ incorporates a novel loss function that addresses label dependency and imbalance and further enhances performance through dynamic weighting of the alignment-based component. A preliminary version of InterLabelGO+ achieved a strong performance in the CAFA5 challenge, ranking sixth out of 1625 participating teams. Comprehensive evaluations on large-scale protein function prediction tasks demonstrate InterLabelGO+'s ability to accurately predict Gene Ontology terms across various functional categories and evaluation metrics., Availability and Implementation: The source code and datasets for InterLabelGO+ are freely available on GitHub at https://github.com/QuanEvans/InterLabelGO. A web-server is available at https://seq2fun.dcmb.med.umich.edu/InterLabelGO/. The software is implemented in Python and PyTorch, and is supported on Linux and macOS., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Bladder dysfunction entails overactive bladder (OAB) defined as symptoms of urinary urgency, frequency, and/or nocturia with or without incontinence if there is no obvious pathology or infection or lower urinary tract symptoms (LUTS) that includes recognized causes of bladder dysfunction., Methods: Literature search., Results: Symptoms of OAB are reported in about 15% of the adult US population. This is increased 2- to 3- fold in patients with congestive heart failure (CHF), hypertension, cardiovascular disease (CVD), chronic kidney disease (CKD) or the elderly where it often accompanies prescription for short, rapid acting loop diuretics. However, less than 2% of patients seeking care for OAB receive treatment. The fear of urinary incontinence from short, rapid acting loop diuretics may contribute to medication nonadherence and less well controlled, apparently resistant hypertension. The bladder contracts to rapid stretch. Thus, less rapid acting diuretics such as thiazides or extended-release formulations of loop diuretics may be preferable for those with bladder dysfunction. Alternatively, the use of a mineralocorticosteroid receptor antagonist, angiotensin receptor antagonist/neprilysin inhibitor or sodium glucose linked transport type 2 inhibitor may allow a reduction in dose of a short, rapid acting loop diuretic for those with bladder dysfunction., Conclusion: A worsening of symptoms from bladder dysfunction by short, rapid acting loop diuretics occurs frequently in patients with CVD, CHF, hypertension and CKD where it can contribute to impaired quality of life and poor adherence and thereby to worsening outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Although synonymous mutations are commonly assumed neutral or nearly so, recent years have seen reports of fitness effects of synonymous mutations detected under laboratory conditions. In a previous study, we used genome editing to construct thousands of yeast mutants each carrying a synonymous or nonsynonymous mutation in one of 21 genes, and discovered that most synonymous and most nonsynonymous mutations are deleterious. A concern was raised that this observation could be caused by the fitness effects of potential CRISPR/Cas9 off-target edits and/or secondary mutations, and an experiment that would be refractory to such effects was proposed. Using genome sequencing, we here show that no CRISPR/Cas9 off-target editing occurred, although some mutants did carry secondary mutations. Analysis of mutants with negligible effects from secondary mutations and new data collected from the proposed experiment confirms the original conclusion. These findings, along with other reports of fitness effects of synonymous mutations from both case and systematic studies, necessitate a paradigm shift from assuming (near) neutrality of synonymous mutations., Competing Interests: Conflict of Interest The authors have no competing interests to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Objectives: We sought to analyze interactive visualizations and animations of health probability data (such as chances of disease or side effects) that have been studied in head-to-head comparisons with either static graphics or numerical communications., Materials and Methods: Secondary analysis of a large systematic review on ways to communicate numbers in health., Results: We group the research to show that 4 types of animated or interactive visualizations have been studied by multiple researchers: those that simulate experience of probabilistic events; those that demonstrate the randomness of those events; those that reduce information overload by directing attention sequentially to different items of information; and those that promote elaborative thinking. Overall, these 4 types of visualizations do not show strong evidence of improving comprehension, risk perception, or health behaviors over static graphics., Discussion: Evidence is not yet strong that interactivity or animation is more effective than static graphics for communicating probabilities in health. We discuss 2 possibilities: that the most effective visualizations haven't been studied, and that the visualizations aren't effective., Conclusion: Future studies should rigorously compare participant performance with novel interactive or animated visualizations against their performance with