Antibiotic route and outcomes for children hospitalized with pneumonia.

BACKGROUND: Emerging evidence suggests that initial oral and intravenous (IV) antibiotics have similar efficacy in pediatric community-acquired pneumonia (CAP), but further data are needed. OBJECTIVE: We determined the association between hospital-level initial oral antibiotic rates and outcomes in pediatric CAP. DESIGNS, SETTINGS AND PARTICIPANTS: This retrospective cohort study included children hospitalized with CAP at 43 hospitals in the Pediatric Health Information System (2016-2022). Hospitals were grouped by whether initial antibiotics were given orally in a high, moderate, or low proportion of patients. MAIN OUTCOME AND MEASURES: Regression models examined associations between high versus low oral-utilizing hospitals and length of stay (LOS, primary outcome), intensive care unit (ICU) transfers, escalated respiratory care, complicated CAP, cost, readmissions, and emergency department (ED) revisits. RESULTS: Initial oral antibiotics were used in 16% (interquartile range: 10%-20%) of 30,207 encounters, ranging from 1% to 68% across hospitals. Comparing high versus low oral-utilizing hospitals (oral rate: 32% [27%-47%] and 10% [9%-11%], respectively), there were no differences in LOS, intensive care unit, complicated CAP, cost, or ED revisits. Escalated respiratory care occurred in 1.3% and 0.5% of high and low oral-utilizing hospitals, respectively (relative ratio [RR]: 2.96 [1.12, 7.81]), and readmissions occurred in 1.5% and 0.8% (RR: 1.68 [1.31, 2.17]). Initial oral antibiotics varied across hospitals without a difference in LOS. While high oral-utilizing hospitals had higher escalated respiratory care and readmission rates, these were rare, the clinical significance of these small differences is uncertain, and there were no differences in other clinically relevant outcomes. This suggests some children may benefit from initial IV antibiotics, but most would probably do well with oral antibiotics.

An Evaluation of Sex- and Gender-Based Analyses in Oncology Clinical Trials.

BACKGROUND: The objective of this study was to evaluate whether sex- and gender-based analyses and proper sex and gender terminology were used in oncology trials leading to regulatory drug approval. METHODS: The Food and Drug Administration (FDA) Hematology/Oncology Approvals and Safety Notifications page was used to identify all anticancer therapies that received FDA approval between 2012 and 2019. The trials used to support FDA drug approval were collected along with all available supplemental tables and study protocols. Documents were reviewed to determine if there was a plan to analyze results according to sex and gender and to determine if consistent sex and gender terminology were used. RESULTS: We identified 128 randomized, controlled trials corresponding to a cancer medicine, which received FDA approval. No study specified how sex and gender were collected or analyzed. No study reported any information on the gender of participants. Sex and gender terminology were used inconsistently at least once in 76% (97 of 128) of studies. Among the 102 trials for nonsex-specific cancer sites, 89% (91 of 102) presented disaggregated survival outcome data by sex. No study presented disaggregated toxicity data by sex or gender. CONCLUSION: The majority of pivotal clinical trials in oncology fail to account for the important distinction between sex and gender and conflate sex and gender terminology. More rigor in designing clinical trials to include sex- and gender-based analyses and more care in using sex and gender terms in the cancer literature are needed. These efforts are essential to improve the reproducibility, generalizability, and inclusiveness of cancer research.

Alternative polyadenylation is a determinant of oncogenic Ras function.

Alternative polyadenylation of mRNA has important but poorly understood roles in development and cancer. Activating mutations in the Ras oncogene are common drivers of many human cancers. From a screen for enhancers of activated Ras (let-60) in Caenorhabditis elegans, we identified cfim-1, a subunit of the alternative polyadenylation machinery. Ablation of cfim-1 increased penetrance of the multivulva phenotype in let-60/Ras gain-of-function (gf) mutants. Depletion of the human cfim-1 ortholog CFIm25/NUDT21 in cancer cells with KRAS mutations increased their migration and stimulated an epithelial-to-mesenchymal transition. CFIm25-depleted cells and cfim-1 mutants displayed biased placement of poly(A) tails to more proximal sites in many conserved transcripts. Functional analysis of these transcripts identified the multidrug resistance protein mrp-5/ABCC1 as a previously unidentified regulator of C. elegans vulva development and cell migration in human cells through alternative 3'UTR usage. Our observations demonstrate a conserved functional role for alternative polyadenylation in oncogenic Ras function.

Mining of high throughput screening database reveals AP-1 and autophagy pathways as potential targets for COVID-19 therapeutics.

The recent global pandemic of the Coronavirus disease 2019 (COVID-19) caused by the new coronavirus SARS-CoV-2 presents an urgent need for the development of new therapeutic candidates. Many efforts have been devoted to screening existing drug libraries with the hope to repurpose approved drugs as potential treatments for COVID-19. However, the antiviral mechanisms of action of the drugs found active in these phenotypic screens remain largely unknown. In an effort to deconvolute the viral targets in pursuit of more effective anti-COVID-19 drug development, we mined our in-house database of approved drug screens against 994 assays and compared their activity profiles with the drug activity profile in a cytopathic effect (CPE) assay of SARS-CoV-2. We found that the autophagy and AP-1 signaling pathway activity profiles are significantly correlated with the anti-SARS-CoV-2 activity profile. In addition, a class of neurology/psychiatry drugs was found to be significantly enriched with anti-SARS-CoV-2 activity. Taken together, these results provide new insights into SARS-CoV-2 infection and potential targets for COVID-19 therapeutics, which can be further validated by in vivo animal studies and human clinical trials.

