bluuebunny/crossref_metadata_2025_split huggingface dataset:
Seeking order in patterns of polysubstance use
Authors: Connor Jason P. , Leung Janni , Chan Gary C.K. , Stjepanović Daniel 
Published: May 2023

Purpose of review
This review provides an overview of recent developments in understanding polysubstance use patterns across the lifespan, and advances made in the prevention and treatment of harm arising from polysubstance use.

Recent findings
A comprehensive understanding of the patterns of polysubstance use is hampered by heterogeneity across study methods and types of drugs measured. Use of statistical techniques such as latent class analysis has aided in overcoming this limitation, identifying common patterns or classes of polysubstance use. These typically include, with decreasing prevalence, (1) Alcohol use only; (2) Alcohol and Tobacco; (3) Alcohol, Tobacco, and Cannabis; and finally (4) a low prevalence, Extended Range cluster that includes other illicit drugs, New Psychoactive Substances (NPS), and nonmedical prescription medications.

Summary
Across studies, there are commonalities present in clusters of substances used. Future work that integrates novel measures of polysubstance use and leverages advances in drug monitoring, statistical analysis and neuroimaging will improve our understanding of how and why drugs are combined, and more rapidly identify emerging trends in multiple substance use. Polysubstance use is prevalent but there is a paucity of research exploring effective treatments and interventions.
Clinical Knowledge and Reasoning Abilities of AI Large Language Models in Anesthesiology: A Comparative Study on the ABA Exam
Authors: Angel Mirana C. , Rinehart Joseph B. , Canneson Maxime P. , Baldi Pierre 
Published: May 2023

AbstractOver the past decade, Artificial Intelligence (AI) has expanded significantly with increased adoption across various industries, including medicine. Recently, AI’s large language models such as GPT-3, Bard, and GPT-4 have demonstrated remarkable language capabilities. While previous studies have explored their potential in general medical knowledge tasks, here we assess their clinical knowledge and reasoning abilities in a specialized medical context. We study and compare their performances on both the written and oral portions of the comprehensive and challenging American Board of Anesthesiology (ABA) exam, which evaluates candidates’ knowledge and competence in anesthesia practice. In addition, we invited two board examiners to evaluate AI’s answers without disclosing to them the origin of those responses. Our results reveal that only GPT-4 successfully passed the written exam, achieving an accuracy of 78% on the basic section and 80% on the advanced section. In comparison, the less recent or smaller GPT-3 and Bard models scored 58% and 47% on the basic exam, and 50% and 46% on the advanced exam, respectively. Consequently, only GPT-4 was evaluated in the oral exam, with examiners concluding that it had a high likelihood of passing the actual ABA exam. Additionally, we observe that these models exhibit varying degrees of proficiency across distinct topics, which could serve as an indicator of the relative quality of information contained in the corresponding training datasets. This may also act as a predictor for determining which anesthesiology subspecialty is most likely to witness the earliest integration with AI.
Regularized COVID-19 Forecast Ensemble Methods
Authors: Stephens Alexandra , Mullany Luke C. , Kinsey Matt , Nicholas Paul , Freeman Jeffrey , Rainwater-Lovett Kaitlin 
Published: May 2023

AbstractForecasts of COVID-19 outcomes play an essential role in alerting public health and government officials to the trajectory of the pandemic. The sudden and critical need for these forecasts spurred both the proliferation of diverse epidemiological transmission models from academia and industry across the United States and efforts to standardize and curate these model outputs. In many scientific domains, ensemble models, where individual forecasts are aggregated into one, have demonstrated smaller forecasting error than the individual models from which they are constructed. Using COVID-19 deaths as an index outcome, we developed and evaluated several ensemble approaches where point forecast models were combined via weighted sums based on historical individual model or ensemble model performance. We found that a simple method that minimized the error of the past performance of individual models and used L2 regularization to encourage broader distribution of weights across models outperformed a baseline mean ensemble and all other tested methods across US states for both absolute error and weighted interval scores. This suggests that performance-based ensembles can produce accurate forecasts despite training on only point forecasts and recent historical data, provided that sufficient regularization and constraints are used to capture uncertainty. Availability of an accurate and explainable ensemble forecast model can increase trust among stakeholders and the general public, thus bettering preparedness and response efforts during the COVID-19 pandemic.
Effectiveness of Sotrovimab and Molnupiravir in community settings in England across the Omicron BA.1 and BA.2 sublineages: emulated target trials using the OpenSAFELY platform
Authors:   The OpenSAFELY collaborative, Tazare John , Nab Linda , Zheng Bang , Hulme William J , Green Amelia C A , Curtis Helen J , Mahalingasivam Viyaasan , Higgins Rose , Schultze Anna , Bhaskaran Krishnan , Mehrkar Amir , Schaffer Andrea , Smith Rebecca M , Bates Christopher , Cockburn Jonathan , Parry John , Hester Frank , Harper Sam , Eggo Rosalind M , Walker Alex J , Marks Michael , Brown Mike , Maringe Camille , Leyrat Clémence , Evans Stephen J W , Goldacre Ben , MacKenna Brian , Sterne Jonathan A C , Tomlinson Laurie A , Douglas Ian J 
Published: May 2023

