bluuebunny/crossref_metadata_2025 huggingface dataset:
Within-person changes in objectively measured activity levels as a predictor of brain atrophy in multiple sclerosis
Authors: Fitzgerald Kathryn C. , Sanjayan Muraleetharan , Dewey Blake , Niyogi Pratim Guha , Rjeily Nicole Bou , Fadlallah Yasser , Delaney Alice , Lee Alexandra Zambriczki , Duncan Safiya , Wyche Chelsea , Moni Ela , Calabresi Peter A. , Zipunnikov Vadim , Mowry Ellen M.
Published: January 2025

Objective

The evaluate the association between changes in accelerometry-derived activity patterns and brain atrophy in people with multiple sclerosis (PwMS).

Methods

We included PwMS aged ≥40 years with approximately annual brain MRI who wore GT9X Actigraph accelerometers every three months over two years. Functional principal components analysis (fPCA) summarized overall activity and timing. Additional indices included total and 2-hour specific activity, sedentary time, and circadian rhythm parameters. Whole brain segmentation used SLANT-CRUISE. Generalized estimating equations quantifying between- and within-person effects modeled associations between accelerometry changes and MRI outcomes, adjusting for demographic and clinical factors.

Results

We included 233 PwMS (mean age: 54.4 years, SD: 8.6, 30% male) who wore accelerometers an average of 6.3 times over 58 days across two years. fPCA showed within-person increases in the first fPC, representing low nighttime and high morning activity, were associated with slower brain atrophy (per 1 SD increase: 0.24%; 95% CI: 0.10, 0.40; p=0.0009). Similarly, a 10% increase in 8:00–10:00 AM activity was associated with 0.49% higher whole brain volume (95% CI: 0.19, 0.79; p=0.001) over time, while increased nighttime activity (0:00–2:00) was linked to −0.28% brain volume loss (95% CI: −0.48, −0.08; p=0.007). Higher moderate-to-vigorous activity and daytime activity were associated with greater brain volume preservation longitudinally.

Interpretation

Changes in activity patterns, particularly increased nighttime activity and reduced morning activity, are linked to brain atrophy in PwMS. Accelerometry offers a scalable, sensitive method for tracking MS progression and may be beneficial as a recruitment or outcome measure in trials.
CLINICAL VALIDATION OF SWAASA®ARTIFICIAL INTELLIGENCE PLATFORM USING COUGH SOUNDS FOR SCREENING AND DIAGNOSIS OF RESPIRATORY DISEASES
Authors: Thangakunam Balamugesh , Chandy Sujith Thomas , Rudraraju Gowrisree , Sripada Narayana Rao , Govindaraj Jayanthy , Gottipulla Charishma , Mamidgi Baswaraj , Palreddy Shubha Deepti , Bhoge Nikhil kumar Reddy , Narreddy Harsha Vardhan Reddy , Prasanna Samuel P , Christopher Devasahayam Jesudas , Jain Manmohan , Yechuri Venkat
Published: January 2025

Introduction

Analysis of cough sounds have the potential to give a clue regarding the underlying respiratory disease. The SaaS® platform using artificial intelligence technology can analyze the cough sounds.

Methods

Patients (age >= 18 years) presenting to our departments with respiratory symptoms were prospectively recruited into the study. Patients cough sound was recorded by a mobile device in which the Swaasa software was installed. Spirometry was done and patients’ clinical diagnosis is taken as reference standard for comparison. Polychotomous variables were analyzed in binary form as normal and abnormal. Multi-class outcomes were defined as obstructive, restrictive, or normal spirometry, mild-moderate-severe impairment of spirometry values or disease conditions like asthma, COPD, ILD, Bronchiectasis.

Results

We recruited 2179 patients with respiratory diseases and 827 normal individuals. Sixty-two percent of them were males. The Swaasa platform has 90% accuracy in distinguishing cough from normal individuals and patients as well as distinguishing normal from abnormal spirometry. The performance was consistent across demographic parameters such as age, gender, and BMI. Its accuracy in differentiating into various severity subtypes of spirometry as well as disease types can be improved further.

Conclusion

Swaasa®commends an elevated level of precision in classifying normal and abnormal conditions across demographic subgroups indicating its promise as a screening tool. While the accuracy measures emphasize further refinement to ensure consistent high performance across disease scenarios and severity levels, the study shows Swaasa®’s reasonable potential in identification of specific respiratory diseases and their severity.
Validation of an AI for Skin Diseases in Korea and Global Usage Statistics
Authors: Han Seung Seog , Cho Soo Ick , Chang Sung Eun , Kim Seong Hwan , Na Jung-Im
Published: January 2025

Background

To address the diversity of skin conditions and the low prevalence of skin cancers, we curated a large dataset and collected real-world data, to evaluate the real-world performance.

Methods

We evaluated a neural network model using the NIA dataset (70 diseases; 152,443 images from 92,004 cases from 9 hospitals). The NIA dataset was used to calculate the algorithm’s sensitivity for detecting skin cancer. Global usage statistics (1,690,849 queries) were analyzed to estimate the algorithm’s specificity for malignancy predictions, assuming all predictions were false positives.

A global reader test (61,066 questionnaires) was performed using the SNU dataset (80 diseases; 240 images).

