bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting involuntary admission following inpatient psychiatric treatment using machine learning trained on electronic health record data
Authors: Perfalk Erik , Damgaard Jakob Grøhn , Bernstorff Martin , Hansen Lasse , Danielsen Andreas Aalkjær , Østergaard Søren Dinesen
Published: April 2024

Background

Involuntary admissions to psychiatric hospitals are on the rise. If patients at elevated risk of involuntary admission could be identified, prevention may be possible.

Objectives

To develop and validate a prediction model for involuntary admission of patients receiving care within a psychiatric service system using machine learning trained on routine clinical data from electronic health records (EHRs).

Methods

EHR data from all adult patients who had been in contact with the Psychiatric Services of the Central Denmark Region between 2013 and 2021 were retrieved. We derived 694 patient predictors (covering e.g., diagnoses, medication, and coercive measures) and 1,134 predictors from free text using term frequency - inverse document frequency and sentence transformers. At every voluntary inpatient discharge (prediction time), without an involuntary admission in the two years prior, we predicted involuntary admission 180 days ahead. XGBoost and Elastic Net regularized logistic regression models were trained on 85% of the dataset. The best performing model was tested on the remaining 15% of the data.

Results

The model was trained on 50,634 voluntary inpatient discharges among 17,968 unique patients. The cohort comprised 1,672 voluntary inpatient discharges followed by an involuntary admission. The XGBoost model performed best in the training phase and obtained an area under the receiver operating curve of 0.84 in the test phase.

Conclusion

A machine learning model using routine clinical EHR data can accurately predict involuntary admission. If implemented as a clinical decision support tool, this model may guide interventions aimed at reducing the risk of involuntary admission.
The effect of Alzheimer’s disease and its progression on pyramidal cell gain and connectivity
Authors: Lanskey Juliette H , Jafarian Amirhossein , Karadag Melek , Kocagoncu Ece , Williams Rebecca , Yadav Pranay , Quinn Andrew J , Pitt Jemma , Thayanandan Tony , Lowe Stephen , Perkinton Michael , Timmers Maarten , Raymont Vanessa , Singh Krish D , Woolrich Mark , Nobre Anna C , Henson Richard N , Rowe James B ,   the NTAD study group
Published: April 2024

Alzheimer’s disease affects our cognitive neurophysiology by loss of neurones, synapses and neurotransmitters. An improved mechanistic understanding of the human disease will facilitate new treatments. To this end, biophysically-informed dynamic causal models can support inferences around laminar and cell-specific disease effects from human non-invasive imaging. Based on pre-clinical models and effects of cholinesterase inhibitors, we hypothesised that Alzheimer’s disease would affect the modulation of superficial pyramidal cell gain and extrinsic connectivity between pyramidal cells of different regions in hierarchical cognitive networks. Magnetoencephalography (MEG) was recorded during an auditory mismatch negativity task from healthy adults (n=14) and people with symptomatic Alzheimer’s disease or mild cognitive impairment (n=45, all amyloid-biomarker positive) at baseline and after 16 months. Fourteen people from the symptomatic group had repeat magnetoencephalography at two weeks to assess test-retest reliability. Sensor-level data were analysed using t-tests of the mismatch negativity amplitude from 140ms to 160ms. The repetition effect was assessed with repeated-measures analysis of covariance, using the average evoked response in the mismatch negativity time window as the repeated measure. An absolute, intraclass correlation model of the test-retest data assessed mismatch negativity amplitude reliability. We then fitted dynamic causal models to the evoked responses over 500ms. Second-level parametric empirical Bayes across participants examined the effect of (1) group, patients vs controls, and (2) progression, baseline vs follow-up, on the model parameters reflecting pyramidal cell gain modulation and extrinsic connectivity. There was a significant effect of both disease and progression on the mismatch negativity amplitude (patients vs controls, T=-1.80, p=0.04; patient baseline vs follow-up, T=-2.72, p=.005), which had excellent reliability (ICC=0.95, p<.001). Parametric empirical Bayes revealed strong evidence (posterior probability>95%) that Alzheimer’s disease reduced extrinsic connectivity and superficial pyramidal cell gain modulation, which was reduced further at follow up assessment. The mechanistic modelling confirmed the hypothesis that reduced superficial pyramidal cell gain modulation and extrinsic connectivity can explain the observed neurophysiological effect of Alzheimer’s disease. This approach to non-invasive magnetoencephalography data may be used for experimental medicine studies of candidate treatments, and bridge clinical to preclinical models of drug efficacy.
The Danish Lymphoid Cancer Research (DALY-CARE) data resource: the basis for developing data-driven hematology
Authors: Brieghel Christian , Werling Mikkel , Frederiksen Casper Moller , Parviz Mehdi , da Cunha-Bang Caspar , Faitova Tereza , Teglgaard Rebecca Svanberg , Vainer Noomi , Lacoppidan Thomas , Rotbain Emelie , Agius Rudi , Niemann Carsten Utoft
Published: April 2024