AbstractBackgroundThe effectiveness of COVID-19 monoclonal antibody and antiviral therapies against severe COVID-19 outcomes is unclear. Initial benefit was shown in unvaccinated patients and before the Omicron variant emerged. We used the OpenSAFELY platform to emulate target trials to estimate the effectiveness of sotrovimab or molnupiravir, versus no treatment.MethodsWith the approval of NHS England, we derived population-based cohorts of non-hospitalised high-risk individuals in England testing positive for SARS-CoV-2 during periods of dominance of the BA.1 (16/12/2021-10/02/2022) and BA.2 (11/02/2022-21/05/2022) Omicron sublineages. We used the clone-censor-weight approach to estimate the effect of treatment with sotrovimab or molnupiravir initiated within 5 days after positive test versus no treatment. Hazard ratios (HR) for COVID-19 hospitalisation or death within 28 days were estimated using weighted Cox models.ResultsOf the 35,856 [BA.1 period] and 39,192 [BA.2 period] patients, 1,830 [BA.1] and 1,242 [BA.2] were treated with molnupiravir and 2,244 [BA.1] and 4,164 [BA.2] with sotrovimab. The estimated HRs for molnupiravir versus untreated were 1.00 (95%CI: 0.81;1.22) [BA.1] and 1.22 (0.96;1.56) [BA.2]; corresponding HRs for sotrovimab versus untreated were 0.76 (0.66;0.89) [BA.1] and 0.92 (0.79;1.06) [BA.2].InterpretationCompared with no treatment, sotrovimab was associated with reduced risk of adverse outcomes after COVID-19 in the BA.1 period, but there was weaker evidence of benefit in the BA2 period. Molnupiravir was not associated with reduced risk in either period.FundingUKRI, Wellcome Trust, MRC, NIHR and HDRUK.
DERIVED-BAND AUDITORY BRAINSTEM RESPONSES: COCHLEAR CONTRIBUTIONS DETERMINED BY NARROWBAND MASKERS
Authors: Stapells David R. , Fok Maxine R. 
Published: May 2023

AbstractObjectiveThe present study sought to determine the cochlear frequency regions represented by Audtory Brainstem Responses (ABRs) obtained using the high-pass noise/derived response (HP/DR) technique.DesignBroadband noise sufficient to mask the ABR to 50 dB nHL clicks was HP filtered (96 dB/oct) at 8000, 4000, 2000, 1000 and 500 Hz. Mixed with the clicks and high-pass noise masker was narrowband noise. Three DR bands, denoted by the upper and lower high-pass noise frequencies, were obtained: DR4000-2000, DR2000-1000, and DR1000-500.Study sampleTen adults with normal hearing, aged 19-27 years (mean age: 22.4 years), were recruited from the community.ResultsFrequencies contributing to each DR were determined from the wave V percent amplitude (or latency shift) vs narrowband masker frequency profiles (relative to a no-narrowband-noise condition). Overall, results indicate derived band center frequencies were closer to the lower HP cutoff frequencies for DR4000-2000 and DR2000-1000, and approximately halfway between the lower HP cutoff and the geometric mean of the two HP frequencies for DR1000-500, with bandwidths of 0.5-1 octave in width.ConclusionsThese results confirm the validity of the HP/DR technique for assessing narrow cochlear regions (≤1.0 octave wide), with center frequencies within ½-octave of the lower HP cutoff frequency.
Pulmonary Vascular Disease in Veterans with Post-Deployment Respiratory Syndrome
Authors: Gutor Sergey S. , Richmond Bradley W. , Agrawal Vineet , Brittain Evan L. , Mart Matthew F. , Shaver Ciara M. , Wu Pingsheng , Boyle Taryn K. , Mallugari Ravinder R. , Douglas Katrina , Piana Robert N. , Johnson Joyce E. , Miller Robert F. , Newman John H. , Blackwell Timothy S. , Polosukhin Vasiliy V. 
Published: May 2023