Results

For malignancy diagnosis (NIA dataset), the sensitivity of the algorithm was 78.2% based on the three predicted differentials. In global usage statistics, among predictions for tumorous conditions, the malignancy prediction rates from the three differentials were 12.0% in Korea and 10.0% globally. The algorithm’s predictions for benign tumors were most prevalent in Asia (55.5%), Oceania (46.8%), and Europe (46.5%), while predictions for infectious diseases were more common in Africa (17.1%)

In the reader test (SNU dataset), sensitivity / specificity of the algorithm (87.5% / 91.0%) outperformed those of participants (Korea = 56.9% / 87.2%, global = 55.5% / 84.3%).

Conclusion

For skin cancer diagnosis in Korea, the sensitivity and specificity of the algorithm were estimated to be 78.2% and 88.0%. Further research on appropriate indications is required for screening use, taking overdiagnosis into consideration.
mRNA lipid nanoparticle-incorporated nanofiber-hydrogel composite generates a local immunostimulatory niche for cancer immunotherapy
Authors: Zhu Yining , Yao Zhi-Cheng , Li Shuyi , Ma Jingyao , Wei Christine , Yu Di , Stelzel Jessica L. , Ni Bobby Y.X. , Miao Yang , Van Batavia Kyra , Lu Xiaoya , Lin Jinghan , Dai Yifan , Kong Jiayuan , Shen Ruochen , Goodier Kailei D. , Liu Xiang , Cheng Leonardo , Vuong Ivan , Howard Gregory P. , Livingston Natalie K. , Choy Joseph , Schneck Jonathan P. , Doloff Joshua C. , Reddy Sashank K. , Hickey John W. , Mao Hai-Quan
Published: January 2025

Hydrogel materials have emerged as versatile platforms for various biomedical applications. Notably, the engineered nanofiber-hydrogel composite (NHC) has proven effective in mimicking the soft tissue extracellular matrix, facilitating substantial recruitment of host immune cells and the formation of a local immunostimulatory microenvironment. Leveraging this feature, here we report an mRNA lipid nanoparticle (LNP)-incorporated NHC microgel matrix, termed LiNx, by incorporating LNPs loaded with mRNA encoding tumour antigens. Harnessing the potent transfection efficiency of LNPs in antigen-presenting cells (APCs), LiNx demonstrates remarkable immune cell recruitment, antigen expression and presentation, and cellular interaction. These attributes collectively create an immunostimulating milieu and yield a potent immune response achievable with a single dose, comparable to the conventional three-dose LNP immunization regimen. Further investigations reveal that the LiNx not only generates heightened Th1 and Th2 responses but also elicits a distinctive Type 17 T helper cell-mediated response pivotal for bolstering antitumour efficacy. Our findings elucidate the mechanism underlying LiNx’s role in potentiating antigen-specific immune responses, presenting a new strategy for cancer immunotherapy.
ZUGC-RNA degradation generates immunosuppressor to evade immune responses in eukaryotes
Authors: Gao Shuliang , Chen Mengting , Wich Douglas , Bloomer Hanan , Qu Zhiyuan , Guan Huiwen , Xu Qiaobing
Published: January 2025

Among the hundreds of modified nucleosides identified in terrestrial life, 2-amino-6-aminopurine (Z) is widely recognized as a prominent modified purine. Recently, RNA written with the ZUGC alphabet shows significant potential in RNA therapeutics as a synthetic biosystem. Here, we demonstrate that ZUGC-RNA can evade immune recognition in eukaryotes, independent of factors such as RNA length, sequence, 5’-triphosphate, modified uridine, and secondary structure. Notably, we discovered that both the degradation of ZUGC-RNA and metabolites of Z-nucleotides can function as immunosuppressors, silencing TLR7 sensing to block immune responses. This mechanism differs from that of pseudo-uridine (Ψ) modified RNA currently in use. ZUGC-RNAs also demonstrate broad applicability across multiple neural cell types. Our findings provide valuable insights for developing more tolerable RNA-based drugs and designing immunomodulators targeting TLR7. In addition to the potential prebiotic relevance of Z, our finding not only contributes to understanding the RNA world hypothesis but also provides new insights into the exploration of the origin of life.
FLIM Imaging of mCherryTYG Deciphers pH Dynamics and Lifestyles ofSalmonellaTyphimurium
Authors: Singh Moirangthem Kiran , Fernandez Marion , Dilawari Rahul , Zangoui Parisa , Kenney Linda J.
Published: January 2025

