bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional nonsense constraint offers clinical and biological insights into rare genetic disorders
Authors: Blakes Alexander , Whiffin Nicola , Johnson Colin , Ellingford Jamie M , Banka Siddharth
Published: October 2024

Understanding the molecular consequences of variants which introduce premature termination codons (PTCs) is essential to predicting their clinical impact. Although transcripts with PTCs are generally expected to undergo nonsense-mediated mRNA decay (NMD), up to 45% of all possible PTCs in the human genome are predicted to escape NMD. Existing studies of constraint against predicted loss-of-function variants at the transcript level do not account for regional differences in NMD efficiency. Here, we developed an NMD-informed constraint metric using sequencing data from 730,947 individuals and found 2,764 transcripts with regional nonsense constraint. In rare disease cohorts, de novo nonsense and frameshift variants in constrained regions are up to 9.4-fold enriched and associated with up to 6.4-fold higher odds of diagnosis than in unconstrained regions. We prioritise fourteen candidate disease genes in which constrained regions harbour clusters of nonsense and frameshift variants. These findings will enhance variant interpretation, deliver mechanistic insights, and empower the discovery of novel disease genes.
Multi-modal profiling identifies CD4+CXCR5+PD-1- Tfh cells as prognostic and predictive biomarkers for response to R-CHOP therapy in human DLBCL
Authors: Yu Sisi , Kong Hao , Luo Huaichao , Zhao Xingzhong , Zhu Guanghui , Feng Xiuqin , Yang Jie , Wu Xiangji , Dai Yu , Wu Chunwei , Wang James Q. , Cao Dan , Xu Yang , Jiang Hong , Wang Ping
Published: October 2024

Despite the improvements in clinical outcomes for patients with Diffuse Large B-Cell Lymphoma (DLBCL), a significant proportion of those patients still face challenges with refractory/relapsed (R/R) disease after receiving first-line R-CHOP treatment. Characterizing the heterogeneity of the tumor microenvironment (TME) in diffuse large B cell lymphoma (DLBCL) is crucial for understanding relapsed/refractory disease. However, the complex and diverse nature of the TME has impeded progress. Here, using single-cell RNA sequencing(scRNA-seq), we explored the DLBCL landscape at single-cell resolution, profiling 77,344 cells from both primary and relapsed DLBCL patients. We further investigated the shared and distinct molecular and cellular features of tumor microenvironment in both primary and relapsed DLBCL tumors by integrating next-generation DNA sequencing data and multiple scRNA-seq datasets from total 72,351 cells. Our results demonstrated that there was a significant decrease of CD4+CXCR5+PD-1- Tfh cells, along with excessive activation of the TNF-NFκB signaling pathways in malignant B cells in R/R disease. Furthermore, by using multiplex IHC, we confirmed that CD4+CXCR5+PD-1- Tfh cells are prognostic and predictive biomarkers for response to R-CHOP treatment. As a proof of concept, we successfully generated mutilplexed images of CD4+CXCR5+PD-1- Tfh cells from a single DAPI staining in human DLBCL tissues through using generative artificial intelligence. Our study offers critical insights into the heterogeneity and molecular features of DLBCL, shedding light on the crucial role of CD4+CXCR5+PD-1- Tfh cells in the recurrent process.

Highlights

Shared and distinct molecular and cellular features of tumor microenvironment in both primary and relapsed DLBCL tumors;

The characteristic of relapsed DLBCL TME is a dysfunctional immune microenvironment with a significant decrease of CD4+CXCR5+PD-1- Tfh cells.

CD4+CXCR5+PD-1- Tfh cells are prognostic and predictive biomarkers for response to R-CHOP treatment

Determination of CD4+CXCR5+PD-1- Tfh cells in human DLBCL tissues through using generative artificial intelligence.
Testing for age- and sex- specific mitonuclear epistasis inDrosophila
Authors: Garlovsky Martin D. , Dobler Ralph , Guo Ruijian , Voigt Susanne , Dowling Damian K. , Reinhardt Klaus
Published: October 2024

