bluuebunny/crossref_metadata_2025 huggingface dataset:
A scoping review of AI, speech and natural language processing methods for assessment of clinician-patient communication
Authors: Albert Pierre , McKinstry Brian , Luz Saturnino
Published: December 2024

Introduction

There is growing research interest in applying Artificial Intelligence (AI) methods to medicine and healthcare. Analysis of communication in healthcare has become a target for AI research, particularly in the field of analysis of medical consultations, an area that so far has been dominated by manual rating using measures. This opens new perspectives for automation and large scale appraisal of clinicians’ communication skills. In this scoping review we summarised existing methods and systems for the assessment of patient doctor communication in consultations.

Methods

We searched EMBASE, MEDLINE/PubMed, the Cochrane Central Register of Controlled Trials, and the ACM digital library for papers describing methods or systems that employ artificial intelligence or speech and natural language processing (NLP) techniques with a view to automating the assessment of patient-clinician communication, in full or in part. The search covered three main concepts: dyadic communication, clinician-patient interaction, and systematic assessment.

Results

We found that while much work has been done which employs AI and machine learning methods in the analysis of patient-clinician communication in medical encounters, this evolving research field is uneven and presents significant challenges to researchers, developers and prospective users. Most of the studies reviewed focused on linguistic analysis of transcribed consultations. Research on non-verbal aspects of these encounters are fewer, and often hindered by lack of methodological standardisation. This is true especially of studies that investigate the effects of acoustic (paralinguistic) features of speech in communication but also affects studies of visual aspects of interaction (gestures, facial expressions, gaze, etc). We also found that most studies employed small data sets, often consisting of interactions with simulated patients (actors).

Conclusions

While our results point to promising opportunities for the use of AI, more work is needed for collecting larger, standardised, and more easily available data sets, as well as on better documentation and sharing of methods, protocols and code to improve reproducibility of research in this area.
Tay-Sachs and Sandhoff Diseases: Diffusion tensor imaging and correlational fiber tractography findings differentiate late-onset GM2 Gangliosidosis
Authors: Lewis Connor J. , Chipman Selby I. , Johnston Jean M. , Acosta Maria T. , Toro Camilo , Tifft Cynthia J.
Published: December 2024

GM2 gangliosidosis is lysosomal storage disorder caused by deficiency of the heterodimeric enzyme β-hexosaminidase A. Tay-Sachs disease is caused by variants inHEXAencoding the α-subunit and Sandhoff disease is caused by variants inHEXBencoding the β-subunit. Due to shared clinical and biochemical findings, the two have been considered indistinguishable. We applied diffusion tensor imaging (DTI) and correlational fiber tractography to assess phenotypic differences in these two diseases. 40 DTI scans from 16 Late-Onset GM2 patients (NCT00029965) with either Sandhoff (n = 4), or Tay-Sachs (n = 12) disease. DTI metrics including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD), and quantitative anisotropy (QA) were calculated in fiber tracts throughout the whole brain, arcuate fasciculus, corpus callosum, and cerebellum. Correlational tractography was also performed to identify fiber tracts with group wide differences in DTI metrics between Tay-Sachs and Sandhoff patients. A linear mixed effects model was used to analyze the differences between Tay-Sachs and Sandhoff patients. Tay-Sachs patients had higher MD in the left cerebellum (p= 0.003703), right cerebellum (p= 0.003435), superior cerebellar peduncle (SCP,p= 0.007332), and vermis (p= 0.01007). Sandhoff patients had higher FA in the left cerebellum (p= 0.005537), right cerebellum (p= 0.01905), SCP (p= 0.02844), and vermis (p= 0.02469). Correlational fiber tractography identified fiber tracts almost exclusively in cerebellar pathways with higher FA and QA, and lower MD, AD, and RD in Sandhoff patients compared to Tay-Sachs patients. Our study shows neurobiological differences between these two related disorders. To our knowledge, this is the first study using correlational tractography in a lysosomal storage disorder demonstrating these differences. This result indicates a greater burden of cerebellar pathology in Tay-Sachs patients compared with Sandoff patients.
Epidemiology of early- and late-onset serious bacterial infections in Australian neonates and infants: A retrospective multicentre study
Authors: Williams Phoebe CM , Mostaghim Mona , Harrison Jackson , Lahra Monica , Greenhalgh Mark , O’Sullivan Matthew , Maley Michael , Oei Ju-Lee , Koirala Archana , Popat Himanshu , Lui Kei , McMullan Brendan , Palasanthiran Pamela , Kesson Alison , Isaacs David , Bartlett Adam W
Published: December 2024

Background

There has been little decline in neonatal mortality rates over recent decades, and this is now further challenged by the rising prevalence of antimicrobial resistance (AMR). In Australia, the incidence of neonatal sepsis is low on a global scale, yet there are increasingly frequent outbreaks of multidrug-resistant (MDR) infections in neonatal intensive care units, alongside rising rates of colonisation with MDR bacteria.

Methods

We analysed positive blood and cerebrospinal fluid (CSF) cultures collected from infants (aged 0 to ≤180 days) across five clinical sites in Australia between 2010 and 2019, to determine evolving antimicrobial susceptibility profiles.

