bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantifying absolute treatment effect heterogeneity for time-to-event outcomes across different risk strata: divergence of conclusions with risk difference and restricted mean survival difference
Authors: Maas Carolien C.H.M. , Kent David M. , Dinmohamed Avinash G. , van Klaveren David 
Published: December 2024

AbstractBackgroundRisk-based analyses are increasingly popular for understanding heterogeneous treatment effects (HTE) in clinical trials. For time-to-event analyses, the assumption that high-risk patients benefit most on the clinically important absolute scale when hazard ratios (HRs) are constant across risk strata might not hold. Absolute treatment effects can be measured as either the risk difference (RD) at a given time point or the difference in restricted mean survival time (ΔRMST) which aligns more closely with utilitarian medical decision-making frameworks. We examined risk-based HTE analyses strata in time-to-event analyses to identify the patterns of absolute HTE across risk strata, and whether ΔRMST may lead to more meaningful treatment decisions than RD.MethodsUsing artificial and empirical time-to-event data, we compared RD—the difference between Kaplan-Meier estimates at a certain time point—and ΔRMST—the area between the Kaplan-Meier curves—across risk strata and show how these metrics can prioritize different subgroups for treatment. We explored scenarios involving constant HRs while varying both the overall event rates and the discrimination of the risk models.ResultsWhen event rates and discrimination were low, RD and ΔRMST increased monotonically, with high-risk patients benefitting more than low-risk patients. As the event rate increased and/or discrimination increased: 1) a “sweet spot” pattern emerged: intermediate-risk patients benefit more than low-risk and high-risk patients; and 2) RD understates the benefit in high-risk patients.ConclusionsThe pattern of HTE characterized by RD may diverge substantially from ΔRMST, potentially leading to treatment mistargeting. Therefore, we recommend ΔRMST for assessing absolute HTE in time-to-event data.Key messagesTo quantify absolute heterogeneous treatment effect (HTE) in time-to-event data, the difference in restricted mean survival time (ΔRMST) is more intuitive and comprehensive, less dependent on the time horizon, and better captures HTE when the hazard ratio (HR) of treatment varies over time, compared to the risk difference (RD).We examined risk-based HTE analyses in time-to-event analyses to identify the patterns of absolute HTE across different risk strata, and whether ΔRMST may lead to more meaningful treatment decisions than RD.Even with a constant HR, intermediate-risk patients may benefit more than low-risk and high-risk patients as event rates increase, a phenomenon known as a “sweet spot” pattern.The RD does not accurately reflect the benefit for high-risk patients when event rates and/or discrimination of the risk model are high, unlike to the ΔRMST.We recommend the ΔRMST for assessing absolute HTE, as the RD may potentially lead to treatment mistargeting.
Bayesian Feature Selection for Multi-valued Treatment Comparisons: An Electronic Health Records Study of Vasopressor Effectiveness
Authors: Qian Yunzhe , Ma Bowen 
Published: December 2024

AbstractAnalyzing treatment effectiveness from electronic health records (EHR) presents unique challenges in causal inference, particularly when comparing multiple treatment options with high-dimensional covariates. We propose a novel framework combining instrumental variable (IV) analysis with advanced Bayesian feature selection methods and neural networks to estimate causal effects in multi-valued treatment settings. Our approach addresses three key methodological challenges: handling multiple treatment comparisons simultaneously, comparing Bayesian feature selection methods, and selecting relevant features while capturing complex nonlinear relationships in outcome models.Through extensive simulation studies, we demonstrate that spike-and-slab priors achieve superior performance in treatment effect estimation with the lowest mean absolute bias (0.071) compared to ALL (0.074), LASSO (0.080), and Bayesian LASSO (0.083) methods. The consistency of bias control across treatment pairs demonstrates the robustness of our Bayesian feature selection approach, particularly in identifying clinically relevant predictors.We apply this framework to compare three commonly used vasopressors (norepinephrine, vasopressin, and phenylephrine) using MIMIC-IV data[1]. Using physician prescribing preferences as instruments[2, 3, 4], our analysis reveals a clear hierarchical pattern in treatment effectiveness. Vasopressin demonstrated superior effectiveness compared to both norepinephrine (ATE = 0.134, 95% CI [0.115, 0.152]) and phenylephrine (ATE = 0.173, 95% CI [0.156, 0.191]), while phenylephrine showed inferior outcomes compared to norepinephrine (ATE = -0.040, 95% CI [-0.048, -0.031]).Our methodological framework provides a robust approach for analyzing multi-valued treatments in high-dimensional observational data, with broad applications beyond vessopressors in critical care. The integration of instrumental variable analysis, Bayesian feature selection, and advanced modeling techniques offers a promising direction for using EHR data to inform treatment decisions while addressing key challenges in causal inference.
«The LAMP-CRISPR-Cas13a technique for detecting CBASS-mechanism of phage resistance in bacteria»
Authors: Ortiz-Cartagena Concha , Fernández-Grela Patricia , Armán Lucia , Ibarguren Clara , Blasco Lucía , Pablo-Marcos Daniel , Bleriot Inés , Fernández-García Laura , Fernández Cuenca Felipe , Barrio-Pujante Antonio , Aracil Belén , Tomás María 
Published: December 2024