AbstractBackgroundIncreased frequency of exertional dyspnea has been documented in U.S. military personnel after deployment to Southwest Asia and Afghanistan. We studied whether continued exertional dyspnea in this patient population is associated with pulmonary vascular disease (PVD).MethodsWe recruited five Iraq and Afghanistan Veterans with post-deployment respiratory syndrome (PDRS) and continued exertional dyspnea to undergo a detailed clinical evaluation including symptom questionnaire, pulmonary function testing (PFT), surface echocardiography, and right heart catheterization (RHC) with exercise. We then performed detailed histomorphometry of blood vasculature in 52 Veterans with PDRS, 13 patients with advanced idiopathic pulmonary arterial hypertension (PAH) and 15 non-diseased (ND) control subjects.ResultsAll five Veterans involved in clinical follow-up study had a continued dyspnea at exertion. On transthoracic echocardiography, we identified borderline or overt RV enlargement in three out of five Veterans. Right ventricle outflow tract (RVOT) acceleration time, a well-established surrogate measure of pulmonary pressure, was mildly reduced in three out of five Veterans. Of the five Veterans with PDRS who underwent RHC at exercise, we found that three had evidence of post-capillary PH at rest and one had PH at exercise. Morphometric evaluation of lung biopsy samples showed mild/moderate increase of fractional thicknesses of intima and media, and significant fibrosis of adventitia in pulmonary arteries in Veterans with PDRS compared to ND controls and PAH patients. Veterans with PDRS did not display plexiform or dilation/angiomatoid lesions, specific for PAH. Pulmonary veins showed similar levels of intima and adventitia fractional thickening in Veterans with PDRS and PAH patients compared to ND controls. In Veterans, IA veins were characterized by marked fibrous intima and adventitia thickening, usually with increased thickening and formation of multiple layers of elastic laminae, but without features of luminal occlusion, muscular hyperplasia or dilation/angiomatoid lesions seen in pulmonary veno-occlusive disease or chronic thromboembolic PH.ConclusionsOur studies suggest that vasculopathy and PVD may explain exertional dyspnea and exercise limitation in some Veterans with PDRS. Evaluation for PVD should be considered in Iraq and Afghanistan Veterans with unexplained dyspnea.
Metabolic syndrome and hemorrhagic stroke among symptomatic CCMs in the Mexican Hispanic Population
Authors: Dwivedi Alok K. , Jang David , Belkin Ofek , Aickareth Justin , Renteria Mellisa , Hawwar Majd , Jacob Croft , Kalas M Ammar , Zuckerman Marc J. , Zhang Jun 
Published: May 2023