Results

After excluding presumed contaminants, we analysed 743 pathogenic bacterial isolates cultured from 624 neonates and infants with early- (≤72 hours), late- (>72 hours to ≤28 days), and very late-onset (>28 days to ≤180 days) infections.Escherichia coli(37%) andStreptococcus agalactiae(31%) were the primary pathogens responsible for early-onset bloodstream infections, whilst coagulase-negative staphylococci,E. coliandStaphylococcus aureuswere responsible for most infections in older neonates and infants. Antimicrobial susceptibility to currently-recommended empiric regimens remains high; however, gram-negative bacteria – including MDR bacteria – were responsible for an increasing proportion of very late-onset infections over the study period (22% in 2010-2014 versus 34% in 2015-2019; p=0.07).

Conclusions

Although empiric antimicrobial regimens remain adequate for most pathogens causing infections in neonates and infants in Australia, there is an increasing burden of invasive infections caused by gram-negative bacteria. Ongoing surveillance is necessary to ensure empiric antimicrobial guidelines remain efficacious and appropriate.
Survival Analysis of Time to First Antenatal Care Visit among Pregnant Women in Ethiopia: Application of Parametric and Non-Parametric Model
Authors: Ayele Yitagesu Eshetu , Gada Zelalem Tolosa , Addisu Tigist Getachew
Published: December 2024

Objective

Antenatal care (ANC) involves monitoring pregnant women to ensure the health of both mother and fetus. This study aimed to assess the timing of the initial ANC visit and its determining factors among Ethiopian pregnant women.

Material and Methods

The analysis used data from the 2016 Ethiopian Demographic and Health Survey (EDHS), focusing on women aged 15-49 who had a live birth within five years prior to the survey across nine regional states and two city administrations. Descriptive statistics and parametric shared frailty models were applied to identify factors influencing the timing of the first ANC visit.

Results

Among 7,559 women, only 20.4% attended their first ANC visit within the recommended 12 weeks. The median time to the first ANC visit in Ethiopia was 18 weeks (4.5 months). Factors that delayed the first ANC visit included rural residence (□= 1.29), higher birth order (□= 1.06-1.21), and long distance to a health facility (□= 1.08). Conversely, factors that shortened the time to the first ANC visit included higher levels of maternal education (□= 0.87-0.91), higher wealth index (□= 0.86-0.87), media access (□= 0.92), and involvement in healthcare decisions (□< 1).

Conclusion

Rural residence, higher birth order, and long travel distances delay the first ANC visit, while higher education, urban residence, media access, and greater wealth accelerate it. The study recommends enhanced community education on the importance of early ANC visits through health extension workers and stakeholders.
COVID-19 mRNA-vaccination and all-cause mortality in the adult population in Norway during 2021-2023: a population-based cohort study
Authors: Dahl Jesper , Tapia German , Bøås Håkon , Landsjøåsen Bakken Inger Johanne , Løvdal Gulseth Hanne
Published: December 2024

Introduction

Most countries worldwide have experienced excess mortality that coincides temporally with the COVID-19 mass vaccination campaigns. This has led to speculation on the potential long-term effects of the vaccines on mortality risk.

Methods

The study was designed as a retrospective cohort study, and included all individuals aged ≥18 years living in Norway during January 1, 2021, through December 31, 2023. Individuals were categorized as either unvaccinated (received no doses), partially vaccinated (received one or two doses) or fully vaccinated (received three or more doses) from the date of vaccination and onwards. Age-stratified Poisson models were used to estimate incidence rate ratios of death (all causes) between vaccination groups, adjusting for sex, calendar time, county of residence and risk group status (nursing home resident or preexisting condition with increased risk of severe COVID-19).

Results

The study included 4 645 910 individuals (49.8% women) with 132 963 deaths during follow-up. There was a higher proportion of individuals that were part of a risk group among fully vaccinated individuals compared to unvaccinated individuals in all age groups, and a lower unadjusted rate of death: 51.5 vs 73.6 per 100 000 person years (py) among individuals aged 18-44 years, 295.1 vs 405.3 per 100 000 py among 45-64 years, and 3620.2 vs 4783.8 per 100 000 py among 65 years or older. The adjusted IRR of death for the same age groups were 0.42 (95% CI 0.38-0.47), 0.39 (95% CI 0.37-0.41) and 0.42 (95% CI 0.41-0.43), respectively. The differences in rate of death between vaccination groups were larger among men and peaked during 2022.

Conclusion

Vaccinated individuals had a lower rate of all-cause death during 2021-2023 in Norway.

Key messages

In Norway, as in many Western countries, there has been an excess mortality during 2021-2023, surpassing the numerical count of COVID-19-associated deaths. The excess mortality coincides temporally with the COVID-19 mass vaccination campaigns, but longitudinal data regarding mortality post-vaccination remain sparse. Using real-time national health registry data, we estimate the risk of all-cause mortality by vaccination status in the total adult population in Norway during 2021-2023 and demonstrate a lower rate of all-cause death among vaccinated individuals.
Change in aperiodic activity over first year of life is associated with later autism diagnosis and 18-month language development in infants with family history of autism
Authors: Wilkinson Carol L. , Chung Haerin , Dave Amy , Tager-Flusberg Helen , Nelson Charles A.
Published: December 2024

