bluuebunny/crossref_metadata_2025_split huggingface dataset:
Which outcomes should be included in a core outcome set for capturing and measuring doctor well-being? A Delphi study
Authors: Simons Gemma , Klepacz Naomi , Baldwin David S. 
Published: April 2024

ABSTRACTObjectivesTo develop a core outcome set (COS) to capture and measure the well-being of doctors working in the NHS.DesignAn online Delphi study.SettingUnited Kingdom National Health Service.ParticipantsParticipants from four stakeholder groups: i) those who might use the COS in research, ii) organisations that measure/capture NHS staff wellbeing, iii) professionals with experience managing NHS staff wellbeing, and iv) NHS doctors, were identified through authorship of relevant publications, attendee lists of doctor well-being conferences and meetings, professional bodies, participation in a previous study and recommendations from others. They were recruited via email.MethodA two-stage process: 1) creating a list of 43 wellbeing outcomes informed by a systematic review of wellbeing measurement instruments, a survey of UK doctors and 2 doctor engagement workshops, and 2) an online modified Delphi study (with two rounds) to reach consensus. Outcomes were rated on a 9-point Likert scale; ‘consensus’ was reached when<75% agreed that an outcome was critical for inclusion in the COS.ResultsFifty-two participants completed both Delphi rounds. Seven wellbeing outcomes met the threshold for inclusion in the COS: General wellbeing, Health, Personal safety, Job satisfaction, Morale, Life work balance, and Good clinical practice.ConclusionUse of the COS has the potential to reduce heterogeneity and standardise the capture and measurement of doctor well-being and ensure outcomes important to all stakeholders are reported.Trial registrationThis study was prospectively registered with the COMET initiativewww.comet-initiative.org(Registration: 1577)
CSF proteomic analysis of semorinemab Ph2 trials in prodromal-to-mild (Tauriel) and mild-to-moderate (Lauriet) Alzheimer’s disease identifies distinct trial cell-type specific proteomic signatures
Authors: Abdel-Haleem Alyaa M. , Casavant Ellen , Toth Balazs , Teng Edmond , Monteiro Cecilia , Pandya Nikhil J. , Hoogenraad Casper C. , Friedman Brad A. , Yeh Felix L. , Anania Veronica G. , Novikova Gloriia 
Published: April 2024

AbstractTargeting of tau pathology has long been proposed as a potential therapeutic strategy for Alzheimer’s disease (AD). Semorinemab is a humanized IgG4 monoclonal antibody that binds to all known isoforms of full-length tau with high affinity and specificity. Semorinemab’s safety and efficacy have been studied in two Phase 2 randomized, double-blind, placebo-controlled, parallel-group clinical trials: Tauriel (prodromal-to-mild AD;NCT03289143) and Lauriet (mild-to-moderate AD;NCT03828747). CSF was collected from a subset of patients at baseline and after 49 or 73 weeks in Tauriel and baseline and after 49 or 61 weeks in Lauriet. We generated a large proteomics dataset, using more than 250 cerebrospinal fluid (CSF) samples and detecting more than 3500 proteins, to investigate the effects of semorinemab in each trial. Treatment-induced proteomic signatures were defined for each study as a set of proteins significantly elevated in the treatment arm in the respective study. Integration of the corresponding gene signatures with two independent brain single-nucleus RNA-seq datasets from AD and healthy aged controls revealed that Lauriet signature genes were enriched in microglial cells, while Tauriel signature genes were more broadly expressed across major brain cell types. Furthermore, the Lauriet trial gene signature was significantly upregulated in microglia from AD patients as compared to non-demented controls. The elevation of proteins such as CHI3L1 and GPNMB with treatment suggested an activated glial state. Taken together, this study utilizes a large CSF clinical proteomics dataset to assess the pharmacodynamic response of semorinemab and contributes to our understanding of how an anti-tau antibody influences disease-relevant pathophysiology in AD.
Propylene Oxide in Exhaled Breath as a Marker for Discriminating TMAU-like Conditions from TMAU
Authors: Gabashvili Irene S. 
Published: April 2024