Intracellular pH regulation is fundamental to bacterial adaptation, virulence, and survival in diverse environments.SalmonellaTyphimurium, a key human pathogen, exploits host and environmental pH cues to transition between planktonic, biofilm, and virulence-associated states. However, precise tools to monitor bacterial pH dynamics at subcellular resolution have been limited. Herein, we report the development and application of mCherryTYG, a genetically encoded pH-sensitive fluorophore optimized for fluorescence lifetime imaging (FLIM), enabling robust and high-resolution pH measurements across diverse conditions. mCherryTYG demonstrated exceptional sensitivity across a broad pH range (5.5–8.5) with consistent lifetime responses, and was unaffected by temperature, buffer composition, or ionic strength. Using FLIM, we characterized the pH dynamics ofSalmonellaacrossin vitro, host, and biofilm contexts. Under acidic stressin vitro,Salmonellamaintained a uniform intracellular pH (∼6.04), providing clarity on previously debated heterogeneity. In infections of HeLa cells,Salmonellaexisted in distinct pH environments: acidic vacuolar pH (∼5.89) and neutral cytoplasmic pH (∼7.10). During the late infection stage, ∼17% of the bacterial population retained an acidic pH. Biofilm studies revealed stratified pH profiles, with acidic pH near the bottom and neutral pH at the surface, mirroring patterns observed in other pathogens. In heterologous host models, pH gradients shaped bacterial adaptation strategies. InC. elegans,Salmonellaexperienced a progressive pH gradient from neutral pH (∼7.10) in the anterior lumen to acidic pH (∼6.45) in the posterior. Similarly, in zebrafish,Salmonellaencountered acidic lysosome-rich enterocytes (∼5.84) and neutral regions (∼7.33) in the anterior gut. This study establishes mCherryTYG-FLIM as a transformative tool for studying bacterial pH regulation, revealing pH as a critical modulator ofSalmonellalifestyle transitions: virulence, and persistence. Our findings provide new insights into host-microbe interactions and present pH as a promising target for therapeutic interventions against bacterial infections.
Loss of tumor cell MHC Class II drives insensitivity of BRAF-mutant anaplastic thyroid cancers to MAPK inhibitors
Authors: Tiedje Vera , Greenberg Jillian , Qin Tianyue , Im Soo-Yeon , Krishnamoorthy Gnana P. , Boucai Laura , Xu Bin , French Jena D. , Sherman Eric J , Ho Alan L , de Stanchina Elisa , Socci Nicholas D. , Jin Jian , Ghossein Ronald , Knauf Jeffrey A. , Koche Richard P , Fagin James A.
Published: January 2025

Cancer cells present neoantigens dominantly through MHC class I (MHCI) to drive tumor rejection through cytotoxic CD8+ T-cells. There is growing recognition that a subset of tumors express MHC class II (MHCII), causing recognition of antigens by TCRs of CD4+ T-cells that contribute to the anti-tumor response. We find that mouse BrafV600E-driven anaplastic thyroid cancers (ATC) respond markedly to the RAF + MEK inhibitors dabrafenib and trametinib (dab/tram) and that this is associated with upregulation of MhcII in cancer cells and increased CD4+ T-cell infiltration. A subset of recurrent tumors lose MhcII expression due to silencing ofCiita, the master transcriptional regulator of MhcII, despite preserved interferon gamma signal transduction, which can be rescued by EZH2 inhibition. Orthotopically-implanted Ciita-/-and H2-Ab1-/-ATC cells into immune competent mice become unresponsive to the MAPK inhibitors. Moreover, depletion of CD4+, but not CD8+ T-cells, also abrogates response to dab/tram. These findings implicate MHCII-driven CD4+ T cell activation as a key determinant of the response of Braf-mutant ATCs to MAPK inhibition.
An oligo walk to identify siRNAs against the circular Tau 12->7 RNA
Authors: Welden Justin R. , Margvelani Giorgi , Miaro Megan , Mathews David , Rodgers David W. , Stamm Stefan
Published: January 2025

Circular RNAs are associated with numerous diseases and recent evidence shows that they can be translated into proteins after undergoing RNA modification. Circular RNAs differ from their ‘linear’ mRNA counterparts in their backsplice site, allowing selective targeting using RNA interference, which however limits the options to place the siRNA. We tested all possible siRNAs against the backsplice site of the circTau 12->7 RNA after it was subjected to adenosine to inosine RNA editing, a modification that promotes translation of the circRNA. Most siRNAs reduced the circRNA and protein abundance, which however did not correlate. We identified an siRNA with an IC50 of 750 pmol efficacy on protein expression. This circRNA fulfilled six of the eight criteria for siRNAs targeting mRNAs. Thus, modified circRNAs expressing protein can be targeted with siRNAs, but their optimal sequence needs to be determined empirically.
Combining Directed Evolution with Machine Learning Enables Accurate Genotype-to-Phenotype Predictions
Authors: Howard Alexander J. , Rim Ellen Y. , Garrett Oscar D. , Shim Yejin , Notwell James H. , Ronald Pamela C.
Published: January 2025

Linking sequence variation to phenotypic effects is critical for efficient exploitation of large genomic datasets. Here we present a novel approach combining directed evolution with protein language modeling to characterize naturally-evolved variants of a rice immune receptor. Using high-throughput directed evolution, we engineered the rice immune receptorPik-1to bind and recognize the fungal proteins Avr-PikC and Avr-PikF, which evade detection by currently characterizedPik-1alleles. A protein language model was fine-tuned on this data to correlate sequence variation with ligand binding behavior. This modeling was then used to characterizePik-1variants found in the 3,000 Rice Genomes Project dataset. Two variants scored highly for binding against Avr-PikC, andin vitroanalyses confirmed their improved ligand binding over the wild-typePik-1receptor. Overall, this machine learning approach identified promising sources of disease resistance in rice and shows potential utility for exploring the phenotypic variation of other proteins of interest.
Unconventionally primed type 1 follicular helper T cells are required for long-lived IgA plasma cell development following mucosal viral infection
Authors: Haniuda Kei , Edner Natalie M. , Makita Yuko , Watts Tania H. , Wu Gregory F. , Dileepan Thamotharampillai , Gommerman Jennifer L.
Published: January 2025