The need for efficient ATP production is predicted to result in the evolution of cooperation between the mitochondrial and nuclear encoded components of the electron transport system. Novel (i.e., mismatched) mitonuclear genotype combinations are therefore predicted to result in negative fitness consequences, which may become more prevalent with ageing. Such negative fitness effects are expected to be prominent in males, since maternal inheritance of mitochondria is predicted to lead to accumulation of male-harming mutations (the mother’s curse hypothesis). To test these predictions, we measured female and male fertility traits using a genetically diverse panel of 27 mitonuclear populations ofDrosophila melanogasterwith matched or experimentally mismatched mitonuclear genomes at different ages. We found no overall effect of mitonuclear mismatch. In females, we found no effect of mitonuclear epistasis. In males, we found limited evidence of mitonuclear epistasis affecting fitness in old age, however, not in the direction predicted. Experimentally mismatched males sired more offspring in one comparison. Sex-specific advantages of mismatched males might arise if novel nuclear alleles compensate for deleterious mitochondrial alleles that have accumulated. If such compensatory effects of novel mitonuclear combinations increasing fitness occur in nature, they could represent a possible counterforce to the mother’s curse.
WITHDRAWN: A comparative analysis of salt stress adaptiveness between two flax (Linum usitatissimumL.) genotypes, Flanders and Astella, having contrasting lignan contents
Authors: Debnath Anirban Jyoti , Harenčár Ľubomír , Kučka Matúš , Kovár Marek , Ivanišová Eva , Mistríková Veronika , Gažo Ján , Ražná Katarína
Published: October 2024

WITHDRAWAL STATEMENT

The authors have withdrawn their manuscript because of the necessary revisions to the manuscript that may reorient the study findings. Its publication will be possible only after the peer review process in a scientific journal. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author
Benchmarking Cell Type Annotation by Large Language Models with AnnDictionary
Authors: Crowley George ,   Tabula Sapiens Consortium, Quake Stephen R.
Published: October 2024

We developed an open-source package called AnnDictionary (https://github.com/ggit12/anndictionary/) to facilitate the parallel, independent analysis of multiple anndata. AnnDictionary is built on top of LangChain and Scanpy and supports all common large language model (LLM) providers. AnnDictionary only requires 1 line of code to configure or switch the LLM backend and it contains numerous multithreading optimizations to support the analysis of many anndata and large anndata. We used AnnDictionary to benchmark all major LLMs at de novo cell-type annotation in Tabula Sapiens. We found that cell type annotation with AnnDictionary outperformed previous annotation with the same LLM by ∼20% (58% vs 77%), and with other LLMs by ∼25%. LLMs varied greatly in absolute agreement with manual annotation based on model size. Inter-LLM agreement also varied with model size. We find that LLM annotation of most major cell types to be more than 80-90% accurate, and will maintain a leaderboard of LLM cell type annotation athttps://singlecellgpt.com/celltype-annotation-leaderboard.
Do flowers with specialized morphologies produce more nectar and pollen?
Authors: Keasar Tamar , Bodner Levona
Published: October 2024

Premise of the study

Flower morphology influences the wiring of plant-pollinator interaction networks. Flowers with deep corolla tubes and bilateral symmetry have a narrower pollinator range, hence are considered more specialized than shallow radial flowers. Past inter-specific comparisons revealed positive correlations between flower depth and nectar production rates in a few plant communities, suggesting that specialized flowers may allocate more resources into food rewards for pollinators.

Methods

To evaluate this hypothesis, we compiled a global dataset of flower morphology vs. nectar sugar production rates (n = 494 plant species) and per-flower pollen counts (n = 164 species). We applied phylogenetically controlled mixed models to examine the effects of symmetry and tube length on floral rewards.

Key results

Corolla tube lengths, symmetry type and their interaction significantly predicted nectar production rates, with the larger effect attributed to tube length. Neither tube length nor symmetry predicted pollen number. Both nectar and pollen production were affected by phylogeny in a larger dataset that included 854 nectar-producing and 1040 pollen-producing species. Plant genus explained more of the variation in nectar production, and less of the variation in pollen production, than plant family.

Conclusions

Our findings suggest that visual signals associated with specialized flowers honestly advertise nectar production, but not pollen rewards. Other visual and chemical family-specific floral displays potentially advertise pollen availability to pollinators. We propose experiments to test whether nectar foragers indeed use flower depth as a visual signal that guides their choices of nectar sources.
Identifying potential dopamine receptor D2 antagonist from Rauwolfia serpentina – An in-silico virtual screening approach
Authors: Chakraborty Souvik , Bhowmick Sushmita , Maiti Tarasankar
Published: October 2024

Background

To combat the alarming rise of neuropsychiatric diseases like Schizophrenia, new drugs with fewer side effects have to be identified and characterized for the symptomatic treatment of Scz. Positive symptoms associated with Scz are hallucinations and delusions mainly due to the overactivation of the D2 dopaminergic receptors in the cortical pathways. D2 receptor antagonists identified fromRauwolfia serpentinaare employed for controlling positive symptoms.

Materials and methods

The IMPPAT database was used to identify phytoconstituents from the root ofRauwolfia serpentinathat can be used for antagonizing D2 dopaminergic receptor. 39 compounds were identified and SDF files were obtained from the PubChem database molecular docking with the modelled dopamine D2 receptor was used as a virtual screening tool followed by ADMET screening of the potential lead compound.