static visualizations. Such evidence would help determine whether health communicators should emphasize novel interactive visualizations or rely on older forms of visual communication, which may be accessible to broader audiences, including those with limited digital access., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Background: The use of androgen biosynthesis and second-generation androgen receptor inhibitors for advanced prostate cancer is increasing. Because these therapies alter the androgen pathway, they have been associated with cardiometabolic and neurocognitive toxicities. Although their safety profiles have been assessed in clinical trials, real-world data are limited., Methods: A 20% sample of national Medicare claims was used to perform a retrospective cohort study of Medicare beneficiaries with advanced prostate cancer treated with androgen biosynthesis (ie, abiraterone) and second-generation androgen receptor inhibitors between 2012 and 2019. Outcomes were assessed after the first fill of either class of drug for the 12-month period after starting therapy. The primary outcome was a hospital admission or emergency department visit for a cardiometabolic event. Secondary outcomes included neurocognitive events and fractures. Multivariable regression was used to assess the association between the class of drug and occurrence of an adverse event., Results: There were 3488 (60%) men started on an androgen biosynthesis inhibitor and 2361 (40%) started on an androgen receptor inhibitor for the first time. Cardiometabolic adverse events were more common in men managed with androgen biosynthesis inhibitor (9.2% vs 7.5%, P = .027). No difference between androgen biosynthesis and androgen receptor inhibitors was observed for neurocognitive events (3.3% vs 3.4%, respectively; P = .71) or fractures (4.2% vs 3.6%, respectively; P = .26)., Conclusions: Men with advanced prostate cancer initiating an androgen biosynthesis inhibitor for the first time more commonly had cardiometabolic events than those started on androgen receptor inhibitors. Neurocognitive events and fractures did not differ by drug class., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The benefits of colorectal cancer (CRC) screening programs rely on completing follow-up colonoscopy when a noncolonoscopy test is abnormal and on quality of colonoscopy screening as measured by the endoscopists' adenoma detection rate. Existing data demonstrate substantially lower follow-up colonoscopy rates and adenoma detection rate for Black Americans than White Americans. However, the contributions of racial differences in follow-up colonoscopy and adenoma detection rate on CRC outcomes have not been rigorously evaluated., Methods: We used established and validated CRC-Adenoma Incidence and Mortality (CRC-AIM) model as our analysis platform, with inputs from published literature that report lower follow-up colonoscopy rates and adenoma detection rate in Black adults compared with White adults (15% and 10% lower, respectively). We simulated screening with annual fecal immunochemical test, triennial multitarget stool DNA, and colonoscopy every 10 years between ages 45 and 75 years using real-world utilization of the screening modalities vs no screening. We reported lifetime outcomes per 1000 Black adults., Results: Elimination of Black-White disparities in follow-up colonoscopy rates would reduce CRC incidence and mortality by 5.2% and 9.3%, respectively, and improve life-years gained with screening by 3.4%. Elimination of Black-White disparities in endoscopists' adenoma detection rate would reduce CRC incidence and mortality by 9.4% and improve life-years gained by 3.7%. Elimination of both disparities would reduce CRC incidence and mortality by 14.6% and 18.7%, respectively, and improve life-years gained by 7.1%., Conclusions: This modeling study predicts eliminating racial differences in follow-up colonoscopy rates, and quality of screening colonoscopy would substantially reduce Black-White disparities in CRC incidence and mortality., (© The Author(s) 2024. Published by Oxford University Press.)

Objective: To examine disease and target engagement biomarkers in the RISE-SSc trial of riociguat in early diffuse cutaneous systemic sclerosis and their potential to predict the response to treatment., Methods: Patients were randomized to riociguat (n = 60) or placebo (n = 61) for 52 weeks. Skin biopsies and plasma/serum samples were obtained at baseline and week 14. Plasma cyclic guanosine monophosphate (cGMP) was assessed using radio-immunoassay. α-Smooth muscle actin (αSMA) and skin thickness were determined by immunohistochemistry, mRNA markers of fibrosis by qRT-PCR in skin biopsies, and serum CXC motif chemokine ligand 4 (CXCL-4) and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) by enzyme-linked immunosorbent assay., Results: By week 14, cGMP increased by 94 (78)% with riociguat and 10 (39)% with placebo (P < 0.001, riociguat vs placebo). Serum sPECAM-1 and CXCL-4 decreased with riociguat vs placebo (P = 0.004 and P = 0.008, respectively). There were no differences in skin collagen markers between the two groups. Higher baseline serum sPECAM-1 or the detection of αSMA-positive cells in baseline skin biopsies