ABSTRACTCerebral cavernous malformations (CCMs) are neurological disorders that make individuals more susceptible to hemorrhagic stroke. The Mexican-Hispanic population has a higher prevalence of both CCMs and metabolic syndrome (MetS), which is also associated with hemorrhagic stroke. A study was conducted with 184 Mexican-Hispanic CCM subjects and age- and sex-matched Hispanic and non-Hispanic white controls. The CCM cohort had a higher proportion of epilepsy and hemorrhagic stroke but a lower proportion of MetS. Higher blood pressure and fasting glucose levels were observed in the CCM cohort. MetS and epilepsy were associated with increased odds of hemorrhagic stroke among elderly CCM patients, and increased systolic blood pressure was significantly linked to increased odds of hemorrhagic stroke in the CCM cohort. To minimize the risk of hemorrhagic stroke, it is important to manage blood pressure and comorbidities like MetS and epilepsy in CCM patients, particularly those older than 50.SUMMARUYWhat is already known about this subjectMetabolic Syndrome (MetS) is widely associated with cardiovascular conditions, including stroke,The association between MetS and ischemic stroke is well establishedThe relationship between MetS and hemorrhagic stroke remains unclearCurrently, one two studies explored the relationship between MetS and hemorrhagic stroke in CCM patients; one n sporadic CCM (sCCM) and one in familial CCM cases, with inconsistent results.What are the new findingsIn this study, a strong association was observed between systolic blood pressure (SBP) and hemorrhagic stroke in the CCM cohort, independent of obesity or fasting glucose levels.This study also suggests that MetS is associated with hemorrhagic stroke among CCM patients, specifically in the older age group.How might it impact on clinical practice in the foreseeable futureThis study demonstrates many of the unique characteristics of symptomatic CCMs within the Mexican-Hispanic populationOur results suggests that of Mexican-Hispanic CCM subjects are at a greater risk for hemorrhagic stroke and epilepsy than other ethnic groups.This study highlights the importance of reducing blood pressure and managing comorbidities such as MetS and epilepsy in CCM patients, especially those who are older than 50 years to minimize the risk of hemorrhagic stroke among CCM subjects
Deep-learning quantified cell-type-specific nuclear morphology predicts genomic instability and prognosis in multiple cancer types
Authors: Abel John , Jain Suyog , Rajan Deepta , Padigela Harshith , Leidal Kenneth , Prakash Aaditya , Conway Jake , Nercessian Michael , Kirkup Christian , Javed Syed Ashar , Biju Raymond , Harguindeguy Natalia , Shenker Daniel , Indorf Nicholas , Sanghavi Darpan , Egger Robert , Trotter Benjamin , Gerardin Ylaine , Brosnan-Cashman Jacqueline A. , Dhoot Aditya , Montalto Michael C. , Parmar Chintan , Wapinski Ilan , Khosla Archit , Drage Michael G. , Yu Limin , Taylor-Weiner Amaro 
Published: May 2023

ABSTRACTWhile alterations in nucleus size, shape, and color are ubiquitous in cancer, comprehensive quantification of nuclear morphology across a whole-slide histologic image remains a challenge. Here, we describe the development of a pan-tissue, deep learning-based digital pathology pipeline for exhaustive nucleus detection, segmentation, and classification and the utility of this pipeline for nuclear morphologic biomarker discovery. Manually-collected nucleus annotations were used to train an object detection and segmentation model for identifying nuclei, which was deployed to segment nuclei in H&E-stained slides from the BRCA, LUAD, and PRAD TCGA cohorts. Interpretable features describing the shape, size, color, and texture of each nucleus were extracted from segmented nuclei and compared to measurements of genomic instability, gene expression, and prognosis. The nuclear segmentation and classification model trained herein performed comparably to previously reported models. Features extracted from the model revealed differences sufficient to distinguish between BRCA, LUAD, and PRAD. Furthermore, cancer cell nuclear area was associated with increased aneuploidy score and homologous recombination deficiency. In BRCA, increased fibroblast nuclear area was indicative of poor progression-free and overall survival and was associated with gene expression signatures related to extracellular matrix remodeling and anti-tumor immunity. Thus, we developed a powerful pan-tissue approach for nucleus segmentation and featurization, enabling the construction of predictive models and the identification of features linking nuclear morphology with clinically-relevant prognostic biomarkers across multiple cancer types.
A Virus-like particle-based bivalent PCSK9 vaccine lowers LDL-cholesterol levels in Non-Human Primates
Authors: Fowler Alexandra , Van Rompay Koen K. A. , Sampson Maureen , Leo Javier , Watanabe Jennifer K. , Usachenko Jodie L. , Immareddy Ramya , Lovato Debbie M. , Schiller John T. , Remaley Alan T. , Chackerian Bryce 
Published: May 2023

AbstractElevated low-density lipoprotein cholesterol (LDL-C) is an important risk factor in the development of atherosclerotic cardiovascular disease (ASCVD). Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of LDL-C metabolism, have emerged as promising approaches for reducing elevated LDL-C levels. Here, we evaluated the cholesterol lowering efficacy of virus-like particle (VLP) based vaccines that target epitopes found within the LDL receptor (LDL-R) binding domain of PCSK9. In both mice and non-human primates, a bivalent VLP vaccine targeting two distinct epitopes on PCSK9 elicited strong and durable antibody responses and lowered cholesterol levels. In macaques, a VLP vaccine targeting a single PCSK9 epitope was only effective at lowering LDL-C levels in combination with statins, whereas immunization with the bivalent vaccine lowered LDL-C without requiring statin co-administration. These data highlight the efficacy of an alternative, vaccine-based approach for lowering LDL-C.
Generalizing Stepping Concepts To Non-Straight Walking
Authors: Dingwell Jonathan B. , Render Anna C. , Desmet David M. , Cusumano Joseph P. 
Published: May 2023