ABSTRACTAntimicrobial resistance (AMR) is an important threat to public health that has led to the development of innovative alternative treatments for bacterial infections, such as phage therapy. However, one of the greatest disadvantages of phage therapy is the generation of phage-resistant bacterial mutants via bacterial defence mechanisms, which are mainly contained in genomic islands (GIs) and controlled by the quorum sensing (QS) network. In this study, 309 pathogenic islands (PAIs) harbouring a total of 22.1 % of proteins related to anti-phage defence (APD) were detected in the genome of 48 K. pneumoniae strains. Several type I and type II CBASS systems were also detected in the genome of the 48 K. pneumoniae strains, but only 2 type II CBASS systems were located in PAIs. We constructed a knockout K. pneumoniae strain, not expressing the cyclase gene from the type II CBASS system present in PAIs, to study the regulatory role of QS in expressing the gene. As the anti-phage CBASS system is an abortive infection (Abi) system, the role of the type II CBASS system in regulating cell viability was assessed. The knockout strain was confirmed by targeting the LAMP-CRISPR-Cas13a technique specifically to the cyclase gene, and the same protocol was also used to detect the gene of the main cyclase in these type I CBASS systems, i.e. APECO1. The study findings demonstrate the regulatory role of the QS network in anti-phage defence systems.Finally, this is the first work which development an innovative biotechnological application for the LAMP-CRISPR-Cas13a rapid-technique (<2 hours) in optimizing phage therapy by detecting bacterial resistance mechanisms, by predicting the potential inefficacy of a therapeutic phage and thus improving patient prognosis.
Development of Learning Objectives for Non-Major Introductory Biology Using a Delphi Method
Authors: Brickman Peggy , Gormally Cara 
Published: December 2024

AbstractBiology faculty have consensus-based guidelines based on Vision and Change principles about what to teach introductory biology majors. In contrast, faculty have not reached a consensus concerning the learning goals for introductory non-majors courses. Yet, more than 8 out of 10 undergraduates are not science majors. The goal of this study was to develop and evaluate learning objectives for non-majors introductory biology courses. We performed a modified-Delphi study of learning objectives (LOs) for non-majors biology. We engaged a total of 38 biology faculty experts from institutions across the US in three iterative rounds to identify, rate, discuss, and re-rate >300 LOs for non-majors biology courses. Faculty provided feedback to determine whether the LOs are critical for students to learn and if the LOs encompass what students need to learn about this issue, as well as if anything is missing. As a result of expert evaluation, 60.7% of LOs (164) were deemed critical. Experts also suggested 22 additional new LOs.
Sex differences in frailty and the impact of frailty on blood pressure control in older adults with hypertension: a multi-center observational study in Vietnam
Authors: Nguyen Tan Van , Nguyen Vien Thi , Wong Wei Jin , Amsalu Erkihun , Ngo Trinh Kim Thi , Woodward Mark , Nguyen Tu Ngoc 
Published: December 2024