was associated with a larger reduction of modified Rodnan skin score from baseline at week 52 with riociguat vs placebo (interaction P-values 0.004 and 0.02, respectively)., Conclusion: Plasma cGMP increased with riociguat, suggesting engagement with the nitric oxide-soluble guanylate cyclase-cGMP pathway. Riociguat was associated with a significant reduction in sPECAM-1 (an angiogenic biomarker) vs placebo. Elevated sPECAM-1 and the presence of αSMA-positive skin cells may help to identify patients who could benefit from riociguat in terms of skin fibrosis., Trial Registration: Clinicaltrials.gov, NCT02283762., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: To understand healthcare providers' experiences of using GlucoGuide, a mockup tool that integrates visual data analysis with algorithmic insights to support clinicians' use of patientgenerated data from Type 1 diabetes devices., Materials and Methods: This qualitative study was conducted in three phases. In Phase 1, 11 clinicians reviewed data using commercial diabetes platforms in a think-aloud data walkthrough activity followed by semistructured interviews. In Phase 2, GlucoGuide was developed. In Phase 3, the same clinicians reviewed data using GlucoGuide in a think-aloud activity followed by semistructured interviews. Inductive thematic analysis was used to analyze transcripts of Phase 1 and Phase 3 think-aloud activity and interview., Results: 3 high level tasks, 8 sub-tasks, and 4 challenges were identified in Phase 1. In Phase 2, 3 requirements for GlucoGuide were identified. Phase 3 results suggested that clinicians found GlucoGuide easier to use and experienced a lower cognitive burden as compared to the commercial diabetes data reports that were used in Phase 1. Additionally, GlucoGuide addressed the challenges experienced in Phase 1., Discussion: The study suggests that the knowledge of analytical tasks and task-specific visualization strategies in implementing features of data interfaces can result in tools that lower the perceived burden of engaging with data. Additionally, supporting clinicians in contextualizing algorithmic insights by visual analysis of relevant data can positively influence clinicians' willingness to leverage algorithmic support., Conclusion: Task-aligned tools that combine multiple data-driven approaches, such as visualization strategies and algorithmic insights, can improve clinicians' experience in reviewing device data., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Mammalian genomes contain thousands of genes for long noncoding RNA (lncRNAs), some of which have been shown to affect protein coding gene expression through diverse mechanisms. The lncRNA transcripts are longer than 200 nucleotides and are often capped, spliced, and polyadenylated, but not translated into protein. Nuclear lncRNAs can modify chromatin structure and transcription in trans or cis by interacting with the DNA, forming R-loops, and recruiting regulatory proteins. Not much is known about the role of lncRNA in pituitary gland differentiation and function. We mined transcriptome data from mouse pituitary glands collected at embryonic days 12.5 and 14.5 and identified over 200 different lncRNA transcripts. To develop a research resource for the study of lncRNA, we used pituitary cre transgenes to tag pituitary cell types in adult mice with fluorescent markers, and enriched for thyrotropes, gonadotropes, and somatotropes using fluorescence-activated cell sorting. We determined the transcriptome of each cell population using RNA sequencing and mined the data for lncRNA. We detected hundreds of lncRNAs in adult pituitary cells; a few were located immediately nearby genes that encode pituitary hormones or lineage-specific transcription factors. The location of these lncRNAs suggests the possibility of a cis-acting regulatory role in pituitary development or function, and we observe coordinated expression of 2 of them with their putative target genes in transgenic mice. This research resource sets the foundation for examining the actions of lncRNAs on their putative target genes and determining whether they have roles during development and in response to physiological demand., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Introduction: Withdrawal of nucleos(t)ide analog (NA) therapy is associated with hepatitis B surface antigen (HBsAg) loss and sustained, off-therapy partial cure (normal ALT [≤30 U/L males, ≤20 U/L females) with HBV DNA <2000 IU/mL) but should be offered only to those most likely to benefit. HBVRNA may be useful for risk stratification., Methods: The Hepatitis B Research Network Immune-Active Trial prospectively evaluated treatment with tenofovir (TDF) for 192 weeks ± peginterferon-α (PegIFN) for initial 24 weeks followed by protocolized withdrawal of TDF amongst eligible participants (NCT01369212). HBV RNA was evaluated as predictor of ALT flares and sustained partial cure (HBV DNA<2000 IU/mL) 48 weeks after TDF withdrawal., Results: Of 93 participants discontinuing TDF (52 in TDF+PegIFN and 41 in TDF alone), 52 (55.9%) had unquantifiable HBVRNA at end-of-treatment. ALT flares (>5xULN) at 48 weeks off-therapy occurred in 33.3%, with pre-treatment age (≥35 years) and quantifiable