Although IgA+long-lived plasma cells (LLPCs) generated following mucosal viral infection provide durable protection against reinfection, little is known about their generation. Here, we show that oral RV infection induces gut-resident LLPCs that produce highly mutated protective IgA. Unlike RV-specific IgG+LLPCs, IgA+LLPCs were generated independently of MHCII expression by dendritic cells – rather MHCII expression by B cells was both necessary and sufficient. B cell MHCII was also sufficient to induce a unique population of T-bet+follicular helper T (TFH1) cells which were crucial for RV-specific IgA+LLPC accumulation in the gut via IFNγ- and CXCR3-dependent mechanisms. Similar to RV infection, TFH1 cells were required for influenza-specific IgA response. However, unlike RV infection, B cell MHCII was not sufficient to induce influenza-specific IgA+LLPCs, suggesting the operation of mucosal site-specific priming mechanisms. Collectively, our data reveal that unconventionally primed TFH1 cells support IgA responses to mucosal viral infections.
Designing biochemical circuits with tree search
Authors: Bhamidipati Pranav S. , Thomson Matthew
Published: January 2025

Discovering biochemical circuits that exhibit a desired behavior is an outstanding problem in biological engineering. The traditional approach of enumerating every possible circuit topology becomes intractable for circuits with more than four components due to combinatorial scaling of the search space. Here, we use Monte Carlo Tree Search (MCTS), a reinforcement learning (RL) algorithm, to optimize circuit topology for a target phenotype by approaching circuit design as a sequence of assembly decisions. Our RL-based design framework, which we call CircuiTree, efficiently and comprehensively finds robust designs for three-component oscillators by prioritizing sparsity. CircuiTree can also infer candidate network motifs from its search results, producing similar results to enumeration. Using parallel MCTS, we scale this workflow up to five components and find that highly fault-tolerant designs use a novel strategy, which we call motif multiplexing. Multiplexed circuits contain many overlapping network motifs that each activate in different mutational scenarios. The evolutionary robustness of multiplexing may explain the ubiquity of multiple sub-oscillators in circadian clock circuits. Overall, CircuiTree provides the first scalable computational platform for designing biochemical circuits.
Accelerated Adaptation of SARS-CoV-2 Variants in Mice Lacking IFITM3 Preserves Distinct Tropism and Pathogenesis
Authors: Denz Parker J. , Papa Jonathan L. , McFadden Matthew I. , Rao Prerana R. , Roettger Jack , Forero Adriana , Yount Jacob S.
Published: January 2025

Here we investigated whether interferon induced transmembrane protein 3 (IFITM3), a key antiviral protein deficient in certain human populations, affects interspecies adaptation of SARS-CoV-2. We found that SARS-CoV-2 Beta and Omicron variants passaged through IFITM3-deficient versus wild type mice exhibit enhanced replication and pathogenesis in this new host species. Enhancements associated with amino acid substitutions in the viral genome, suggesting that IFITM3 limits accumulation of adaptive mutations. Mouse-adapted viruses enabled comparative studies of variants in mice. Beta caused lung dysfunction and altered cilia-associated gene programs, consistent with broad viral antigen distribution in lungs. Omicron, which shows low pathogenicity and upper respiratory tract preference in humans, replicated to high nasal titers while showing restrained spatial distribution in lungs and diminished lung inflammatory responses compared to Beta. Our findings demonstrate that IFITM3 deficiency accelerates coronavirus adaptation and reveal that intrinsic SARS-CoV-2 variant traits shape tropism, immunity, and pathogenesis across hosts.

HIGHLIGHTS

IFITM3 is a critical barrier to SARS-CoV-2 adaptation in new host species

Mouse-adapted SARS-CoV-2 strains enable comparative pathology

Omicron favors nose and large airways, leading to mild lung pathology

Beta exhibits broad lung replication, driving severe inflammation and dysfunction
The Host DHX29 RNA Helicase Regulates HCMV Immediate Early Protein Synthesis
Authors: Lenarcic Erik M. , Moorman Nathaniel J.
Published: January 2025

The dead box helicase DHX29 plays a critical role in the translation of mRNAs containing complex RNA secondary structure in their 5’ untranslated regions. The human cytomegalovirus (HCMV) genome has a high GC content, suggesting the 5’UTRs of viral mRNAs may contain significant secondary structure and require DHX29 for their efficient translation initiation. We found that depleting DHX29 from primary human fibroblasts prior to infection reduced viral mRNA and protein levels and decreased HCMV replication. The defect in HCMV replication correlated with decreased expression of the HCMV immediate early proteins IE1 and IE2, which are necessary for the establishment of lytic infection. Analysis of polysome associated mRNAs revealed that the defect in IE1 and IE2 expression is due to decreased mRNA translation efficiency. We found that DHX29 depletion led to reduced levels of the eIF4F translation initiation complex, resulting from decreased translation of the eIF4G mRNA. However, in line with our previous results showing a minimal role for the eIF4F complex in HCMV mRNA translation, we found that depleting eIF4G prior to infection did not impact IE1 and IE2 translation. Together our results define a new role for DHX29 in regulating eIF4F-dependent translation and identify a critical role for DHX29 in the translation of HCMV mRNAs.