Delays in language often co-occur among toddlers diagnosed with autism. Despite the high prevalence of language delays, the neurobiology underlying such language challenges remains unclear. Prior research has shown reduced EEG power across multiple frequency bands in 3-to-6-month-old infants with an autistic sibling, followed by accelerated increases in power with age. Here we apply new methods to decompose the power spectra into aperiodic (broad band neural firing) and periodic (oscillations) activity to explore possible links between aperiodic changes in the first year of life and later language outcomes. Combining EEG data across two longitudinal studies of infants with and without autistic siblings, we assessed whether infants with an elevated familial likelihood (EFL) exhibit altered changes in both periodic and aperiodic EEG activity at 3 and 12 months of age, compared to those with a low likelihood (LL), and whether developmental change in activity is associated with language development. At 3-months of age, we observed that EFL infants have significantly lower aperiodic activity from 6.7-55Hz (p<0.05). However, change in aperiodic activity from 3 to 12 months was significantly increased in infants with a later diagnosis of autism, compared to EFL infants without an autism diagnosis. In addition, greater increases in aperiodic offset and slope from 3-to12-months were associated with worse language development measured at 18 months. Findings suggest that early age-dependent changes in EEG aperiodic power may serve as potential indicators of autism and language development in infants with family history of autism.
Direct expression of CPT1a enables a high throughput platform for the discovery of CPT1a modulators
Authors: Chen Jason , Tran Tuyen , Wong Anthony , Wang Luofei , Annaluru Pranavi , Sreekanth Vibha , Murthy Samika , Munjeti Laasya , Park Tanya , Bhat Utkarsh , Leong Glynnis , Li Yumeng , Chen Simeng , Kong Natalie , Raval Rushika , Xie Yining , Somani Shreya , Bhambhani Aditi , Zhu Zoey , Chu Landen , Dosch Kimai , Njoo Edward , Chen Zhan
Published: December 2024

Carnitine palmitoyltransferase 1 (CPT1), which catalyzes the rate-limiting step of fatty acid oxidation, has been implicated in therapeutic approaches to several human diseases characterized by aberrant lipid metabolism. Isoform-specific quantification of CPT1 activity is essential in the characterization of small molecule inhibitors of CPT1, but several existing means to quantify enzymatic activity, including the use of radioisotope labeled carnitine, are not amenable to scalable, high throughput screening. Here, we demonstrate that mitochondrial extracts from Expi293 cells transfected with a CPT1a plasmid are a reliable and robust source of catalytically active human CPT1. Moreover, with a source of catalytically active enzyme in hand, we modified a previously reported colorimetric method of coenzyme A (CoA) easily scalable to a 96-well format for the screening of CPT1a inhibitors. This assay platform was validated by two previously reported inhibitors of CPT1a:R-etomoxir and perhexiline. To further demonstrate the applicability of this method in small molecule screening, we prepared and screened a library of 87 known small molecule APIs, validating the inhibitory effect of chlorpromazine on CPT1.

Abstract Figure
Tunicate metatranscriptomes reveal ancient virus-host co-divergence and inter-order recombination in the evolutionary history of disease-causing viruses
Authors: Petrone Mary E. , Grove Joe , Parry Rhys H. , Brussel Kate Van , Mifsud Jonathon C.O. , Dindar Zuhairah , Mei Shi-qiang , Shi Mang , Turnbull Olivia M. H. , Marzinelli Ezequiel M. , Holmes Edward C.
Published: December 2024

Tunicates are a key transitional taxon in animal evolution as the closest extant invertebrate relatives of the vertebrates. Their viruses may also reflect this transitional state. Yet, it is not known whether tunicate viruses are more closely related to vertebrate- or invertebrate-infecting viral lineages. We analysed primary and publicly available RNA libraries to extend the known diversity of tunicate-associated viruses and determine their relationship to viruses of other animals. We present evidence that influenza viruses, alphaviruses, and some mononegaviruses emerged prior to the evolution of vertebrates. We also show that the recombination of glycoproteins between different orders of RNA viruses, including between positive- and negative-sense viruses, may have shaped the evolution of multiple lineages. Our study reveals that some disease-causing RNA virus lineages were present in early chordates and highlights that the evolution of structural genes may be incongruent with that of the highly conserved RNA-dependent RNA polymerase.
The blood metabolome of cognitive function and brain health in middle-aged adults – influences of genes, gut microbiome, and exposome
Authors: Ahmad Shahzad , Wu Tong , Arnold Matthias , Hankemeier Thomas , Ghanbari Mohsen , Roshchupkin Gennady , Uitterlinden André G. , Neitzel Julia , Kraaij Robert , Van Duijn Cornelia M. , Ikram M. Arfan , Kaddurah-Daouk Rima , Kastenmüller Gabi ,   the Alzheimer’s Disease Metabolomics Consortium
Published: December 2024