HBV RNA at end-of-treatment, the best predictors (AUROC 0.74 and 0.85, training and test set) of ALT flare. A total of 26 (28.3%) had sustained partial cure; 3 (11.5%) with ALT flare. Non-quantifiable HBVRNA and qHBsAg <100 IU/mL at end-of-treatment were the best predictors of sustained partial cure (AUROC 0.84 and 0.93, training and test set). If HBVRNA was quantifiable at end-of-treatment, the likelihood of sustained partial cure was only 3% whereas if HBV RNA was unquantifiable and qHBsAg <100 IU/mL, this likelihood was 73%., Conclusions: HBVRNA is a useful biomarker in predicting likelihood of achieving sustained partial cure and safe withdrawal of NAs., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Antibiotic resistance is an urgent public health threat. Actions to reduce this threat include requiring prescriptions for antibiotic use, antibiotic stewardship programs, educational programs targeting patients and healthcare providers, and limiting antibiotic use in agriculture, aquaculture, and animal husbandry. Wastewater surveillance might complement clinical surveillance by tracking time/space variation essential for detecting outbreaks and evaluating efficacy of evidence-based interventions; identifying high-risk populations for targeted monitoring; providing early warning of the emergence and spread of antibiotic resistant bacteria and identifying novel antibiotic resistant threats. Wastewater surveillance was an effective early warning system for SARS-CoV-2 spread and detection of the emergence of new viral strains. In this data-driven commentary we explore whether monitoring wastewater for antibiotic resistant genes and/or bacteria resistant to antibiotics might provide useful information for public health action. Using carbapenem resistance as an example, we highlight technical challenges associated with using wastewater to quantify temporal/spatial trends in antibiotic resistant bacteria (ARBs) and antibiotic resistant genes (ARGs) and compare with clinical information. While ARGs and ARBs are detectable in wastewater enabling early detection of novel ARGs, quantitation of ARBs and ARGs with current methods is too variable to reliably track space/time variation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Transfer RNAs (tRNAs) contain dozens of chemical modifications. These modifications are critical for maintaining tRNA tertiary structure and optimizing protein synthesis. Here we advance the use of Nanopore direct RNA-sequencing (DRS) to investigate the synergy between modifications that are known to stabilize tRNA structure. We sequenced the 42 cytosolic tRNA isoacceptors from wild-type yeast and five tRNA-modifying enzyme knockout mutants. These data permitted comprehensive analysis of three neighboring and conserved modifications in T-loops: 5-methyluridine (m5U54), pseudouridine (Ψ55), and 1-methyladenosine (m1A58). Our results were validated using direct measurements of chemical modifications by mass spectrometry. We observed concerted T-loop modification circuits-the potent influence of Ψ55 for subsequent m1A58 modification on more tRNA isoacceptors than previously observed. Growing cells under nutrient depleted conditions also revealed a novel condition-specific increase in m1A58 modification on some tRNAs. A global and isoacceptor-specific classification strategy was developed to predict the status of T-loop modifications from a user-input tRNA DRS dataset, applicable to other conditions and tRNAs in other organisms. These advancements demonstrate how orthogonal technologies combined with genetics enable precise detection of modification landscapes of individual, full-length tRNAs, at transcriptome-scale., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Evolutionary innovations have played an important role in shaping the diversity of life on Earth. However, how these innovations arise and their downstream effects on patterns of morphological diversification remain poorly understood. Here, we examine the impact of evolutionary innovation on trait diversification in tetraodontiform fishes (pufferfishes, boxfishes, ocean sunfishes, and allies). This order provides an ideal model system for studying morphological diversification owing to their range of habitats and divergent morphologies, including the fusion of the teeth into a beak in several families. Using three-dimensional geometric morphometric data for 176 extant and fossil species, we examine the effect of skull integration and novel habitat association on the evolution of innovation. Strong integration may be a requirement for rapid trait evolution and facilitating the evolution of innovative structures, like the tetraodontiform beak. Our results show that the beak arose in the presence of highly conserved patterns of integration across the skull, suggesting that integration did not limit the range of available phenotypes to tetraodontiforms. Furthermore, we find that beaks have allowed tetraodontiforms to diversify into novel ecological niches, irrespective of habitat. Our results suggest that general rules pertaining to evolutionary innovation may be more nuanced than previously thought., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Society for the Study of Evolution (SSE).)