AbstractBackgroundFrailty is common in older adults with hypertension and can affect blood pressure (BP) control. Sex differences related to frailty and cardiovascular physiology may contribute to the effective treatment of hypertension.Aimto examine the prevalence of frailty in older adults with hypertension and its association with uncontrolled BP, with a particular focus on differences by sex.MethodsThis study was conducted at the outpatient clinics of two major hospitals in Vietnam from June 2023 to June 2024. Frailty was defined by a Clinical Frailty Scale of ≥4. Uncontrolled BP was defined as systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, averaged over recordings in the last 6 months. Multivariable logistic regression was applied to identify the association between frailty and uncontrolled BP. The odds ratios (ORs) for uncontrolled BP of each risk factor were estimated by sex, with interaction terms fitted between each risk factor and sex to obtain the women-to-men ratio of ORs (ROR).ResultsThere were 1038 participants (326 women, 712 men). They had a mean age of 73.3 (SD7.4). The prevalence of frailty was 28.6% in all participants, higher in women (35.3%) than men (25.6%), p=0.001. The overall rate of uncontrolled BP was 26.7%. In women, the frail had a significantly higher rate of uncontrolled BP (33.9%) compared to the non-frail (20.9%), but no significant differences among men (26.4% in the frail vs. 27.5% in the non-frail). The adjusted ORs of frailty on uncontrolled BP were 1.70 (1.00–2.90) in women, 0.84 (0.57–1.25) in men; women-to-men ROR 2.02 (1.04–3.92).ConclusionIn older adults with hypertension, frailty was more common in women and was associated with an increased risk of having uncontrolled BP in women only. These findings highlight the need for sex-specific approaches in managing hypertension in older populations.
Evaluation of Large Language Models in Thailand’s National Medical Licensing Examination
Authors: Saowaprut Prut , Rodis Wabina Romen Samuel , Yang Junwei , Siriwat Lertboon 
Published: December 2024

AbstractAdvanced general-purpose Large Language Models (LLMs), including OpenAI’s Chat Generative Pre-trained Transformer (ChatGPT), Google’s Gemini and Anthropic’s Claude, have demonstrated capabilities in answering clinical questions, including those with image inputs. The Thai National Medical Licensing Examination (ThaiNLE) lacks publicly accessible specialist-confirmed study materials. This study aims to evaluate whether LLMs can accurately answer Step 1 of the ThaiNLE, a test similar to Step 1 of the United States Medical Licensing Examination (USMLE). We utilized a mock examination dataset comprising 300 multiple-choice questions, 10.2% of which included images. LLMs capable of processing both image and text data were used, namely GPT-4, Claude 3 Opus and Gemini 1.0 Pro. Five runs of each model were conducted through their application programming interface (API), with the performance assessed based on mean accuracy. Our findings indicate that all tested models surpassed the passing score, with the top performers achieving scores more than two standard deviations above the national average. Notably, the highest-scoring model achieved an accuracy of 88.9%. The models demonstrated robust performance across all topics, with consistent accuracy in both text-only and image-enhanced questions. However, while the LLMs showed strong proficiency in handling visual information, their performance on text-only questions was slightly superior. This study underscores the potential of LLMs in medical education, particularly in accurately interpreting and responding to a diverse array of exam questions.
Anthelmintic resistance against benzimidazoles and macrocyclic lactones in strongyle populations on cattle farms in northern Germany
Authors: Ehnert Paula , Krücken Jürgen , Fiedler Stefan , Horn Fabian , Helm Christina S. , Neubert Ann , Weiher Wiebke , Terhalle Werner , Steuber Stephan , Daher Ricarda , von Samson-Himmelstjerna Georg 
Published: December 2024