Lymphoid-lineage cancers (LC: lymphoma, chronic lymphocytic leukemia, multiple myeloma, and their precursors) share many epidemiological and clinical features. To develop data-driven hematology, we gathered electronic health data and created open-source data processing pipelines to create a comprehensive data resource for Danish LC Research (DALY-CARE) approved for epidemiological, molecular, and data-driven research. We included all Danish adults registered with LC diagnoses since 2002 (n=65,774) and combined 10 nationwide registers, electronic health records (EHR), and laboratory data on a high-powered cloud-computer to develop a secure research environment. We herein exemplify how DALY-CARE has been used to develop novel prognostic markers using biobank data, real-world evidence to evaluate the efficacy of care, and medical artificial intelligence algorithms deployed directly into EHR systems. The DALY-CARE data resource allows for development of both near real-time decision-support tools and extrapolation of clinical trial results to clinical practice, thereby improving care for patients with LC.
Pilot trial of perampanel on peritumoral hyperexcitability and clinical outcomes in newly diagnosed high-grade glioma
Authors: Tobochnik Steven , Regan Michael S. , Dorotan Maria K. C. , Reich Dustine , Lapinskas Emily , Hossain Md Amin , Stopka Sylwia , Santagata Sandro , Murphy Melissa M. , Arnaout Omar , Bi Wenya Linda , Chiocca E. Antonio , Golby Alexandra J. , Mooney Michael A. , Smith Timothy R. , Ligon Keith L. , Wen Patrick Y. , Agar Nathalie Y. R. , Lee Jong Woo
Published: April 2024

Background

Glutamatergic neuron-glioma synaptogenesis and peritumoral hyperexcitability promote glioma growth in a positive feedback loop. The objective of this study was to evaluate the feasibility and estimated effect sizes of the AMPA-R antagonist, perampanel, on intraoperative electrophysiologic hyperexcitability and clinical outcomes.

Methods

An open-label trial was performed comparing perampanel to standard of care (SOC) in patients undergoing resection of newly-diagnosed radiologic high-grade glioma. Perampanel was administered as a pre-operative loading dose followed by maintenance therapy until progressive disease or up to 12-months. SOC treatment involved levetiracetam for 7-days or as clinically indicated. The primary outcome of hyperexcitability was defined by intra-operative electrocorticography high frequency oscillation (HFO) rates. Seizure-freedom and overall survival (OS) were estimated by the Kaplan-Meier method. Tissue concentrations of perampanel, levetiracetam, and metabolites were measured by mass spectrometry.

Results

HFO rates were similar between perampanel-treated and SOC cohorts. The trial was terminated early after interim analysis for futility, and outcomes assessed in 11 patients (7 perampanel-treated, 4 SOC). Over a median 281 days of post-enrollment follow-up, 27% of patients had seizures, including 14% treated with perampanel and 50% treated with SOC. OS in perampanel-treated patients was similar to a glioblastoma reference cohort (p=0.81). Glutamate concentrations in surface biopsies were positively correlated with HFO rates in adjacent electrode contacts and were not significantly associated with treatment assignment or drug concentrations.