Results

After docking analysis, 11 compounds having binding affinity ≥ -9 kcal/mol were shortlisted for ADMET analysis. After analysis, 4 compounds (1,2-dihydrovomilenine, Corynanthine, Rauwolscine, and Yohimbine) were identified as potential leads. Among these 4 compounds, 1,2-dihydrovomelenine has been identified as the lead compound.

Conclusion

The present study identified a potential new therapeutic compound that can be used for controlling the positive symptoms of Scz patients in vitro as well as in vivo.
Dual-Approach Co-expression Analysis Framework (D-CAF) Enables Identification of Novel Circadian Regulation From Multi-Omic Timeseries Data
Authors: Chuah Joshua , Cordi Carmalena , Hahn Juergen , Hurley Jennifer
Published: October 2024

The circadian clock is a central driver of many biological and behavioral processes, regulating the levels of many genes and proteins, termed clock controlled genes and proteins (CCGs/CCPs), to impart biological timing at the molecular level. While transcriptomic and proteomic data has been analyzed to find potential CCGs and CCPs, multi-omic modeling of circadian data, which has the potential to enhance the understanding of circadian control of biological timing, remains relatively rare due to several methodological hurdles. To address this gap, a Dual-approach Co-expression Analysis Framework (D-CAF) was created to perform perturbation-robust co-expression analysis on time-series measurements of both transcripts and proteins. Applying this D-CAF framework to previously gathered transcriptomic and proteomic data from mouse macrophages gathered over circadian time, we identified small, highly significant clusters of oscillating transcripts and proteins in the unweighted similarity matrices and larger, less significant clusters of of oscillating transcripts and proteins using the weighted similarity network. Functional enrichment analysis of these clusters identified novel immunological response pathways that appear to be under circadian control. Overall, our findings suggest that D-CAF is a tool that can be used by the circadian community to integrate multi-omic circadian data to improve our understanding of the mechanisms of circadian regulation of molecular processes.
Population genomics reveals strong impacts of genetic drift without purging and guides conservation of bull and giant kelp
Authors: Bemmels Jordan B. , Starko Samuel , Weigel Brooke L. , Hirabayashi Kaede , Pinch Alex , Elphinstone Cassandra , Dethier Megan N. , Rieseberg Loren H. , Page Jonathan E. , Neufeld Christopher J. , Owens Gregory L.
Published: October 2024

Kelp forests are declining in many parts of the northeast Pacific1–4. In small populations, genetic drift can reduce adaptive variation and increase fixation of recessive deleterious alleles5–7, but natural selection may purge harmful variants8–10. To understand evolutionary dynamics and inform restoration strategies, we investigated genetic structure and the outcomes of genetic drift and purging by sequencing the genomes of 429 bull kelp (Nereocystis luetkeana) and 211 giant kelp (Macrocystis pyriferasensu lato11; cf.12) from the coastlines of British Columbia and Washington. We identified 6-7 geographically and genetically distinct clusters in each species. Low effective population size was associated with low genetic diversity and high inbreeding coefficients (including increased selfing rates), with extreme variation in these genetic health indices among bull kelp populations but more moderate variation in giant kelp. We found no evidence that natural selection is purging putative recessive deleterious alleles in either species. Instead, genetic drift has fixed many such alleles in small populations of bull kelp, leading us to predict (1) reduced within-population inbreeding depression in small populations, which may be associated with an observed shift toward increased selfing rate, and (2) hybrid vigour in crosses between small populations. Our genomic findings imply several strategies for optimal sourcing and crossing of populations for restoration and aquaculture, but which require experimental validation. Overall, our work reveals strong genetic structure and suggests that conservation strategies should consider the multiple health risks faced by small populations whose evolutionary dynamics are dominated by genetic drift.
Biodiversity forecasting in natural plankton communities reveals temperature and biotic interactions as key predictors
Authors: Merz Ewa , Pomati Francesco , Saavedra Serguei , Gilarranz Luis J.
Published: October 2024

As natural ecosystems experience unprecedented human-made degradation, it is urgent to deliver quantitative anticipatory forecasts of biodiversity change and identify relevant biotic and abiotic predictors. Forecasting natural ecosystems has been challenging due to their complexity, chaotic nonlinear nature and the availability of adequate data. Here, we use four years of daily abundance of a complex lake planktonic ecosystem and its abiotic environment to model and forecast biodiversity metrics. Using a state-of-the-art equation-free modelling technique, we forecast community richness and turnover with a proficiency greater than the constant predictor several generations ahead (30 days). Short-term forecasts improve substantially using biotic predictors (i.e., autoregressive term or community richness). Long-term forecasts require a more complex set of variables (i.e., biotic interactions), and the forecast proficiency depends strongly on including abiotic predictors such as water temperature. Depending on the forecast horizon, biotic and abiotic predictors can interact nonlinearly and synergistically, enhancing each other’s effects on biodiversity metrics. Our findings showcase the challenges of forecasting biodiversity in natural ecosystems and stress the importance of monitoring focal biotic and abiotic predictors to anticipate undesired changes.
MicrobiomeKG: Bridging Microbiome Research and Host Health Through Knowledge Graphs
Authors: Goetz Skye L. , Glen Amy K. , Glusman Gwênlyn
Published: October 2024