AbstractVolatile Organic Compounds (VOCs) triggering respiratory irritation are implicated in conditions such as Trimethylaminuria (TMAU) and “people are allergic to me” (PATM) which occur in otherwise healthy individuals without clear syndromic associations. Despite the absence of established non-targeted non-challenge-based diagnostic procedures, recent studies have identified discriminatory VOCs associated with PATM using gas chromatography-mass spectrometry. Breath VOCs, originating from the bloodstream, hold promise for non-invasive diagnosis.We conducted breath analysis on 23 individuals exhibiting TMAU-like symptoms and identified a diverse array of volatile organic compounds (VOCs) that discriminate between different subgroups. Using logistic regression, we achieved an accuracy of 88%, with both precision and recall at 88-89%, in distinguishing TMAU-negative individuals from those who tested positive at some point in their lives, solely based on the presence of Propylene Oxide ((2R)-2-Methyloxirane and (2S)-2-Methyloxirane). However, due to the limited subset and missing data, it cannot serve as the sole discriminating biomarker. Inclusion of additional VOCs in the analysis increased accuracy of the model to 85-95%, with precision and recall ranging from 85% to 100%, depending on the combinations of VOCs used.Unsupervised learning algorithms generally grouped positively tested individuals together based on endogenous VOCs, while negatively tested individuals were clustered into two distinct groups. Toluene, previously found to be elevated in PATM individuals, was identified as a discriminatory marker for those previously diagnosed with TMAU, but had since tested negative while still experiencing symptoms. Other PATM biomarkers, such as p-Xylene and Hexanal, were generally higher in TMAU positive individuals and were good predictors of TMAU history when combined with other VOCs.Our analysis revealed that the TMAU-positive group exhibited a greater abundance of biomarkers indicative of advanced oxidative stress in their breath samples and primary oxidative stress in their air samples, likely originating from their skin. Conversely, the TMAU-negative group demonstrated a higher likelihood of biomarkers associated with secondary oxidative stress in their air samples.Our findings highlight the potential of breath analysis as a non-invasive diagnostic tool for idiopathic malodor conditions. They underscore the importance of analyzing exogenous chemicals for insights into metabolism, detoxification, and elimination of toxins. This approach could help eliminate unnecessary challenge tests and emphasize the role of metabolomics in understanding the mechanisms underlying these conditions.Trial registrationClinicalTrials.govNCT03451994;https://clinicaltrials.gov/study/NCT03451994Dataavailable athttps://osf.io/w7682via the Open Science Framework
Health-economic burden attributable to novel serotypes in candidate 24- and 31-valent pneumococcal conjugate vaccines
Authors: King Laura M , Lewnard Joseph A 
Published: April 2024

ABSTRACTBackgroundNext-generation pneumococcal vaccines currently in clinical trials include 24- and 31-valent pneumococcal conjugate vaccines (PCV24, PCV31), which aim to prevent upper-respiratory carriage and disease involving the targeted serotypes. We aimed to estimate the comprehensive health-economic burden associated with acute respiratory infections (ARIs) and invasive pneumococcal disease (IPD) attributable to PCV24- and PCV31-additional (non-PCV20) serotypes in the United States.MethodsWe multiplied all-cause incidence rate estimates for acute otitis media (AOM), sinusitis, and non-bacteremic pneumonia by estimates of the proportions of each of these conditions attributable to pneumococci and the proportions of pneumococcal infections involving PCV24- and PCV31-additional serotypes. We obtained serotype-specific IPD incidence rates from US Active Bacterial Core surveillance data. We accounted for direct medical and non-medical costs associated with each condition to estimate resulting health-economic burden. Non-medical costs included missed work and lost quality-adjusted life years due to death and disability.ResultsThe health-economic burden of PCV24-additional serotypes totaled $1.3 billion ($1.1-1.7b) annually in medical and non-medical costs, comprised of $0.9b ($0.7-1.2b) due to ARIs and $0.4b ($0.3-0.5b) due to IPD. For PCV31-additional serotypes, medical and non-medical costs totaled $7.5b ($6.6-8.6b) annually, with $5.5b ($4.7-6.6b) due to ARIs and $1.9b ($1.8-2.1b) due to IPD. The largest single driver of costs was non-bacteremic pneumonia, particularly in adults aged 50-64 and ≥65 years.ConclusionsAdditional serotypes in PCV24 and PCV31, especially those included in PCV31, account for substantial health-economic burden in the United States.SummaryNovel serotypes in 24- and 31-valent pneumococcal conjugate vaccines, currently in clinical trials, account for substantial health-economic burdens in the United States, especially in adults ≥50 years. Vaccines targeting these serotypes may prevent pneumococcal disease and reduce associated costs.
Friendship Bench Intervention to Address Depression and Improve HIV Care Engagement Among Adolescents Living with HIV in Malawi: Study Protocol for a Pilot Randomized Controlled Trial
Authors: Dao Thuy T. , Gaynes Bradley N. , Pence Brian W. , Mphonda Steven M. , Kulisewa Kazione , Udedi Michael , Stockton Melissa A. , Kramer Jack , Faidas Maria , Mortensen Hillary , Bhushan Nivedita L. 
Published: April 2024