Significance

Expression of the HCMV immediate early proteins IE1 and IE2 is critical for the establishment of lytic replication and the reactivation of latent HCMV infections. Defining the mechanisms controlling HCMV IE1 and IE2 protein expression has the potential to identify new strategies for therapeutic interventions that can limit HCMV disease in immune naïve and immune compromised individuals. Our finding that the cellular DHX29 helicase is necessary for the efficient translation of mRNAs encoding IE1 and IE2 suggests that therapies that inhibit DHX29 could potentially be useful in treating HCMV disease and adds to the growing body of literature suggesting DHX29 activity is a disease driver in multiple indications including viral disease, inflammation and cancer.
Zmap: an intelligent region-allocation method to map single-cell into spatial data
Authors: Cai Quanyou , Lin Lihui , Liu Xin , Chen Jiekai
Published: January 2025

Integration of single-cell and spatial transcriptome represents as a fundamental strategy to enhance spatial data quality. However, existing methods for mapping single-cell data to spatial coordinates struggle with large-scale datasets comprising millions of cells. Here, we introduce Zmap, an intelligent region-allocation method inspired by the region-of-interest (ROI) concept from image processing. By using gradient descent, Zmap allocates cells to structured spatial regions that matching the most significant biological information, optimizing the integration of data and improving speed and accuracy. Zmap excels in integrating data even in the presence of various sequencing artifacts, such as cell segmentation errors and imbalanced cell-type representations. Zmap outperforms state-of-the-art methods by 10 to 1000 times in speed, and it is the only approach capable of integrating datasets containing millions of cells in a single run. As a result, Zmap uncovers originally hidden gene expression patterns in the brain section, offers new insights into organogenesis and tumor microenvironments, all with exceptional efficiency and accuracy.
Data-Driven Feed Optimization for Sustainable Aquaculture through Integrated Omics Analysis and Two-stage Bayesian optimization
Authors: Terayama Kei , Soma Satoshi , Furuita Hirofumi , Shimizu Tomohito , Iwasaki Takashi , Sakata Kenji , Akagi Ken-ichi , Asakura Taiga , Sanda Tetsuya , Yamaguchi Tomofumi , Fujikura Yuji , Hongo Yuki , Shima Hideaki , Yokota Hideo , Kikuchi Jun , Yasuike Motoshige , Mekuchi Miyuki
Published: January 2025

In aquaculture and livestock farming, developing feed that promotes efficient growth while minimizing environmental impact is crucial for sustainability. We developed a data-driven feed optimization system (DFOS) that integrates omics analysis with machine learning-based optimization technologies. First, DFOS employed Bayesian optimization (BO) to identify the optimal proportions of proteins and lipids, which are crucial feed components. Simultaneously, omics analysis was conducted to assess the physiological response of the targets to a given feed and identify key dietary components essential for growth. Next, BO was used to efficiently modify the combination and proportion of the specific additives identified in the first stage. We demonstrated the efficacy of DFOS by applying it to develop a new feed for the high-demand leopard coral grouper (Plectropomus leopardus) in Southeast Asia. This system provides an efficient data-driven framework for feed optimization across aquaculture and livestock, contributing significantly to more sustainable and productive farming practices.
Targeting deubiquitinating enzymes (DUBs) and ubiquitin pathway modulators to enhance host defense against bacterial infections
Authors: Santelices John , Schultz Alexander C , Walker Alyssa , Adams Nicole , Tirado Deyaneira , Barker Hailey , Eshraghi Aria , Czyz Daniel M. , Ferraro Mariola J
Published: January 2025

The rise of antibiotic-resistant bacterial pathogens poses a critical global health challenge, necessitating innovative therapeutic approaches. This study explores host-targeted therapies (HTTs) by focusing on deubiquitinating enzymes (DUBs), essential modulators of the ubiquitin-proteasome system (UPS) that regulate host-pathogen interactions during many bacterial infections. Using Salmonella-infected macrophages as a model, we identified UPS modulators that enhance bacterial clearance and observed significant changes in DUB expression, particularly USP25, USP46, and Otud7b. The small-molecule DUB inhibitor AZ-1 significantly reduced intracellular bacterial loads in vitro and mitigated early disease severity in a murine model by decreasing fecal bacterial loads and preserving host weight. However, AZ-1 alone did not achieve complete clearance of Salmonella and required combination with extracellular-targeting antibiotics for optimal efficacy. Notably, AZ-1 demonstrated broad-spectrum activity against multidrug-resistant pathogens, including Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. Transcriptomic analyses revealed infection-induced DUB regulation and highlighted pathways modulating immune responses, including TNF-α secretion. These findings highlight the potential of targeting the UPS as a host-directed antimicrobial strategy and provide a foundation for developing innovative therapies to combat antimicrobial resistance.
Effectiveness of Computer-Aided interventions and Virtual Reality in Wrist and Hand rehabilitation: a Scoping Review Protocol
Authors: Tonial Nicola , Scalise Valentina , Maselli Filippo , Benedettini Elena , Pili Michela , Santandrea Sheila
Published: January 2025

Background

To date, advances in the technological and medical fields have increased the application of virtual reality tools, smartphone apps, and computer-aided therapy in clinical and rehabilitation settings. These tools have been shown to enhance patient involvement and improve self-efficacy in their treatment pathways. However, in orthopaedic and rheumatology fields, studies remain limited, and comprehensive reviews providing an exhaustive overview are lacking.

Objective

The purpose of this Scoping Review is to provide a general overview of the use of virtual reality and computer aided equipment in musculoskeletal and rheumatological rehabilitation of the wrist and hand, outlining the main types of instruments used, how they are applied, describing any gaps in the literature and possible future developments on the use of VR and PC-aided treatments.

Eligibility criteria

This study will contain articles that included a population with hand and/or wrist deficits attributable to musculoskeletal and/or rheumatological pathologies or traumas and who undertook a rehabilitation programme focusing on virtual reality or computer aided devices. All studies with subjects suffering from neurological pathologies, such as stroke or Parkinson’s disease, will be excluded.