Conclusions

A peri-operative loading regimen of perampanel was safe and well-tolerated, with similar peritumoral hyperexcitability as in levetiracetam-treated patients. Maintenance anti-glutamatergic therapy was not observed to impact survival outcomes.
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

Objectives

To develop a core outcome set (COS) to capture and measure the well-being of doctors working in the NHS.

Design

An online Delphi study.

Setting

United Kingdom National Health Service.

Participants

Participants 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.

Method

A 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.

Results

Fifty-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.

Conclusion

Use 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 registration

This 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

Targeting 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

Volatile 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 registration

ClinicalTrials.govNCT03451994;

https://clinicaltrials.gov/study/NCT03451994

Data

available 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

Background

Next-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.

Methods

We 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.

Results

The 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.

Conclusions

Additional serotypes in PCV24 and PCV31, especially those included in PCV31, account for substantial health-economic burden in the United States.

Novel 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

Background

Adolescents 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.

Methods

Design: 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.

Discussion

This 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 registration

ClinicalTrials.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

Background

Stroke 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.

Methods

Utilizing 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.

Results

In 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.

Conclusion

This 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

Background

Multiplexed 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).

Methods

We 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.

Results

Using 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.

Conclusions

Generation 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

Objectives

UK 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.

Methods

Comparison 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.

Results

Carers 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.

Conclusions

Case 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

Impulsive 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

We 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.
Cerebro-spinal somatotopic organization uncovered through functional connectivity mapping
Authors: Landelle Caroline , Kinany Nawal , De Leener Benjamin , Murphy Nicholas D. , Lungu Ovidiu , Marchand-Pauvert Véronique , Van De Ville Dimitri , Doyon Julien
Published: April 2024

Somatotopy, the topographical arrangement of sensorimotor pathways corresponding to distinct body parts, is a fundamental feature of the human central nervous system (CNS). Traditionally, investigations into brain and spinal cord somatotopy have been conducted independently, primarily utilizing body stimulations or movements. To date, however, no study has probed the somatotopic arrangement of cerebro-spinal functional connectionsin vivoin humans. In this study, we used simultaneous brain and cervical spinal cord functional magnetic resonance imaging (fMRI) to demonstrate how the coordinated activities of these two CNS levels at rest can reveal their shared somatotopy. Using functional connectivity analyses, we mapped preferential correlation patterns between each spinal cord segment and distinct brain regions, revealing a somatotopic gradient within the cortical sensorimotor network. We then validated this large-scale somatotopic organization through a complementary data-driven analysis, where we effectively identified spinal cord segments through the connectivity profiles of their voxels with the sensorimotor cortex. These findings underscore the potential of resting-state cerebro-spinal cord fMRI to probe the large-scale organization of the human sensorimotor system with minimal experimental burden, holding promise for gaining a more comprehensive understanding of normal and impaired somatosensory-motor functions.
Top-down modulation of visual cortical stimulus encoding and gamma independent of firing rates
Authors: Lewis Christopher M. , Wunderle Thomas , Fries Pascal
Published: April 2024

Neurons in primary visual cortex integrate sensory input with signals reflecting the animal’s internal state to support flexible behavior. Internal variables, such as expectation, attention, or current goals, are imposed in a top-down manner via extensive feedback projections from higher-order areas. We optogenetically activated a high-order visual area, area 21a, in the lightly anesthetized cat (OptoTD), while recording from neuronal populations in V1. OptoTD induced strong, up to several fold, changes in gamma-band synchronization together with much smaller changes in firing rate, and the two effects showed no correlation. OptoTD effects showed specificity for the features of the simultaneously presented visual stimuli. OptoTD-induced changes in gamma synchronization, but not firing rates, were predictive of simultaneous changes in the amount of encoded stimulus information. Our findings suggest that one important role of top-down signals is to modulate synchronization and the information encoded by populations of sensory neurons.
Cortexa – a comprehensive resource for studying gene expression and alternative splicing in the murine brain
Authors: Weißbach Stephan , Milkovits Jonas , Pastore Stefan , Heine Martin , Gerber Susanne , Todorov Hristo
Published: April 2024