Increasing evidence suggests the involvement of metabolic alterations in neurological disorders, including Alzheimer’s disease (AD), and highlights the significance of the peripheral metabolome, influenced by genetic factors and modifiable environmental exposures, for brain health. In this study, we examined 1,387 metabolites in plasma samples from 1,082 dementia-free middle-aged participants of the population-based Rotterdam Study. We assessed the relation of metabolites with general cognition (G-factor) and magnetic resonance imaging (MRI) markers using linear regression and estimated the variance of these metabolites explained by genes, gut microbiome, lifestyle factors, common clinical comorbidities, and medication using gradient boosting decision tree analysis. Twenty-one metabolites and one metabolite were significantly associated with total brain volume and total white matter lesions, respectively. Fourteen metabolites showed significant associations with G-factor, with ergothioneine exhibiting the largest effect (adjusted mean difference = 0.122,P= 4.65x10-7). Associations for nine of the 14 metabolites were replicated in an independent, older cohort. The metabolite signature of incident AD in the replication cohort resembled that of cognition in the discovery cohort, emphasizing the potential relevance of the identified metabolites to disease pathogenesis. Lifestyle, clinical variables, and medication were most important in determining these metabolites’ blood levels, with lifestyle, explaining up to 28.6% of the variance. Smoking was associated with ten metabolites linked to G-factor, while diabetes and antidiabetic medication were associated with 13 metabolites linked to MRI markers, including N-lactoyltyrosine. Antacid medication strongly affected ergothioneine levels. Mediation analysis revealed that lower ergothioneine levels may partially mediate negative effects of antacids on cognition (31.5%). Gut microbial factors were more important for the blood levels of metabolites that were more strongly associated with cognition and incident AD in the older replication cohort (beta-cryptoxanthin, imidazole propionate), suggesting they may be involved later in the disease process. The detailed results on how multiple modifiable factors affect blood levels of cognition- and brain imaging-related metabolites in dementia-free participants may help identify new AD prevention strategies.
Data Anonymization for Open Science: A Case Study
Authors: Francis Paul , Jurak Gregor , Leskošek Bojan , Otte Karen , Prasser Fabian
Published: December 2024

One of many challenges to open science is anonymization of personal data so that it may be shared. This paper presents a case study of the anonymization of a dataset containing cardio-respiratory fitness and commuting patterns for Slovenian school children. It evaluates three different anonymization tools, ARX, SDV, and SynDiffix. The fitness study was selected because its small size (N=713) and generally low statistical significance make it particularly challenging for data anonymization. Unlike most prior anonymization tool evaluations, this paper examines whether the scientific conclusions of the original study would have been supported by the anonymized datasets. It also considers the burden imposed on researchers using the tools both for data generation and data analysis.
DunedinPACE Predicts Incident Metabolic Syndrome: Cross-sectional and Longitudinal Data from the Berlin Aging Study II (BASE-II)
Authors: Demuth Ilja , Vetter Valentin Max , Homann Jan , Regitz-Zagrosek Vera , Gerstorf Denis , Lill Christina M. , Bertram Lars
Published: December 2024

Importance

Data on the capacity of more recently developed epigenetic age measures to predict a future onset of Metabolic Syndrome (MetS) are lacking.

Objective

The aim of the study was a comparative analysis of different DNA methylation (DNAm)-based epigenetic clocks with regard to their ability to predict a future onset of MetS. In addition, cross-sectional relationships between epigenetic age measures, MetS and its components were investigated.

Design, Setting and Participants

MetS was diagnosed in participants of the Berlin Aging Study II at baseline (n=1,671, mean age 68.8 ±3.7 years, 51.6% women) and at follow-up (n=1,083; 7.4 ±1.5 years later). DNAm age (DNAmA) and its deviation from chronological age, i.e., DNAmA acceleration (DNAmAA), were calculated for a total of five epigenetic clocks at baseline. In addition, DunedinPACE, a DNAm-based measure of the pace of aging, was calculated. The relationship of MetS with DNAmAA and DunedinPACE was investigated by fitting regression models. Furthermore, receiver operating characteristic statistics were calculated to investigate the capacity of DNAm clocks assessed at baseline to predict incident MetS at follow-up.

Exposures

Six different epigenetic age measures including DunedinPACE assessed at baseline to predict MetS in the future.

Main Outcomes and Measures

Diagnosis of incident MetS on average 7.4 ±1.5 years after baseline.

Results

DunedinPACE was associated with incident MetS at follow-up on average 7.4 years later (OR: 9.84, p=0.028). Interestingly, we observed no significant differences (p>0.05) in the area under the curve in predicting MetS between a model that only included clinical parameters and a model that only used GrimAge DNAmAA. Cross-sectional differences between participants with and without MetS remained statistically significant for DunedinPACE only after covariate adjustment (baseline: β=0.042, follow-up: β=0.031, p<0.0001 in both cases).

Conclusions and Relevance

Systematic comparison of epigenetic clocks within a single dataset in relation to MetS and its diagnostic components showed strong and consistent associations with DunedinPACE, but not with other epigenetic clocks. Our results highlight the potential of using certain DNAm-based measures of biological ageing in predicting the onset of clinical outcomes, such as MetS.

Key Points

Question

Are epigenetic age measures able to predict the future onset of Metabolic Syndrome?

Findings

This longitudinal observational study revealed that individuals with a one-year faster pace of aging (DunedinPACE) had 2.3-fold increased odds for incident Metabolic Syndrome ∼7.5-years later.

Meaning

The data reported here will potentially help to implement epigenetic measures in clinical risk assessment.
Dynamic pressure ulcer risk predictions for hospitalized patients: development and validation of a machine learning model with an expert group of nurses
Authors: Greup Steffen , Spoon Denise , de Vroed Annemarie , Werkhoven Ben , Timmerman Enrico , Ista Erwin , van Dijk Monique
Published: December 2024

Background

Pressure ulcers (PU) are a source of harm and discomfort in hospitalized patients. To identify patients at risk for developing PU nurses use validated risk assessment instruments which have insufficient predictive power, also leading to increased nursing workload. Machine learning on electronic health records (EHR) has the potential to provide better risk predictions while also reducing nursing workload.

Objective

To develop and validate a dynamic prediction model for daily PU risk predictions together with an expert group of nurses, while considering factors important to successful clinical implementation like explainability and robustness during the modelling process.