Methods

This scoping review will be carried out following the guidance of the Joanna Briggs Institute (JBI). Articles will be searched in databases such as PubMed (Medline), Cochrane central, Scopus, Pedro and CINHALcomplete from December 2024. Additional studies will be selected through grey literature, such as Google Scholar. Article selection and data mining will be done by three reviewers, while a fourth will resolve any discrepancies or disputes. No restrictions on type of publication will apply; only articles written since 2014 and written in Italian or English will be considered.

Ethics and dissemination

Ethical approval is unnecessary for this study.
Process evaluation of the first universally designed asynchronous Multiple Mini Interview for optimised accessibility across neurotypes
Authors: Callwood Alison , Harris Jenny , Coe Madeleine , Sutton Katie , Gillam Lee , Brewis Ivan , Tiffin Paul
Published: January 2025

Many jurisdictions legally require reasonable adjustments in personnel selection, to support individuals with disabilities, such as those with neurodevelopmental conditions. Recruitment to healthcare professions and education programmes is no exception. These measures often depend on applicants having formal diagnoses or a willingness to disclose their needs, overlooking the natural heterogeneity in cognition, learning, and behaviour. Consequently, traditional selection methods may inadvertently disadvantage certain candidates, Thus, more inclusive personnel selection practices are needed. We aimed to assess the effect of co-designed interview modifications on differential performance between neurodivergent and neurotypical participants in a process evaluation. The co-design approach was employed to advance an existing online interview that utilised the Multiple Mini Interview (MMI) methodology in an asynchronous digital format. The interview was evaluated in two configurations: standard and modified. The modified version enhanced the standard version by incorporating a practice portal and accessibility features identified by neurodivergent volunteers. A total of 292 individuals, comprising 148 neurotypical and 146 participants self-identifying as neurodivergent from across the United Kingdom, took part in mock MMIs scored by independent assessors using a seven-point Likert scale. Participants who self-identified as neurodivergent achieved significantly higher mean scores on the modified interview compared to the standard format (mean scores; 141.6 vs. 121.4 points; p<0.0001). In contrast, no statistically significant inter-group differences were observed for neurotypical participants for those taking the standard or modified interview. Scoring differences between neurodivergent and neurotypical participants reduced when the modified interview was used; no statistically significant intergroup difference in mean scores was observed in this condition (141.6 vs. 136.6; p=0.06). Inter-rater reliability for a random sample of double-blind scored interviews (10%) was high (ICC 0.8; p<0.001). Furthermore, 92% of neurodivergent participants reported that the optimised features facilitated the interview process, 70% perceived the outcomes as fair and objective, and 70% reported experiencing reduced anxiety compared to the unmodified interview. These findings provide evidence that interview modifications can substantially reduce pre-existing disadvantages neurodivergent applicants may face when participating in online, digital interviews in this context. Such enhancements should be universally implemented to promote greater equity in personnel selection processes.
Prevalence and drug-resistance patterns of methicillin-resistantStaphylococcus aureusand extended-spectrum β-lactamase producingEnterobacteriaceaeamong raw vegetables
Authors: Ahmed Duressa Shafi , Gebre Alemitu Beyene , Erancho Hadbacho Tsegaye , Shinato Habtamu Teshale , Ormago Moges Desta
Published: January 2025

Background

Antimicrobial resistance is a top global public health and development threat. Antibiotic-resistant bacteria in food items, such as vegetables, have become a public health issue. Contamination of vegetables sold in various places can cause foodborne illnesses in many countries, including Ethiopia, and affect the health of consumers. Many bacterial pathogens are now resistant to multiple drugs. In recent years, several multi-drug resistant bacterial pathogens with epidemiological significance have emerged, such as MRSA and ESBL-PE.

Methods

A cross-sectional study was conducted in Aroge Gebeya Market, Hawassa City, from March to May 2024. Six types of raw vegetables with a total of 216 (6×36) were collected. Identification of methicillin-resistantStaphylococcus aureusand extended-spectrum β-lactamase producingEnterobacteriaceaeand drug resistance patterns were done by using the Kirby-Bauer disk diffusion method. Data on sociodemographic variables and hygiene practices were collected using semi-structured questionnaires on Kobo Toolbox Software and imported to SPSS Software Version 29.0.1 for analysis.

Results

The overall prevalence of MRSA and/or ESBL-PE among vegetables was 18.1% (39/216). Among the isolates, 56.9% (91/160) were MDR, 29.2% (14/48) were MRSA, and 24.1% (27/112) were ESBL producers. The most frequently detected isolates wereS. aureus30.0% (48/160),Enterobacter spp.15.6% (25/160),Citrobacter spp.15.0% (24/160),E. coli10.6% (17/160),Salmonella spp.10.0% (16/160) andKlebsiella spp.8.1% (13/160). The highest frequency of bacterial isolates was found in tomatoes 21.9% (35/160), kale 18.1% (29/160), and lettuce 16.9% (27/160). Vegetables bought from vendors with untrimmed nails were significantly more likely to have a higher prevalence of MRSA and/or ESBL-PE compared to those from vendors with trimmed nails (AOR = 4.123; 95% CI: 1.681 - 10.109, p = 0.002).