ABSTRACTBackgroundAdolescents in Sub-Saharan Africa are disproportionately affected by the HIV epidemic. Comorbid depression is prevalent among adolescents living with HIV (ALWH) and poses numerous challenges to HIV care engagement and retainment. We present a pilot trial designed to investigate feasibility, fidelity, and acceptability of anadapted and anenhancedFriendshipBench intervention (henceforth: AFB and EFB) in reducing depression and improving engagement in HIV care among ALWH in Malawi.MethodsDesign: Participants will be randomized to one of three conditions: the Friendship Bench intervention adapted for ALWH (AFB, n=35), the Friendship Bench intervention enhanced with peer support (EFB, n=35), or standard of care (SOC, n=35). Recruitment is planned for early 2024 in four clinics in Malawi.Participants: Eligibility criteria (1) aged 13-19; (2) diagnosed with HIV (vertically or horizontally); (3) scored ≥ 13 on the self-reported Beck’s Depression Inventory (BDI-II); (4) living in the clinic’s catchment area with intention to remain for at least 1 year; and (5) willing to provide informed consent.Interventions: AFB includes 6 counseling sessions facilitated by young, trained non-professional counselors. EFB consists of AFB plus integration of peer support group sessions to facilitate engagement in HIV care. SOC for mental health in public facilities in Malawi includes options for basic supportive counseling, medication, referral to mental health clinics or psychiatric units at tertiary care hospitals for more severe cases.Outcomes: The primary outcomes are feasibility, acceptability, and fidelity of the AFB and EFB assessed at 6 months and 12 months and compared across 3 arms. The secondary outcome is to assess preliminary effectiveness of the interventions in reducing depressive symptoms and improving HIV viral suppression at 6 months and 12 months.DiscussionThis pilot study will provide insights into youth-friendly adaptations of the Friendship Bench model for ALWH in Malawi and the value of adding group peer support for HIV care engagement. The information gathered in this study will lead to a R01 application to test our adapted intervention in a large-scale cluster randomized controlled trial to improve depression and engagement in HIV care among ALWH.Trial registrationClinicalTrials.govIdentifierNCT06173544
Leveraging Machine Learning for Enhanced and Interpretable Risk Prediction of Venous Thromboembolism in Acute Ischemic Stroke Care
Authors: Jiang Youli , Li Ao , Li Zhihuan , Li Yanfeng , Li Rong , Zhao Qingshi , Li Guisu 
Published: April 2024