Motivation

Gene expression and alternative splicing are strictly regulated processes that shape brain development and determine the cellular identity of differentiated neural cell populations. Despite the availability of multiple valuable datasets, many functional implications, especially those related to alternative splicing, remain poorly understood. Moreover, neuroscientists working primarily experimentally often lack the bioinformatics expertise required to process alternative splicing data and produce meaningful and interpretable results. Notably, re-analyzing publicly available datasets and integrating them with in-house data can provide substantial novel insights. However, such analyses necessitate devel-oping harmonized data handling and processing pipelines which in turn requires considerable computational resources and in-depth bioinformatics expertise.

Results

Here, we present Cortexa – a comprehensive web-portal that incorporates RNA-sequencing datasets from the mouse cerebral cortex (longitudinal or cell-specific) and the hippocampus. Cortexa facilitates understandable visualization of the expression and alternative splicing patterns of individual genes. Our platform also provides SplicePCA – a tool that allows users to integrate their alternative splicing dataset and compare it to cell-specific or developmental neocortical splicing patterns. All gene expression and alternative splicing data have been processed in a standardized manner and they can also be downloaded for further in-depth down-stream analysis.

Availability

The data portal is available athttps://cortexa-rna.com/

Contact

hristo.todorov@uni-mainz.de.
Comparative analysis based on shared amplicon sequence variants reveals that cohabitation influences gut microbiota sharing between humans and dogs
Authors: Ito Yutaro , Nagasawa Miho , Koyama Kahori , Ito Kohei , Kikusui Takefumi
Published: April 2024

Introduction

The One Health concept is a comprehensive understanding of the interaction between humans, animals, and the environment. The cohabitation of humans and dogs positively affects their physical, mental, and social well-being. It is recognized as an essential factor from the One Health perspective. Furthermore, a healthy balance in the gut microbiome is essential for good health, and the sharing of gut microbes between humans and dogs may positively impact the health of both hosts. Therefore, elucidating the sharing of gut bacteria between humans and dogs is important for understanding One Health. However, most studies have examined sharing at the taxonomic level, and it remains unclear whether the same bacteria are transferred between humans and dogs, and whether they mutually influence each other.

Methods

Here, microbiome analysis and 16S rRNA gene amplicon sequence variant (ASV) analysis was performed to address this question.

Results

16S rRNA gene ASVs analysis indicated that gut microbes have been transferred between humans and dogs. The overall structure of the gut microbiota within human-dog pairs remained unchanged after three months of adaptation. However, some ASVs were shared within human-dog pairs. Many shared ASVs were highly abundant within each host, and this high abundance may be considered a factor that influences bacterial transfer between hosts.

Discussion

Our results demonstrate the possibility of the direct transfer of gut bacteria between humans and dogs, providing an important insight for achieving good health through human-dog cohabitation.
Triglyceride metabolism controls inflammation andAPOE4-associated disease states in microglia
Authors: Stephenson Roxan A. , Johnson Kory R. , Cheng Linling , Yang Linda G. , Root Jessica T. , Gopalakrishnan Jaanam , Shih Han-Yu , Narayan Priyanka S.
Published: April 2024