Conclusion

This study found that vegetables were notable for the presence of MDR bacteria, specifically ESBL-PE and MRSA. Consequently, we strongly recommend that local health authorities develop and implement effective control strategies to mitigate these resistant bacteria among vegetables.
Proteomic associations with fluctuation and long-term changes in BMI: A 40-year follow-up study
Authors: Obeso Alvaro , Drouard Gabin , Palviainen Teemu , Wang Xiaoling , Ollikainen Miina , Silventoinen Karri , Kaprio Jaakko
Published: January 2025

Introduction

While some studies have explored associations between weight change and blood proteins, most have been intervention-based, offering limited insight into proteomic associations with long-term weight gain. It remains unclear whether plasma proteins are related to BMI fluctuation over time. This study investigates associations of long-term BMI changes and fluctuations with over 1,000 plasma proteins involved in cardiometabolic and inflammation functions.

Data and Methods

The study included 304 Finnish adult twins (117 men) born before 1958 from the Older Finnish Twin Cohort, with BMI data spanning five time points (1975, 1981, 1990, 2011, and 2012–2014). Proteomic data were derived from blood samples collected at the last BMI measurement. Linear mixed-effects models analyzed individual BMI trajectories, producing intercepts (baseline BMI) and slopes (BMI change rates). BMI fluctuation was calculated as the average squared deviation from expected BMI across time points. Associations between BMI changes/fluctuation and (i) 1,231 plasma proteins related to cardiometabolic and inflammatory functions and (ii) polygenic risk scores for BMI (PRSBMI), as well as interaction effects between PRSBMIand baseline BMI on protein-BMI relationships were studied. Within-pair analyses using monozygotic twins were conducted to account for shared confounding factors.

Results

A total of 135 proteins were associated with changes in BMI over 40 years, while 17 proteins were linked to fluctuation in BMI: 12 associations (10 with BMI changes and 2 with fluctuation) remained significant in within-twin pair analyses. PRSBMIassociated with BMI changes but not with fluctuations. PRSBMI-protein interactions explaining BMI changes or fluctuation was found, though a single interaction between the CD72 protein and baseline BMI was observed.

Conclusion

This study highlights significant associations between plasma proteins and long-term BMI changes and fluctuations, with no evidence of PRSBMI-protein interactions influencing BMI trends. These findings underscore the substantial role of environmental factors in shaping proteome-BMI associations over adulthood.
Comparing the Cost-Effectiveness of Alternative Policies for Recommending and Providing HIV Pre-exposure Prophylaxis to Men Who Have Sex With Men in the EU
Authors: WANG Boxuan , Brazia Joao , Teixeira Andreia Sofia , Valdano Eugenio
Published: January 2025

In the European Union, HIV disproportionately affects men who have sex with men (MSM), with prevalence rates ranging from 2.4% to 29%. Despite the high efficacy of pre-exposure prophylaxis (PrEP) in preventing HIV, its accessibility and uptake remain uneven across countries. This study examines the effectiveness and cost-effectiveness of different PrEP policies across 20 EU countries. We employed a stochastic agent-based model of HIV transmission among MSM. The model incorporated data on sexual behavior, PrEP adherence and healthcare costs to evaluate the impact of five distinct PrEP eligibility policies. Outcomes included HIV infections averted, HIV-related deaths prevented, PrEP coverage, and incremental cost-effectiveness ratio. Policies by the US CDC and Belgian authorities were the most effective in reducing HIV infections and deaths, driven by higher PrEP coverage. However, the WHO policy emerged as the most costeffective across the 20 countries, despite its current use being limited to Denmark. The European AIDS Clinical Society guidelines also showed potential, although not currently implemented. In countries without PrEP reimbursement, reducing drug costs would significantly expand the range of cost-effective policy options. Optimizing PrEP policies is crucial for reducing HIV incidence among MSM in the EU. Broad eligibility criteria maximize effectiveness, while WHO guidelines offer a cost-effective alternative in constrained economic contexts. Our findings highlight the need for policy adjustments to enhance PrEP accessibility, inform national health strategies, and achieve sustainable HIV prevention across diverse settings.
Critically ill patients with a reverse blood pressure dipping phenotype at increased risk for delirium and death
Authors: El Jamal Nadim , Brooks Thomas G. , Mrcela Antonijo , Genuardi Michael V. , FitzGerald Garret A. , Skarke Carsten
Published: January 2025

Background

The ICU environment is disruptive to a patient’s biological rhythms where sleep-wake cycles are often desynchronized from the environmental day-night changes. This puts patients at increased risk to develop delirium with consequent fiscal pressure for the health care system. An underappreciated dimension is how time-specific patient phenotypes in the critical care environment relate to clinical outcomes. We set out to analyze how rhythmic components (or the lack thereof) in physiological data streams sampled at high resolution in the ICU were associated with the future incidence of delirium and death. To offer cues for further interrogation into mechanism and risk prognosis, we examined differences in 24-hour fluctuations of clinical labs in ICU patient populations at risk.

Methods

Rhythmic components using dipping ratios and JTK_CYCLE statistics were derived from 24-hour blood pressure and heart rate measurements available from ICU patient admissions recorded in the MIMIC IV database. Logistic adjusted regression models assessed the association between disrupted vital sign rhythms and the future incidence of delirium during the same hospital admission and death. Aggregation of numeric clinical lab measurements across the first 24 hours from all patient admissions allowed modelling of rhythmic patterns and subsequent association studies to link potential biochemical mechanisms to perturbed vital sign rhythms and adverse ICU outcomes.