Aims: The Shock Academic Research Consortium (SHARC) recently proposed pragmatic consensus definitions to standardize classification of cardiogenic shock (CS) in registries and clinical trials. We aimed to describe contemporary CS epidemiology using the SHARC definitions in a cardiac intensive care unit (CICU) population., Methods and Results: The Critical Care Cardiology Trials Network (CCCTN) is a multinational research network of advanced CICUs coordinated by the TIMI Study Group (Boston, MA). Cardiogenic shock was defined as a cardiac disorder resulting in SBP < 90 mmHg for ≥30 min [or the need for vasopressors, inotropes, or mechanical circulatory support (MCS) to maintain SBP ≥ 90 mmHg] with evidence of hypoperfusion. Primary aetiologic categories included acute myocardial infarction-related CS (AMI-CS), heart failure-related CS (HF-CS), and non-myocardial (secondary) CS. Post-cardiotomy CS was not included. Heart failure-related CS was further subcategorized as de novo vs. acute-on-chronic HF-CS. Patients with both cardiogenic and non-cardiogenic components of shock were classified separately as mixed CS. Of 8974 patients meeting shock criteria (2017-23), 65% had isolated CS and 17% had mixed shock. Among patients with CS (n = 5869), 27% had AMI-CS (65% STEMI), 59% HF-CS (72% acute-on-chronic, 28% de novo), and 14% secondary CS. Patients with AMI-CS and de novo HF-CS were most likely to have had concomitant cardiac arrest (P < 0.001). Patients with AMI-CS and mixed CS were most likely to present in more severe shock stages (SCAI D or E; P < 0.001). Temporary MCS use was highest in AMI-CS (59%). In-hospital mortality was highest in mixed CS (48%), followed by AMI-CS (41%), similar in de novo HF-CS (31%) and secondary CS (31%), and lowest in acute-on-chronic HF-CS (25%; P < 0.001)., Conclusion: SHARC consensus definitions for CS classification can be pragmatically applied in contemporary registries and reveal discrete subpopulations of CS with distinct phenotypes and outcomes that may be relevant to clinical practice and future research., Competing Interests: Conflict of interest: D.D.B., E.A.B., S.M.P., V.M.B.-Z., J.-G.P., and D.A.M. are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Abiomed, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc., AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, Inc., Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Roche, Siemens Healthcare Diagnostics, Inc., Softcell Medical Limited, The Medicines Company, and Zora Biosciences. D.D.B. has received consulting fees from AstraZeneca, Pfizer, Mobility Bio, Inc., and Youngene Therapeutics; honoraria from the Metabolic Endocrine Education Foundation, and USV Private Limited; and participates on clinical endpoint committees for studies sponsored by Beckman Coulter, Kowa Pharmaceuticals, Novo Nordisk, and Tosoh Biosciences. L.S. reports speakers bureaus for Abiomed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Global ocean warming is affecting keystone species distributions and fitness, resulting in the degradation of marine ecosystems. Coral reefs are one of the most diverse and productive marine ecosystems. However, reef-building corals, the foundational taxa of coral reef ecosystems, are severely threatened by thermal stress. Models predict 40-80% of global coral cover will be lost by 2100, which highlights the urgent need for widespread interventions to preserve coral reef functionality. There has been extensive research on coral thermal stress and resilience, but 95% of studies have focused on adult corals. It is necessary to understand stress during early life stages (larvae, recruits, and juveniles), which will better inform selective breeding programs that aim to replenish reefs with resilient stock. In this review, we surveyed the literature on coral thermal resilience in early life stages, and we highlight that studies have been conducted on relatively few species (commonly Acropora spp.) and in limited regions (mainly Australia). Reef-building coral management will be improved by comprehensively understanding coral thermal resilience and fitness across life stages, as well as in diverse species and regions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology.)

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: The goal of the present study was to examine teachers' perceptions of neuropsychological reports broadly and their preparedness to support the educational needs of students with chronic health conditions., Method: Teachers were selected from across the United States using stratified random sampling. 280 teachers (76.2% female; 58.4% public school; 53.9% rural setting) completed an anonymous electronic survey via Qualtrics., Results: Half of the teachers were familiar with neuropsychology and previously read a neuropsychological report, which the majority found useful with a preference toward shorter reports. Most found listed recommendations to be appropriate, but half of teachers identified limited resources as a barrier to implementation. Teachers reported limited education, training, and comfort for providing accommodations to children with chronic health conditions, which was significantly lower for cancer, congenital heart disease, and sickle cell disease. Older teachers, more years of experience, and special education teachers demonstrated significantly higher levels of education, training, and comfort. Frequency of implementing accommodations was significantly negatively correlated with perceived burden and positively correlated with perceived benefit across most accommodations. Teachers reported a preference for single-page handouts and speaking directly to neuropsychologists about the specific learning needs of students with chronic health conditions., Conclusions: Results highlight areas for future research and intervention regarding teacher's preparedness for working with children with chronic health groups and opportunities to improve communication between neuropsychologists and teachers to ultimately improve access to educational supports and overall quality of life of students with chronic health conditions., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)