AbstractBackgroundStroke is the second leading cause of death globally, with acute ischemic strokes constituting the majority. Venous thromboembolism (VTE) poses a significant risk during the acute phase post-stroke, and early recognition is critical for preventive intervention of VTE.MethodsUtilizing data from the Shenzhen Neurological Disease System Platform to develop multiple machine learning models that included variables such as demographics, clinical data, and laboratory results. Advanced technologies such as K nearest neighbor and synthetic minority oversampling technique are used for data preprocessing, and algorithms such as gradient boosting machine and support vector machine are used for model development.Feature analysis of optimal models using SHapley Additive exPlanations interpretable algorithm.ResultsIn our study of 1,632 participants, in which women were more prevalent, the median age of patients with VTE was significantly older than that of non-VTE individuals. Data analysis showed that key predictors such as age, alcohol consumption, and specific medical conditions were significantly associated with VTE outcomes. The AUC of all prediction models is above 0.7, and the GBM model shows the highest prediction accuracy with an AUC of 0.923. These results validate the effectiveness of this model in identifying high-risk patients and demonstrate its potential for clinical application in post-stroke VTE risk management.ConclusionThis study presents an innovative, machine learning-based approach to predict VTE risk in acute ischemic stroke patients, offering a tool for personalized patient care. Future research could explore integration into clinical decision systems for broader application.
Defining and Reducing Variant Classification Disparities
Authors: Dawood Moez , Fayer Shawn , Pendyala Sriram , Post Mason , Kalra Divya , Patterson Karynne , Venner Eric , Muffley Lara A. , Fowler Douglas M. , Rubin Alan F. , Posey Jennifer E. , Plon Sharon E. , Lupski James R. , Gibbs Richard A. , Starita Lea M. , Robles-Espinoza Carla Daniela , Coyote-Maestas Willow , Gallego Romero Irene 
Published: April 2024

AbstractBackgroundMultiplexed Assays of Variant Effects (MAVEs) can test all possible single variants in a gene of interest. The resulting saturation-style data may help resolve variant classification disparities between populations, especially for variants of uncertain significance (VUS).MethodsWe analyzed clinical significance classifications in 213,663 individuals of European-like genetic ancestry versus 206,975 individuals of non-European-like genetic ancestry fromAll of Usand the Genome Aggregation Database. Then, we incorporated clinically calibrated MAVE data into the Clinical Genome Resource’s Variant Curation Expert Panel rules to automate VUS reclassification forBRCA1, TP53, and PTEN.ResultsUsing two orthogonal statistical approaches, we show a higher prevalence (p≤5.95e-06) of VUS in individuals of non-European-like genetic ancestry across all medical specialties assessed in all three databases. Further, in the non-European-like genetic ancestry group, higher rates of Benign or Likely Benign and variants with no clinical designation (p≤2.5e-05) were found across many medical specialties, whereas Pathogenic or Likely Pathogenic assignments were higher in individuals of European-like genetic ancestry (p≤2.5e-05).Using MAVE data, we reclassified VUS in individuals of non-European-like genetic ancestry at a significantly higher rate in comparison to reclassified VUS from European-like genetic ancestry (p=9.1e-03) effectively compensating for the VUS disparity. Further, essential code analysis showed equitable impact of MAVE evidence codes but inequitable impact of allele frequency (p=7.47e-06) and computational predictor (p=6.92e-05) evidence codes for individuals of non-European-like genetic ancestry.ConclusionsGeneration of saturation-style MAVE data should be a priority to reduce VUS disparities and produce equitable training data for future computational predictors.
Judgements about carer assessments for carers of people with dementia: case vignette study
Authors: Clarkson Paul , Mills Lucie , Butt Asif , Malik Baber , Eley Ruth , Toole Cecilia , Sanders Caroline , Sheriff Ian 
Published: April 2024

AbstractObjectivesUK carer assessments, in primary and social care, intend to discover what carers need in their caring roles and more widely. Evidence points to these not being configured sufficiently around carers of people with dementia, with potentially their breadth of needs not being recognised. We evaluated the extent of agreement, between carers of people with dementia, primary care, and social care professionals, on their recommendations from assessing carers’ needs in a range of circumstances. It is intended for findings to be taken forward as recommendations for policy and practice.MethodsComparison of judgements, between carers, primary and social care professionals, on whether real-life circumstances in 9 anonymised case vignettes necessitated a range of 14 services to support carers appropriately. Participants were 6 carers of people with dementia, 7 primary care staff, and 2 social care staff. We presented participants with each vignette and asked them to make binary judgements of whether they would recommend a range of services in each case. Percentage agreement and Fleiss’ kappa coefficients measured the level of agreement amongst multiple carers, primary and social care staff and overall. These agreements were then compared.ResultsCarers agreed in their judgements more than primary or social care professionals. The overall level of agreement from judgements made by all participants, however, was ‘slight’ with variability between participant groups and overall. The need for First Language Support in some cases was recognised, an improvement from previous evidence.ConclusionsCase vignettes are useful for investigating judgements concerning these carers’ needs, so raising issues for policy and practice. It is essential for carer assessments to be more reliable in recommending services based on need to ensure less variability, depending on assessor and carers circumstances.
More widespread and rigid neuronal representation of reward expectation underlies impulsive choices
Authors: Cowan Rhiannon L. , Davis Tyler , Kundu Bornali , Rahimpour Shervin , Rolston John D. , Smith Elliot H. 
Published: April 2024