Microglia modulate their cell state in response to various stimuli. Changes to cellular lipids often accompany shifts in microglial cell state, but the functional significance of these metabolic changes remains poorly understood. In human induced pluripotent stem cell-derived microglia, we observed that both extrinsic activation (by lipopolysaccharide treatment) and intrinsic triggers (the Alzheimer’s disease-associatedAPOE4genotype) result in accumulation of triglyceride-rich lipid droplets. We demonstrate that lipid droplet accumulation is not simply concomitant with changes in cell state but rather necessary for microglial activation. We discovered that both triglyceride biosynthesis and catabolism are needed for the transcription and secretion of proinflammatory cytokines and chemokines in response to extrinsic stimuli. Additionally, we reveal that triglyceride biosynthesis and catabolism are necessary for the activation-associated phagocytosis of multiple substrates including the disease-associated amyloid-beta peptide. In microglia harboring the Alzheimer’s disease riskAPOE4genotype, triglyceride-rich lipid droplets accumulate even in the absence of any external stimuli. Inhibiting triglyceride biosynthesis inAPOE4microglia not only modifies the transcription of immune response genes but also attenuates disease-associated transcriptional states. This work establishes that triglyceride metabolism is necessary for microglia to respond to extrinsic activation. InAPOE4microglia, this metabolic process modulates both immune signaling and a disease-associated transcriptional state. Importantly, our work identifies metabolic pathways that can be used to tune microglial immunometabolism inAPOE4-associated disease.
Safety, effectiveness, and skin immune response in a controlled human infection model of sand fly transmitted cutaneous leishmaniasis
Authors: Parkash Vivak , Ashwin Helen , Dey Shoumit , Sadlova Jovana , Vojtkova Barbora , Bocxlaer Katrien Van , Wiggins Rebecca , Thompson David , Dey Nidhi Sharma , Jaffe Charles L. , Schwartz Eli , Volf Petr , Lacey Charles J. N. , Layton Alison M. , Kaye Paul M.
Published: April 2024

The leishmaniases are globally important parasitic diseases for which no human vaccines are currently available. To facilitate vaccine development, we conducted an open label observational study to establish a controlled human infection model of sand fly-transmitted cutaneous leishmaniasis caused byL. major. Between 24thJanuary and 12thAugust 2022, we exposed 14 (8F, 6M) participants to infectedPhlebotomus duboscqi. The primary objective was to demonstrate effectiveness (take rate) and safety (absence of CL lesion at 12 months), whereas secondary and exploratory objectives included rate of lesion development, parasite load and analysis of local immune responses by immunohistology and spatial transcriptomics. We estimated an overall take rate for CL development of 64% (9/14), or 82% (9/11) if calculated using only participants having confirmed bites following exposure. Lesion development was terminated by therapeutic biopsy in 10 participants with confirmed bites. 2/10 had one and 1/10 had two lesion recurrences 4-8 months after biopsy that were treated successfully with cryotherapy. No severe or serious adverse events were recorded, but scarring was evident as expected. All participants were lesion-free at >12 month follow up. We provide the first comprehensive map of immune cell distribution and cytokine/chemokine expression in human CL lesions, revealing discrete immune niches. This controlled human infection model offers opportunities for rapid vaccine candidate selection and a greater understanding of immune-mediated protection and pathology.
COVID19 vaccines as boosters or first doses: Simulating scenarios to minimize infections and deaths
Authors: El Deeb Omar , El Khoury Edde Joseph
Published: April 2024

Public health authorities face the issue of optimal vaccine distribution during spread of pandemics. In this paper, we study the optimal way to distribute a finite stock of COVID-19 doses between first or second doses for unvaccinated individuals and third doses (booster shots) for fully vaccinated individuals. We introduce a novel compartmental model that accommodates for vaccinated populations. This Booster model is implemented to simulate two prototypes of populations: one with a highly infected and highly vaccinated proportion, and another with a low infected and vaccinated percentage. We namely use sample data from Russia and Djibouti respectively.