Methods

All admissions to general wards in a single-center tertiary university hospital in the Netherlands were included. A retrospective dataset with candidate predictors was collected from the EHR and split into a training set (December 2021 – November 2022, N=19931) and a validation set (January 2023 – June 2023, N=11387). Separate models were developed for the first 72 hours of admission, and >72 hours. The PU outcome was identified from both structured and free text registration. Predictor definition, selection and modelling choices were discussed with an expert group of nurses. Several candidate machine learning models were compared using cross-validation on the training set. The same final model and predictor set were selected for both ≤72h and >72h, and predictive performance on the validation set was compared to the Waterlow score.

Results

The difference in performance across candidate models was small on the training set. Logistic regression with an L2 penalty and a spline transformation applied to a limited set of predictors was chosen as the final model, and the candidate predictor set was reduced to a final predictor set. The AUROC for the final model was 0.790 (≤72h) and 0.795 (>72h) on the validation dataset. The model clearly outperformed the Waterlow score (0.816 vs. 0.702 (≤72h) and 0.800 vs. 0.677 (>72h)) for the subset of admissions with a registered Waterlow score. Expected remaining length of stay, age and ADL (activities of daily living) score were the predictors with the strongest contribution.

Conclusions

We developed and validated a dynamic prediction model for daily PU risk predictions, which outperformed the traditional Waterlow risk assessment score. During the development process special care was given to considerations for implementation and user acceptance. The model was named DRAAI (Decubitus Risk Alert based on AI), which means ‘turn’ in Dutch and is a common PU preventive measure.
Imaging Clusters of Pediatric Low-Grade Glioma are Associated with Distinct Molecular Characteristics
Authors: Fathi Kazerooni Anahita , Kraya Adam , Rathi Komal S. , Kim Meen Chul , Kesherwani Varun , Corbett Ryan , Vossough Arastoo , Khalili Nastaran , Gandhi Deep , Khalili Neda , Familiar Ariana M. , Jin Run , Huang Xiaoyan , Zhu Yuankun , Sickler Alex , Lueder Matthew R. , Phul Saksham , Storm Phillip B. , Ware Jeffrey B. , Foster Jessica B. , Mueller Sabine , Rokita Jo Lynne , Fisher Michael J. , Resnick Adam C. , Nabavizadeh Ali
Published: December 2024

Background

Cancers show heterogeneity at various levels, from genome to radiological imaging. This study aimed to explore the interplay between genomic, transcriptomic, and radiophenotypic data in pediatric low-grade glioma (pLGG), the most common group of brain tumors in children.

Methods

We analyzed data from 201 pLGG patients in the Children’s Brain Tumor Network (CBTN), using principal component analysis and K-Means clustering on 881 radiomic features, along with clinical variables (age, sex, tumor location), to identify imaging clusters and examine their association with 2021 WHO pLGG classifications. To determine the transcriptome pathways linked to imaging clusters, we employed a supervised machine learning model with elastic net logistic regression based on the pathways identified through gene set enrichment and gene co-expression network analyses.

Results

Three imaging clusters with distinct radiomic characteristics were identified.BRAF V600Emutations were primarily found in imaging cluster 3, whileKIAA1549::BRAFfusion occurred in subtype 1. The model’s predictive accuracy (AUC) was 0.77 for subtype 1, 0.78 for subtype 2, and 0.70 for subtype 3. Each imaging cluster exhibited unique molecular mechanisms: subtype 1 was linked to oxidative phosphorylation,PDGFRB, and interleukin signaling, whereas subtype 3 was associated with histone acetylation and DNA methylation pathways, related toBRAF V600EpLGGs.

Conclusions

Our radiogenomics study indicates that the intrinsic molecular characteristics of tumors correlate with distinct imaging subgroups in pLGG, paving the way for future multi-modal investigations that may enhance understanding of disease progression and targetability.
Associations of Combined Genetic and Lifestyle Risks with Incident Type 2 Diabetes in the UK Biobank
Authors: Zhao Chi , Hatzikotoulas Konstantinos , Balasubramanian Raji , Bertone-Johnson Elizabeth , Cai Na , Huang Lianyun , Huerta-Chagoya Alicia , Janiczek Margaret , Ma Chaoran , Mandla Ravi , Paluch Amanda , Rayner Nigel W , Southam Lorraine , Sturgeon Susan R. , Suzuki Ken , Taylor Henry J , VanKim Nicole , Yin Xianyong , Lee Chi Hyun , Collins Francis , Spracklen Cassandra N.
Published: December 2024

Background

Type 2 diabetes (T2D) results from a complex interplay between genetic predisposition and lifestyle factors. Both genetic susceptibility and unhealthy lifestyle are known to be associated with elevated T2D risk. However, their combined effects on T2D risk are not well studied. We aimed to determine whether unhealthy modifiable health behaviors were associated with similar increases in the risk of incident T2D among individuals with different levels of genetic risk.

Methods

We performed a genetic risk score (GRS) by lifestyle interaction analysis within 332,251 non-diabetic individuals at baseline from the UK Biobank. Multi-ancestry GRS were calculated by summing the effects of 783 T2D-associated variants and ranked into tertiles. We used baseline self-reported data on smoking, BMI, physical activity level, and diet quality to categorize participants as having a healthy, intermediate, or unhealthy lifestyle. Cox proportional hazards regression models were used to generate adjusted hazards ratios (HR) of T2D risk and associated 95% confidence intervals (CI).