AbstractAnthelmintic resistance (AR) in cattle gastrointestinal nematodes (GIN) is an increasing global concern, with low to moderate levels recently documented in Central Europe. This study reports on resistance against both macrocyclic lactones (MLs) and benzimidazoles (BZs), highlighting that AR is spreading. The Fecal Egg Count Reduction Test (FECRT) remains the primary tool for AR assessment, yet differing methodologies and recent guideline updates complicate resistance interpretation across studies. Statistical methods, such as Bayesian approaches used by eggCounts and bayescount, yield varying confidence intervals, further influencing results. Notably, the nemabiome analysis identifiedOstertagia ostertagiandCooperia oncophoraas predominant species in the region, though unexpected diversity among farms with additional GIN species occurring sometimes even at high frequency, suggests morphological analysis of coprocultures may underestimate species prevalence. Detecting AR against both drug classes on some farms underscores the urgency of implementing sustainable strategies, such as targeted selective treatment and combinations of anthelmintics with different mode of action, to prevent scenarios of multi-drug resistance observed elsewhere. Effective resistance management requires immediate discussions with veterinarians and stakeholders to steer toward informed, preventive measures in cattle farming.
QUANTIFYING ACYL CHAIN INTERDIGITATION IN SIMULATED BILAYERS VIA DIRECT TRANSBILAYER INTERACTIONS
Authors: Chaisson Emily H. , Heberle Frederick A. , Doktorova Milka 
Published: December 2024

ABSTRACTIn a lipid bilayer, the interactions between lipid hydrocarbon chains from opposing leaflets can influence membrane properties. These interactions include the phenomenon of interdigitation, in which an acyl chain of one leaflet extends past the bilayer midplane and into the opposing leaflet. While static interdigitation is well understood in gel phase bilayers from X-ray diffraction measurements, much less is known about dynamic interdigitation in fluid phases. In this regard, atomistic molecular dynamics simulations can provide mechanistic information on interleaflet interactions that can be used to generate experimentally testable hypotheses. To address limitations of existing computational methodologies which provide results that are either indirect or averaged over time and space, here we introduce three novel ways of quantifying the extent of chain interdigitation. Our protocols include the analysis of instantaneous interactions at the level of individual carbon atoms, thus providing temporal and spatial resolution for a more nuanced picture of dynamic interdigitation. We compare the methods on bilayers composed of lipids with equal total number of carbon atoms but different mismatches between the sn-1 and sn-2 chain lengths. We find that these metrics, which use freely available software packages and are easy to implement, provide complementary details that help characterize various features of lipid-lipid contacts at the bilayer midplane. The new frameworks thus allow for a deeper look at fundamental molecular mechanisms underlying bilayer structure and dynamics, and present a valuable expansion of the membrane biophysics toolkit.
Test-retest reliability of TMS-evoked potentials over fMRI-based definitions of non-motor cortical targets
Authors: Sayalı Ceyda , Gogulski Juha , Granö Ida , Lioumis Pantelis , Barrett Frederick S. 
Published: December 2024

AbstractObjectiveThis study assessed the test-retest reliability of TMS-evoked potentials (TEPs) across two cortical regions—dorsolateral prefrontal cortex (DLPFC), and angular gyrus— in comparison to motor cortex (M1), using individualized and literature-based targeting approaches. The study compared the reliability of single-pulse TMS, short-interval intracortical inhibition (SICI), and long-interval intracortical inhibition (LICI) protocols to evaluate TEP consistency in these regions.MethodsSeventeen healthy participants underwent two TMS-EEG sessions spaced by at least one week, with targets for DLPFC and angular gyrus identified using resting-state functional connectivity (RS) and Neurosynth-based functional overlays. Motor cortex was targeted using resting motor threshold (RMT). Early TEPs were quantified as peak-to-peak amplitude, in dBμV. Test-retest reliability of early TEPs was calculated using the concordance correlation coefficient (CCC) for each region and protocol.ResultsM1 demonstrated the highest TEP reliability (CCCmean = 0.59), while DLPFC (CCCmean = 0.40) and angular gyrus (CCCmean = 0.45) showed lower reliability, particularly for anterior DLPFC targets. Neurosynth-based DLPFC targets exhibited slightly higher CCC values (mean CCC = 0.57) compared to RS-based targets (mean CCC = 0.30), but the difference was not statistically significant. No significant differences in reliability were found across single pulse and paired pulse protocols. Lateral targets, DLPFC and angular gyrus, showed lower reliability in comparison to motor cortex which might have been caused by muscle artifacts.ConclusionWhile individualized functional targeting methods provide advantages in engaging specific brain networks, their reliability for TEP measurements remains lower than the RMT-based approach for motor cortex. Future studies should integrate neuroimaging-based targeting with real-time TEP monitoring to enhance reliability in non-motor regions. This approach could enhance the precision of TMS-EEG protocols, especially for clinical applications targeting cortical regions like the DLPFC and angular gyrus.
Implicit modeling of the conformational landscape and sequence allows scoring and generation of stable proteins
Authors: Cho Yehlin , Dauparas Justas , Tsuboyama Kotaro , Rocklin Gabriel , Ovchinnikov Sergey 
Published: December 2024