Our findings show that, to minimize the deaths for the first type of populations, around one quarter of the vaccines should be employed as booster shots and the rest as first and second doses. On the other hand, the second type of populations can minimize their number of deaths by mainly focusing on administering the initial two doses, rather than giving any booster shots. The novel Booster model allows us to study the effect of the third dose on a community and provides a useful tool to draw public policies on the distribution of vaccines during pandemics.
Applying the Nova food classification to food product databases using discriminative ingredients: a methodological proposal
Authors: Fagundes Grilo Mariana , Silva Nunes Beatriz , Duran Ana Clara , Zancheta Ricardo Camila , Galastri Baraldi Larissa , Martinez Steele Euridice , Borges Camila Aparecida
Published: April 2024

Background

Growing interest in the Nova food classification system surged among various stakeholders, driven primarily by compelling evidence linking the consumption of ultra-processed foods (UPF) to negative health outcomes. However, a more standardized approach could incentivize the identification of UPF in regulatory processes.

Objective

To propose replicable methods to identify UPF that, by testing the sensitivity and specificity of these methods using a large sample of packaged foods from the 2017 Brazilian Food Labels Database.

Methods

We created five scenarios to identify UPF using food substances and food additives typically found in UPF and compared them with the most frequently employed Nova food classification process based on the product name and food categories, considered the ‘classic method’ to identify UPF. We estimated the proportion of foods and beverages identified as UPF using different scenarios based on the presence of discriminative ingredients. We used a diagnostic test and a receiver operating characteristic (ROC) to understand which of the five scenarios performed better compared to the ‘classic method’ to identify UPF. Finally, we conducted a sensitivity analysis to test the role of vitamins and minerals in identifying UPF.

Results

We found variations in UPF prevalence from 47% to 72% across scenarios, compared to 70% using the ‘classic method’ to identify UPF in Brazilian packaged foods. Despite its cautious approach, the scenario using additives of a sole cosmetic function and food byproducts (scenario 3) identified a 65% UPF, while maintaining reasonable sensitivity and specificity, and the best-performing ROC curve. There was no significant difference in identifying UPF when comparing the addition of vitamins and minerals to the food additives with sole cosmetic function.

Conclusion

Our study sheds light on the importance of detailed criteria to identify UPF and offers the research community a standardized method to identify UPF.
Linking Altered Neuronal and Synaptic Properties to Nicotinic Receptor Alpha5 Subunit Gene Dysfunction: A Translational Investigation in Rat mPFC and Human Cortical Layer 6
Authors: Yang Danqing , Qi Guanxiao , Delev Daniel , Maskos Uwe , Feldmeyer Dirk
Published: April 2024

Background

Genetic variation in the α5 nicotinic acetylcholine receptor (nAChR) subunit of mice results in behavioral deficits linked to the prefrontal cortex (PFC). A Single Nucleotide Polymorphisms (SNP) in CHRNA5 imparts a partial loss of function to the α5 subunit-containing (α5*) nAChRs and have been demonstrated to be associated with psychiatric disorders in humans, including schizophrenia, nicotine dependence, cocaine and alcohol addiction.

Methods

We performed single cell-electrophysiology combined with morphological reconstructions on layer 6 (L6) excitatory neurons in the medial PFC (mPFC) of wild type (WT) rats (n = 25), rats carrying the human coding polymorphism rs16969968 inChrna5(n = 11) and α5 knockout (KO) rats (n = 28). Neuronal and synaptic properties were compared among three rat genotypes. Galantamine was applied to identified L6 neuron populations to specifically boost the nicotinic responses mediated by α5*nAChRs in the rat mPFC and human neocortex (n = 6 patients).

Results

Compared with neurons in WT rats, L6 regular spiking (RS) neurons in the α5KO group exhibited altered electrophysiological properties, while those in α5SNP rats remained unchanged. L6 RS neurons in mPFC of α5SNP and α5KO rats differed from WT rats in dendritic morphology, spine density and spontaneous synaptic activity. Galantamine acted as a positive allosteric modulator of α5*nAChRs in RS but not burst spiking (BS) neurons in both rat and human cortical L6.

Conclusion

Our findings suggest that dysfunction in the α5 subunit gene leads to aberrant neuronal and synaptic properties, shedding light on the underlying mechanisms of cognitive deficits observed in human populations carrying α5SNPs. They highlight a potential pharmacological target for restoring the relevant behavioral output.