Results

During follow-up (median 13.6 years), 13,128 (4.0%) participants developed T2D. GRS (P< 0.001) and lifestyle classification (P< 0.001) were independently associated with increased risk for T2D. Compared with healthy lifestyle, unhealthy lifestyle was associated with increased T2D risk in all genetic risk strata, with adjusted HR ranging from 7.11 (low genetic risk) to 16.33 (high genetic risk).

Conclusions

High genetic risk and unhealthy lifestyle were the most significant contributors to the development of T2D. Individuals at all levels of genetic risk can greatly mitigate their risk for T2D through lifestyle modifications.
Differential metabolic biomarkers between coronary heart disease and diabetes mellitus
Authors: Wang Zhicai , Cang Yan , Shi Fei , Zhang Yi , Cui Hui-Na , He Yun , Liu Li , Li Yan , Xu Yawei , Wen He , Liu Zheng
Published: December 2024

Background

Coronary heart disease (CHD), the leading cause of death globally, is a complex disease often association with metabolic disorders, particularly when co-occurring with diabetes mellitus (DM). However, the mechanisms underlying the interaction between these two chronic conditions remain poorly understood.

Methods

In this study, we enrolled 320 participants, including 103 healthy controls (HC), 62 individuals with CHD, 44 with DM, and 47 with both CHD and DM (CHDDM)) in the training set, along with 64 participants (20 HC, 18 CHD, 12 DM, and 14 CHDDM) in the test set. Plasma metabolomic profiling was performed using gas chromatograph-mass spectrometry (GC-MS) and ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS)-based multi-platform untargeted metabolomics.

Results

Using multi-platform metabolomics, we identified 453 distinct metabolites. Through multivariate statistical analysis, we assigned 63, 27, and 56 disease-associated metabolic biomarkers for CHD, DM, and CHDDM, respectively, followed by pathway enrichment analysis. Using an area under the receiver operating characteristic (ROC) curve (AUC) cutoff value > 0.77, we identified 10, 4, and 8 disease-specific biomarkers for CHD, DM, and CHDDM, respectively. Notably, N-Formyl-L-methionine, N-Acetyl-L-methionine, PE 36:1p (18:0p/18:1), PE 36:2p (18:0p/18:2), and PE 34:2p (16:0p/18:2) were predominant in CHD, glycerophosphocholine and turanose were distinctive to DM, and xanthine and PE 38:5p (18:1p/20:4) were unique to CHDDM. These disease-specific metabolites showed superior diagnostic performance in their respective conditions. Additionally, 23 metabolites were identified as potential biomarkers for assessing the risk of CHD in DM patients.

Conclusion

This comparative metabolomics approach provided new insights into disease-specific markers and pathogenic pathways, offering potential for improved diagnosis and management of CHD and DM.
Integration of metagenome-assembled genomes with clinical isolates reveals genomic signatures ofKlebsiella pneumoniaein carriage and disease
Authors: Gupta Samriddhi , Almeida Alexandre
Published: December 2024

Klebsiella pneumoniaeis an opportunistic pathogen causing diseases ranging from gastrointestinal disorders to severe liver abscesses. While clinical isolates ofK. pneumoniaehave been extensively studied, less is known about asymptomatic variants colonizing the human gut across diverse populations. Genome-resolved metagenomics has offered unprecedented access to metagenome-assembled genomes (MAGs) from diverse host states and geographical locations, opening opportunities to explore health-associated microbial features. Here we analysed 662 human gut-derivedK. pneumoniaegenomes (319 MAGs, 343 isolates) from 29 countries to investigate the population structure and genomic diversity ofK. pneumoniaein carriage and disease. Only 9% of sequence types were found to be shared between healthy and disease states, highlighting distinct diversity across health conditions. Integrating MAGs nearly doubled gut-associatedK. pneumoniaephylogenetic diversity, and uncovered 86 lineages without representation among >20,000Klebsiellaisolate genomes from various sources. Genomic signatures linked to pathogenicity and carriage included those involved in antibiotic resistance, iron regulation, restriction modification systems and polysaccharide biosynthesis. Notably, machine learning models integrating MAGs and isolates more accurately classified disease and carriage states compared to isolates alone. These findings showcase the value of metagenomics to understand pathogen evolution with implications for public health surveillance strategies.
Poly-ubiquitylated transmembrane proteins outcompete other cargo for limited space inside clathrin-coated vesicles
Authors: Liu Hao-Yang , Ashby Grant , Yuan Feng , Sarkar Susovan , Hayden Carl C. , Huibregtse Jon M. , Stachowiak Jeanne C.
Published: December 2024

Endocytic recycling of transmembrane proteins is essential to cell signaling, ligand uptake, protein traffic and degradation. The intracellular domains of many transmembrane proteins are ubiquitylated, which promotes their internalization by clathrin-mediated endocytosis. How might this enhanced internalization impact endocytic uptake of transmembrane proteins that lack ubiquitylation? Recent work demonstrates that diverse transmembrane proteins compete for space within highly crowded endocytic structures, suggesting that enhanced internalization of one group of transmembrane proteins may come at the expense of other groups. Here we show that preferential internalization of poly-ubiquitylated transmembrane proteins results in reduced endocytosis of mono-ubiquitylated and non-ubiquitylated proteins. Using a combination of live-cell imaging and ligand uptake assays, we confirmed that increased ubiquitylation correlates with increased internalization by clathrin-coated vesicles. Further, poly-ubiquitylated receptors significantly outcompeted their mono-ubiquitylated and non-ubiquitylated counterparts for localization to endocytic sites and uptake of extracellular ligands. These findings demonstrate the inherent interdependence of transmembrane protein recycling, suggesting that clathrin-coated vesicles act as selective filters, prioritizing highly ubiquitylated transmembrane proteins for uptake while leaving proteins with little or no ubiquitylation behind. Given that poly-ubiquitylation is thought to signal protein aging and damage, our findings suggest a mechanism for selective internalization of high priority cargo proteins, with simultaneously exclusion and protection of functional proteins that lack poly-ubiquitylation.