ABSTRACTGenerative protein modeling provides advanced tools for designing diverse protein sequences and structures. However, accurately modeling the conformational landscape and designing sequences—ensuring that the designed sequence folds into the target structure as its most stable structure—remains a critical challenge. In this study, we present a systematic analysis of jointly optimizingP(structure|sequence) andP(sequence|structure), which enables us to find optimal solutions for modeling the conformational landscape. We support this approach with experimental evidence that joint optimization is superior for (1) designing stable proteins using a joint model (TrROS (TrRosetta) and TrMRF) (2) achieving high accuracy in stability prediction when jointly modeling (half-masked ESMFold pLDDT+ ESM2 Pseudo-likelihood). We further investigate features of sequences generated from the joint model and find that they exhibit higher frequencies of hydrophilic interactions, which may help maintain both secondary structure registry and pairing.
Asymmetries in foveal vision
Authors: Jenks Samantha K. , Carrasco Marisa , Poletti Martina 
Published: December 2024

AbstractVisual perception is characterized by known asymmetries in the visual field; human’s visual sensitivity is higher along the horizontal than the vertical meridian, and along the lower than the upper vertical meridian. These asymmetries decrease with decreasing eccentricity from the periphery to the center of gaze, suggesting that they may be absent in the 1-deg foveola, the retinal region used to explore scenes at high-resolution. Using high-precision eyetracking and gaze-contingent display, allowing for accurate control over the stimulated foveolar location despite the continuous eye motion at fixation, we investigated fine visual discrimination at different isoeccentric locations across the foveola and parafovea. Although the tested foveolar locations were only 0.3 deg away from the center of gaze, we show that, similar to more eccentric locations, humans are more sensitive to stimuli presented along the horizontal than the vertical meridian. Whereas the magnitude of this asymmetry is reduced in the foveola, the magnitude of the vertical meridian asymmetry is comparable but, interestingly, reversed: objects presented slightly above the center of gaze are more easily discerned than when presented at the same eccentricity below the center of gaze. Therefore, far from being uniform, as often assumed, foveolar vision is characterized by perceptual asymmetries. Further, these asymmetries differ not only in magnitude but also in direction compared to those present just ∼4deg away from the center of gaze, resulting in overall different foveal and extrafoveal perceptual fields.
Distinct Classes of Lamin-Associated Domains are Defined by Differential Patterns of Repressive Histone Methylation
Authors: Martin Caden J. , Nagarajan Prabakaran , Oser Elizabeth A. , Popova Liudmila V. , Parthun Mark R. 
Published: December 2024

AbstractA large fraction of the genome interacts with the nuclear periphery through lamina-associated domains (LADs), repressive regions which play an important role in genome organization and gene regulation across development. Despite much work, LAD structure and regulation are not fully understood, and a mounting number of studies have identified numerous genetic and epigenetic differences within LADs, demonstrating they are not a uniform group. Here we profile Lamin B1, HP1β, H3K9me3, H3K9me2, H3K27me3, H3K14ac, H3K27ac, and H3K9ac in MEF cell lines derived from the same mouse colony and cluster LADs based on the abundance and distribution of these features across LADs. We find that LADs fall into 3 groups, each enriched in a unique set of histone modifications and genomic features. Each group is defined by a different heterochromatin modification (H3K9me3, H3K9me2, or H3K27me3), suggesting that all three of these marks play important roles in regulation of LAD chromatin and potentially of lamina association. We also discover unique features of LAD borders, including a LAD border-specific enrichment of H3K14ac. These results reveal important distinctions between LADs and highlight the rich diversity and complexity in LAD structure and regulatory mechanisms.