SummaryImpulsive choices prioritize smaller, more immediate rewards over larger, delayed, or potentially uncertain rewards. Impulsive choices are a critical aspect of substance use disorders and maladaptive decision-making across the lifespan. Here, we sought to understand the neuronal underpinnings of expected reward and risk estimation on a trial-by-trial basis during impulsive choices. To do so, we acquired electrical recordings from the human brain while participants carried out a risky decision-making task designed to measure choice impulsivity. Behaviorally, we found a reward-accuracy tradeoff, whereby more impulsive choosers were more accurate at the task, opting for a more immediate reward while compromising overall task performance. We then examined how neuronal populations across frontal, temporal, and limbic brain regions parametrically encoded reinforcement learning model variables, namely reward and risk expectation and surprise, across trials. We found more widespread representations of reward value expectation and prediction error in more impulsive choosers, whereas less impulsive choosers preferentially represented risk expectation. A regional analysis of reward and risk encoding highlighted the anterior cingulate cortex for value expectation, the anterior insula for risk expectation and surprise, and distinct regional encoding between impulsivity groups. Beyond describing trial-by-trial population neuronal representations of reward and risk variables, these results suggest impaired inhibitory control and model-free learning underpinnings of impulsive choice. These findings shed light on neural processes underlying reinforced learning and decision-making in uncertain environments and how these processes may function in psychiatric disorders.
Spatial proteomic analysis of a lung cancer model reveals regulatory T cells attenuate KRAS-G12C inhibitor-induced immune responses
Authors: Cole Megan , Anastasiou Panayiotis , Lee Claudia , Moore Chris , Mugarza Edurne , Jones Martin , Valand Karishma , Rana Sareena , Colliver Emma , Angelova Mihaela , Enfield Katey S.S. , Magness Alastair , Mullokandov Asher , Kelly Gavin , de Gruijl Tanja D. , Molina-Arcas Miriam , Swanton Charles , Downward Julian , van Maldegem Febe 
Published: April 2024

ABSTRACTWe recently showed that lung tumor specific KRAS-G12C inhibition causes remodelling of the tumor immune microenvironment from cold to hot. As a result, KRAS-G12C inhibition is able to synergise with anti-PD-1 treatment, but only in tumor models that were already moderately responsive to immune checkpoint blockade at baseline. To investigate mechanisms that restrain immunotherapy sensitivity in non-responsive tumors, we used multiplex imaging mass cytometry to explore spatial patterns in the tumor microenvironment of the highly immune evasive KRAS mutant murine Lewis Lung Cancer model. Clustering of close neighbour information per cell allowed characterisation of spatial patterns or ‘communities’ in the tissue. We identified a community harbouring features of localised T-cell activation, where CD4+and CD8+T cells and dendritic cells were gathered together. KRAS-G12C inhibition led to increased expression of PD-1 on T cells, CXCL9 expression by dendritic cells, together with increased proliferation and potential cytotoxicity of CD8+T cells, indicating an effector response. However, we also observed a high incidence of regulatory T cells (Tregs) within this community, which had frequent contact with effector T cells, suggesting that Tregs may be able to dampen anti-tumoral immune responses following KRAS-G12C inhibition. Similar communities were detected in human lung adenocarcinoma clinical samples. Depleting Tregsin vivowith anti-CTLA-4 antibody rescued the anti-tumor immune response and led to enhanced tumor control in combination with anti-PD-1 and KRAS-G12C inhibitor. We therefore propose use of KRAS-G12C inhibitor in combination with Treg depletion as a therapeutic opportunity that increases anti-tumoral immune responses and initiates tumor regression.One sentence summary:Spatial analysis identified regulatory T cells as potential source of local T cell repression, mediating resistance to KRAS-G12Ci and anti-PD1 therapy.