AbstractPeople rarely walk in straight lines. Instead, we make frequent turns or other maneuvers. Spatiotemporal parameters fundamentally characterize gait. For straight walking, these parameters are well-defined for that task of walking on a straightpath. Generalizing these concepts tonon-straight walking, however, is not straightforward. People also follow non-straight paths imposed by their environment (store aisle, sidewalk, etc.) or choose readily-predictable, stereotypical paths of their own. People actively maintain lateral position to stay on their path and readily adapt their stepping when their path changes. We therefore propose a conceptually coherent convention that defines step lengths and widths relative to known walking paths. Our convention simply re-aligns lab-based coordinates to be tangent to a walker’s path at the mid-point between the two footsteps that define each step. We hypothesized this would yield results both morecorrectand more consistent with notions from straight walking. We defined several common non-straight walking tasks: single turns, lateral lane changes, walking on circular paths, and walking on arbitrary curvilinear paths. For each, we simulated idealized step sequences denoting “perfect” performance with known constant step lengths and widths. We compared results to path-independent alternatives. For each, we directly quantified accuracy relative to knowntruevalues. Results strongly confirmed our hypothesis. Our convention returned vastly smaller errors and introducednoartificial stepping asymmetries across all tasks. All results for our convention rationally generalized concepts from straight walking. Taking walking paths explicitly into account as important task goals themselves thus resolves conceptual ambiguities of prior approaches.
A new antibiotic from an uncultured bacterium binds to an immutable target
Authors: Shukla Rhythm , Peoples Aaron J. , Ludwig Kevin C. , Maity Sourav , Derks Maik G.N. , de Benedetti Stefania , Krueger Annika M , Vermeulen Bram J.A. , Lavore Francesca , Honorato Rodrigo V. , Grein Fabian , Bonvin Alexandre , Kubitscheck Ulrich , Breukink Eefjan , Achorn Catherine , Nitti Anthony , Schwalen Christopher J. , Spoering Amy L. , Ling Losee Lucy , Hughes Dallas , Lelli Moreno , Roos Wouter H. , Lewis Kim , Schneider Tanja , Weingarth Markus 
Published: May 2023

SummaryAntimicrobial resistance is a leading mortality factor worldwide. Here we report the discovery of clovibactin, a new antibiotic, isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant bacterial pathogens without detectable resistance. Using biochemical assays, solid-state NMR, and atomic force microscopy, we dissect its mode of action. Clovibactin blocks cell wall synthesis by targeting pyrophosphate of multiple essential peptidoglycan precursors (C55PP, Lipid II, LipidWTA). Clovibactin uses an unusual hydrophobic interface to tightly wrap around pyrophosphate, but bypasses the variable structural elements of precursors, accounting for the lack of resistance. Selective and efficient target binding is achieved by the irreversible sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups. Uncultured bacteria offer a rich reservoir of antibiotics with new mechanisms of action that could replenish the antimicrobial discovery pipeline.
Differentiating Agonists and Competitive Antagonists of the Serotonin Type 3A (5-HT3A) Receptor
Authors: Davolio Anthony J. , Jankowski W.J. , Várnai Csilla , Irwin B.W.J. , Payne M.C. , Chau P.-L. 
Published: May 2023

AbstractWhat makes an agonist and a competitive antagonist? In this work, we aim to answer this question by performing parallel tempering Monte Carlo simulations on the serotonin type 3A (5-HT3A) receptor. We use linear response theory to predict conformational changes in the 5-HT3Areceptor active site after applying weak perturbations to its allosteric binding sites. A covariance tensor is built from conformational sampling of its apo state, and a harmonic approximation allows us to substitute the calculation of ligand-induced forces with the binding site’s displacement vector. We show that it is possible to differentiate between agonists and competitive antagonists for multiple ligands while running computationally expensive calculations only once for the protein.