Results

Patients with reverse blood pressure dipping were at a 40% higher risk to have a diagnosis of delirium (Odds Ratio: 1.40, 95% CI: 1.14-1.72) and a 13% increased risk of death (Odds Ratio: 1.13, 95% CI: 1.02-1.26). Compared to the patient population with nocturnal blood pressure dip, reverse dippers showed 24-hour biochemistry profiles suggestive of altered circadian programs specifically in clinical parameters of renal, metabolic, and hemostatic function.

Conclusions

Reverse blood pressure dipping can be an early sign for the future development of delirium in the ICU and is accompanied by disrupted biorhythms across multiple organ systems. Dampened and reversed heart rate and blood pressure rhythms are associated with a higher risk for death in ICU patients. Considering the inclusion of these risk factors in preventive care may improve patient outcomes and reduce burden on the health care system.
Phylogeny-based estimates of epidemic population substructure outperform time series approaches
Authors: Spencer Julie A. , Goldberg Emma E. , Alexander Prescott C. , Del Valle Sara Y.
Published: January 2025

Improving infectious disease models plays a crucial role in mitigating global health impacts. Population-level models have been essential for understanding and anticipating impacts of infectious diseases, but their accuracy has often been limited due to changing environments, rapid pathogen evolution, and insufficient access to detailed transmission data. In particular, due to the lack of granular transmission data, many epidemiological models assume homogeneous disease transmission rather than acknowledge differences between groups within the host population. To address this gap, we conducted a simulation study to assess the potential for inferring group-structured viral transmission dynamics from phylogenetic data and to demonstrate how age structure can be incorporated in case projections. Using a synthetic dataset of 800 age-structured viral phylogenies and their associated case time series, we estimated transmission rates within and between age groups. Our results show that the estimates derived from phylogenies are more accurate than those from case counts alone, although both approaches enabled recovery of age-specific transmission differences. These results suggest that viral phylogenies and case-count time series each provide valuable data that can improve our understanding of population-level disease dynamics, ultimately contributing to more accurate and effective models for informing public policy and reducing disease burden.
Patient Reported Tolerance of 90 Days of Pre-Operative Endocrine Therapy: Results from the POWER Trial
Authors: Millard Trish , Turkheimer Lena , Schlefman Jenna , Petroni Gina , Brighton David , Showalter Shayna
Published: January 2025

Background

Prospective randomized data supports radiation omission in women ≥ 65 years who take adjuvant endocrine therapy (AET) following breast-conserving surgery. Many patients who omit radiation stop AET early due to side effects. In the POWER trial, a prospective single-arm study, patients took 90 days of pre-operative endocrine therapy (pre-ET) to assess tolerance before making adjuvant treatment decisions. We hypothesized that patient-reported outcomes (PROs) during pre-ET would be heterogeneous and that 90 days was sufficient time for symptoms to develop.

Patients and Methods

PRO data from POWER trial participants was obtained before, during, and after pre-ET, including health-related quality of life (HRQoL), depression, and ET symptoms using the EORTC-QLQ, CESD-R, and BCPT-SCL tools. PRO assessments were further analyzed after stratifying patients by high or low perceived sensitivity to medicine (PSM).

Results

Pre-ET PROs were assessed for 75 participants. The majority (73.3%) reported symptoms during pre-ET. Only 10.7% had symptoms severe enough to stop pre-ET before 90 days. Vasomotor (42.7%) and musculoskeletal (41.3%) symptoms were the most common. HRQoL was preserved for 66.6% participants. Patients with high PSM had more ET side effects.

Conclusion

Patients developed similar side effects during pre-ET as those typically seen with AET. PROs and the impact of pre-ET on HRQoL were patient-dependent. A 90-day course of pre-ET is sufficient for patients to develop symptoms reflective of long-term AET. Future analyses will assess the association of pre-ET PROs with AET initiation and adherence.
Modeling the Economic Impact of a CIZ1B Biomarker Blood Test for Lung Cancer Screening in High-Risk Populations
Authors: Hinkel Jennifer , Kavade Rutuja , Joshi Madhura
Published: January 2025

Background

This study evaluates the economic implications of incorporating a CIZ1B biomarker blood test into lung cancer screening protocols for Medicare-eligible high-risk populations. Despite the proven mortality reduction benefits of low-dose computed tomography (LDCT), its adoption remains low. Barriers such as access disparities, logistical challenges, and the high rate of false positives necessitating invasive follow-up limit LDCT’s broader acceptance. The addition of a blood-based biomarker test like CIZ1B could address these barriers by enhancing screening precision, reducing unnecessary diagnostic procedures, and increasing screening participation.

Methods

An economic model was developed to assess the cost savings and public health benefits of integrating CIZ1B in three scenarios: (1) sequential screening with LDCT following a positive biomarker test; (2) using CIZ1B to confirm LDCT-positive cases; and (3) an expanded screening paradigm where CIZ1B reduces barriers, increasing overall screening uptake. The model incorporates Medicare reimbursement rates, prevalence and screening sensitivity data, and cost estimates adjusted for inflation.

Results

Results indicate that integrating CIZ1B testing can yield net savings in the range of $500 Million by avoiding unnecessary biopsies and enabling earlier lung cancer detection and treatment. The expanded screening scenario projects additional savings through higher participation rates. This study highlights the potential of the CIZ1B biomarker to address critical challenges in lung cancer screening, reduce healthcare costs, and improve outcomes for high-risk populations.