Significance

Ubiquitylation is essential for maintaining cellular homeostasis by regulating transmembrane protein trafficking, degradation, and signaling. Traditionally, poly-ubiquitylation has been viewed primarily as a signal for protein degradation, while mono-ubiquitylation is considered sufficient to trigger endocytosis. However, our work reveals a previously unrecognized role for poly-ubiquitylation in clathrin-mediated endocytosis, demonstrating that poly-ubiquitylated transmembrane proteins outcompete their non-ubiquitylated counterparts for incorporation into clathrin-coated vesicles, thereby establishing a competitive framework for endocytic cargo sorting. This mechanism reveals a selective sorting mechanism driven by the extent of ubiquitylation, which could regulate the removal of damaged proteins while protecting functional proteins at the plasma membrane.
Extracellular Exosomal RNAs are Glyco-Modified
Authors: Sharma Sunny , Jiao Xinfu , Yang Jun , Kiledjian Megerditch
Published: December 2024

Epitranscriptomic modifications play pivotal roles in regulating RNA function, encompassing base alterations and the addition of both canonical m7G and noncanonical nucleotide metabolite caps. Recently, the spectrum of modifications has extended to include glyco modification at the 5’ cap or within the RNA. Despite this expansion, the functional implications of glyco modification on RNA remain elusive. Our study reveals that mammalian cells labeled with N-azidoacetylgalactosamine-tetraacylated (Ac4GalNAz) produce small noncoding and nonpolyadenylated glyco-modified RNA (glycoRNA), primarily localized within exosome vesicles. The resistance of glycoRNA-containing exosomes to RNase treatment suggests that Ac4GalNAz-derived glycoRNA constitutes intraluminal cargo, distinct from recently reported cell surface glycoRNAs. Furthermore, we demonstrate that exosome cargo can be transferred to naïve cells, underscoring exosome-mediated intercellular communication of glycoRNAs. Inhibition of exosome biogenesis leads to the accumulation of intracellular glycoRNA while blocking glycan transfer to proteins concomitantly reduced the targeting of glycoRNA within exosomes. These findings highlight a correlation between protein and RNA glycosylation, suggesting that the accumulation of glycoRNAs within exosomes is a regulated process. Our results support a functional role for glyco-modification in mediating RNA targeting into exosomes, offering new insights for enhancing recent advances in exosome-directed diagnostics and therapeutic applications.
Staphylococcus aureusgliding comets: formation and observation
Authors: Davies M.C , Pollitt E.J.G.
Published: December 2024

Staphylococcus aureushas been shown to move across soft agar surfaces by several different mechanisms.S. aureuscan move using either spreading (a form of sliding motility producing generally round/frond like colonies) or by forming comets (slime covered aggregates of cells) that result in long thin dendrites branching out from the central colony. Spreading is agreed to be a form of passive motility whilst the comets are a form of gliding motility (i.e. active). Comets occur under similar conditions to spreading round colonies; however it can be difficult to get the comets to form. Here we examine the variables involved in determining whether comets form as well as report further observations of the comets themselves. We found that the conditions that favoured comet formation (and formed the associated dendrites) occurred over a more limited range than those that enabled spreading motility. Comet formation is very sensitive to the solidifying agents used, the amount of media used and the drying time. We further observed that the comets can propel themselves upwards against gravity unlike spreading motility and thatS. aureusformed unusual dense aggregates and strand-like structures within comets unlike the normal growing arrangement ofS. aureusobserved in spreading. These results may aid others in producing motility assays to study spreading and comet formation inS. aureusand provides further insight into how comets behave.
Reduced trust in bodily sensations predicts suicidal ideation in hospitalized patients with major depression: an observational study
Authors: Eggart Michael , Valdés-Stauber Juan , Müller-Oerlinghausen Bruno
Published: December 2024

Background

Major depressive disorder (MDD) is associated with maladaptive self-reported interoception, i.e., abnormal bodily self-experience. Although diminished body trusting predicts suicidal ideation, interoceptive measures have not been considered in depressed inpatients, whose suicide risk regularly peaks post-discharge. This study aims to explore interoceptive characteristics at admission that help identify inpatients at risk for suicidal ideation at discharge, thereby preventing fatal outcomes.

Methods

The observational study included 87 depressed inpatients providing self-ratings at both hospital admission (T0) and discharge (T1) on the following scales: Multidimensional Assessment of Interoceptive Awareness (MAIA-2); Beck Depression Inventory-II (BDI-II). A hierarchical logistic regression analysis estimated the longitudinal association between self-reported interoception (T0) and suicidal ideation (T1). The optimal cutpoints for predicting suicidal ideation were calculated using ROC curve analysis.