Biological activity-based modeling identifies antiviral leads against SARS-CoV-2.

Computational approaches for drug discovery, such as quantitative structure-activity relationship, rely on structural similarities of small molecules to infer biological activity but are often limited to identifying new drug candidates in the chemical spaces close to known ligands. Here we report a biological activity-based modeling (BABM) approach, in which compound activity profiles established across multiple assays are used as signatures to predict compound activity in other assays or against a new target. This approach was validated by identifying candidate antivirals for Zika and Ebola viruses based on high-throughput screening data. BABM models were then applied to predict 311 compounds with potential activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of the predicted compounds, 32% had antiviral activity in a cell culture live virus assay, the most potent compounds showing a half-maximal inhibitory concentration in the nanomolar range. Most of the confirmed anti-SARS-CoV-2 compounds were found to be viral entry inhibitors and/or autophagy modulators. The confirmed compounds have the potential to be further developed into anti-SARS-CoV-2 therapies.

Massive-scale biological activity-based modeling identifies novel antiviral leads against SARS-CoV-2.

The recent global pandemic caused by the new coronavirus SARS-CoV-2 presents an urgent need for new therapeutic candidates. While the importance of traditional in silico approaches such as QSAR in such efforts in unquestionable, these models fundamentally rely on structural similarity to infer biological activity and are thus prone to becoming trapped in the very nearby chemical spaces of already known ligands. For novel and unprecedented threats such as COVID-19 much faster and efficient paradigms must be devised to accelerate the identification of new chemical classes for rapid drug development. Here we report the development of a new biological activity-based modeling (BABM) approach that builds on the hypothesis that compounds with similar activity patterns tend to share similar targets or mechanisms of action. In BABM, compound activity profiles established on massive scale across multiple assays are used as signatures to predict compound activity in a new assay or against a new target. We first trained and validated this approach by identifying new antiviral lead candidates for Zika and Ebola based on data from ~0.5 million compounds screened against ~2,000 assays. BABM models were then applied to predict ~300 compounds not previously reported to have activity for SARS-CoV-2, which were then tested in a live virus assay with high (>30%) hit rates. The most potent compounds showed antiviral activities in the nanomolar range. These potent confirmed compounds have the potential to be further developed in novel chemical space into new anti-SARS-CoV-2 therapies. These results demonstrate unprecedented ability using BABM to predict novel structures as chemical leads significantly beyond traditional methods, and its application in rapid drug discovery response in a global public health crisis.

The NCATS Pharmaceutical Collection: a 10-year update.

The National Center for Advancing Translational Sciences (NCATS) Pharmaceutical Collection (NPC), a comprehensive collection of clinically approved drugs, was made a public resource in 2011. Over the past decade, the NPC has been systematically profiled for activity across an array of pathways and disease models, generating an unparalleled amount of data. These data have not only enabled the identification of new repurposing candidates with several in clinical trials, but also uncovered new biological insights into drug targets and disease mechanisms. This retrospective provides an update on the NPC in terms of both successes and lessons learned. We also report our efforts in bringing the NPC up-to-date with drugs approved in recent years.

CEP-1, the Caenorhabditis elegans p53 homolog, mediates opposing longevity outcomes in mitochondrial electron transport chain mutants.

Caenorhabditis elegans CEP-1 and its mammalian homolog p53 are critical for responding to diverse stress signals. In this study, we found that cep-1 inactivation suppressed the prolonged lifespan of electron transport chain (ETC) mutants, such as isp-1 and nuo-6, but rescued the shortened lifespan of other ETC mutants, such as mev-1 and gas-1. We compared the CEP-1-regulated transcriptional profiles of the long-lived isp-1 and the short-lived mev-1 mutants and, to our surprise, found that CEP-1 regulated largely similar sets of target genes in the two mutants despite exerting opposing effects on their longevity. Further analyses identified a small subset of CEP-1-regulated genes that displayed distinct expression changes between the isp-1 and mev-1 mutants. Interestingly, this small group of differentially regulated genes are enriched for the "aging" Gene Ontology term, consistent with the hypothesis that they might be particularly important for mediating the distinct longevity effects of CEP-1 in isp-1 and mev-1 mutants. We further focused on one of these differentially regulated genes, ftn-1, which encodes ferritin in C. elegans, and demonstrated that it specifically contributed to the extended lifespan of isp-1 mutant worms but did not affect the mev-1 mutant lifespan. We propose that CEP-1 responds to different mitochondrial ETC stress by mounting distinct compensatory responses accordingly to modulate animal physiology and longevity. Our findings provide insights into how mammalian p53 might respond to distinct mitochondrial stressors to influence cellular and organismal responses.

Gluteal pyomyositis in a non-tropical region as a rare cause of sciatic nerve compression: a case report.

INTRODUCTION: Pyomyositis, or isolated abscess formation within a skeletal muscle, is a relatively common condition in tropical climates but it is only encountered rarely in temperate zones. CASE PRESENTATION: We present a case of non-tropical pyomyositis of the gluteal muscle in a 26-year-old, previously healthy man from the United Kingdom, who initially presented with sciatica-like symptoms which began 3 days after a mosquito bite on his nose, which had become infected and discharged pus. CONCLUSION: Gluteal pyomyositis involving the sciatic nerve may initially present as radiculopathy. Mosquito bites may have been the source of transient bacteraemia that contributed to muscle suppuration in this patient. This may explain, at least in part, the increased incidence of pyomyositis in healthy individuals living in tropical regions.