Results

Suicidal ideation was found in 17.24% patients at discharge, who reported lower baseline MAIA-2Trustingscores than non-ideators (p=0.01). Diminished body trusting (OR=0.19), somatic comorbidity (OR=16.77), and baseline suicidal ideation (OR=24.01) significantly predicted suicidal ideation (T1). For body trusting, we estimated an optimal classification of subsequent suicidal ideation for the cutpoint≤2.33 (AUC=0.70 [95% CI 0.57, 0.83], sensitivity=0.87, specificity=0.44, positive predictive value=0.25, negative predictive value=0.94).

Limitations

Due to the exploratory nature of the study, the findings should be replicated in pre-registered trials with larger sample sizes.

Conclusions

Diminished body trusting is, with acceptable sensitivity, a significant predictor for post-treatment suicidal ideation in depressed inpatients. This finding emphasizes the importance of incorporating body-centered approaches into multimodal treatment strategies especially in inpatients under risk to prevent suicidal incidents.
Evaluating Model Performance with Hard-Swish Activation Function Adjustments
Authors: Pydimarry Sai Abhinav , Khairnar Shekhar Madhav , Palacios Sofia Garces , Sankaranarayanan Ganesh , Nguyen Huu Phong
Published: December 2024

In the field of pattern recognition, achieving high accuracy is essential. While training a model to recognize different complex images, it is vital to fine-tune the model to achieve the highest accuracy possible. One strategy for fine-tuning a model involves changing its activation function. Most pre-trained models use ReLU as their default activation function, but switching to a different activation function like Hard-Swish could be beneficial. This study evaluates the performance of models using ReLU, Swish and Hard-Swish activation functions across diverse image datasets. Our results show a 2.06% increase in accuracy for models on the CIFAR-10 dataset and a 0.30% increase in accuracy for models on the ATLAS dataset. Modifying the activation functions in architecture of pre-trained models lead to improved overall accuracy.
Hexosamine Biosynthesis Disruption Impairs GPI Production and ArrestsPlasmodium falciparumGrowth at Schizont Stages
Authors: Alberione María Pía , Avalos-Padilla Yunuen , Rangel Gabriel W , Ramírez Miriam , Romero-Uruñuela Tais , Fenollar Àngel , Crispim Marcell , Smith Terry K , Llinás Manuel , Izquierdo Luis
Published: December 2024

UDP-N-acetylglucosamine (UDP-GlcNAc) is a crucial sugar nucleotide for glycan synthesis in eukaryotes. In the malaria parasitePlasmodium falciparum, UDP-GlcNAc is synthesized via the hexosamine biosynthetic pathway (HBP) and is essential for glycosylphosphatidylinositol (GPI) anchor production, the most prominent form of protein glycosylation in the parasite. In this study, we explore a conditional knockout of glucosamine-6-phosphate N-acetyltransferase (PfGNA1), a key HBP enzyme.PfGNA1 depletion led to significant disruptions in HBP metabolites, impairing GPI biosynthesis and causing mislocalization of the merozoite surface protein 1 (MSP1), the most abundant GPI-anchored protein in the parasite. Furthermore, parasites were arrested at the schizont stage, exhibiting severe segmentation defects and an incomplete rupture of the parasitophorous vacuole membrane (PVM), preventing egress from host red blood cells. Our findings demonstrate the critical role of HBP and GPI biosynthesis inP. falciparumasexual blood stage development and underscore the potential of targeting these pathways as a therapeutic strategy against malaria.

Author Summary

Malaria remains a major cause of illness and death, particularly in sub-Saharan Africa, with increasing resistance to treatments highlighting the urgent need for new strategies. Malaria parasites rely on the hexosamine biosynthetic pathway to produce UDP-N-acetylglucosamine, an essential metabolite for glycosylphosphatidylinositol synthesis. Glycosylphosphatidylinositol molecules anchor vital proteins to the parasite’s surface and, as free glycolipids, serve as structural components of its membranes. Our study examined the effects of disrupting PfGNA1, a key enzyme in the hexosamine biosynthetic pathway, which is distinct from its human counterparts. Disruption of PfGNA1 blocked the production of glycosylphosphatidylinositol, leading to improper protein localization, developmental arrest, and failure of the parasites to mature or exit infected red blood cells. Our results underscore the central role of the hexosamine biosynthetic pathway and glycosylphosphatidylinositol biosynthesis, which are essential for parasite survival. This pathway represents a promising target for developing novel antimalarial therapies.
Muscle growth by sarcomere divisions
Authors: Rodier Clement , Estabrook Ian D. , Chan Eunice HoYee , Rice Gavin , Loreau Vincent , Raunser Stefan , Görlich Dirk , Friedrich Benjamin M. , Schnorrer Frank
Published: December 2024

The sarcomere is the elementary contractile unit of muscles. Adult muscle cells chain thousands of sarcomeres into long periodic myofibrils that attach to the skeleton. How new sarcomeres are added during muscle growth is unknown. By live imaging and high-throughput image analysis, we have now tracked sarcomeric components duringDrosophilamuscle development and discovered that individual sarcomeres divide along the myofibril tension axis into daughter sarcomeres. This way, new sarcomeres can be inserted into contractile and mechanically intact myofibrils. We propose that sarcomere division is triggered by tension and local sarcomere damage originating from skeletal growth and muscle contractions. Sarcomere divisions repair damaged sarcomeres, ensure their mechanical integrity and synchronise sarcomere addition with skeletal growth during animal development.