The microbiome represents a complex community of trillions of microorganisms residing in various body parts, and plays critical roles in maintaining host health and well-being. Understanding the interactions between microbiota and host offers valuable insights into potential strategies to promote health, including microbiome-targeted interventions. We have created MicrobiomeKG, a Knowledge Graph for microbiome research, bridging various taxa and microbial pathways with host health. This novel knowledge graph derives algorithmically-generated knowledge assertions from the supplemental tables supporting published microbiome papers, and is deployed for integrative analysis and hypothesis generation via the Biomedical Data Translator ecosystem.
Gamma Knife Stereotactic radiotherapy combined with tislelizumab as later-line therapy in pMMR/MSS/MSI-L metastatic colorectal cancer: A Phase II Trial Analysis
Authors: Zhang Yiran , Guan Hanyang , Liu Shijin , Li Haoquan , Bian Zili , He Jiashuai , Zhao Zhan , Qiu Shenghui , Mo Tianmu , Zhang Xiangwei , Chen Zuyang , Ding Hui , Zhao Xiaoxu , Wang Liang , Pan Yunlong , Pan Jinghua
Published: October 2024

An immunosuppressive tumor microenvironment limits the efficacy of immunotherapy, thus patients with MSS and pMMR mCRC often face great challenges.In this phase II trial, patients received Gamma Knife SBRT combined with Tislelizumab. P Biomarker analysis was performed pre- and post-treatment. From November 2022 to July 2024, 13 of 20 patients achieved PR, 6 achieved SD. mPFS was 10.7 months (95% CI, 6.4-15.0). With no grade 4 events noted, common adverse events included nausea (65%), anemia (55%), and fatigue (45%). For patients who had not responded to first and second-line therapies, the combo of Gamma Knife SBRT and tislelizumab showed high efficacy and reasonable safety. Significant post-radiotherapy improvements in the tumor’s immunosuppressive microenvironment. These results imply that patients with pMMR/MSS/MSI-L mCRC who were unresponsive to the first and second-line chemotherapy, Gamma Knife SBRT with tislelizumab provides a safe and powerful later-line treatment alternative.

Statement of significance

This study offers a safe and powerful option for pMMR/MSS/MSI-L mCRC patients fail to first and second-line chemotherapy. And discover Gamma Knife SBRT contributed to potentially converting the suppressive “cold” tumor immune microenvironment into an activated “hot” microenvironment conducive to immunotherapy efficacy in pMMR CRC.
Early establishment and life course stability of sex biases in the human brain transcriptome
Authors: Benoit-Pilven Clara , Asteljoki Juho V. , Leinonen Jaakko , Karjalainen Juha , Daly Mark J. , Tukiainen Taru
Published: October 2024

To elaborate on the origins of the established male-female differences in several brain-related phenotypes, we assessed the patterns of transcriptomic sex biases in the developing and adult human forebrain. We find an abundance of sex differences in expression (sex-DE) in the prenatal brain, driven by both hormonal and sex-chromosomal factors, and considerable consistency in the sex effects between the developing and adult brain, with little sex-DE exclusive to the adult forebrain. Sex-DE was not enriched in genes associated with brain disorder, consistent with systematic differences in the characteristics of these genes (e.g. constraint). Yet, the genes with persistent sex-DE across lifespan were overrepresented in disease gene co-regulation networks, pointing to their potential to mediate sex biases in brain phenotypes. Altogether, our work highlights the prenatal development as a crucial timepoint for the establishment of brain sex differences.
Detection and Annotation of Unique Regions in Mammalian Genomes
Authors: Vieira Mourato Beatriz , Haubold Bernhard
Published: October 2024

Long unique genomic regions have been reported to be highly enriched for developmental genes in mice and humans. In this paper we identify unique genomic regions using a highly efficient method based on fast string matching. We quantify the resource consumption and accuracy of this method before applying it to the genomes of 18 mammals. We annotate their unique regions of at least 10 kb and find that they are strongly enriched for developmental genes across the board. When investigating the subset of unique regions that lack annotations, we found in the tasmanian devil the gene encoding iniositol polyphosphate-5-phosphatase A, which is an essential part of intracellular signaling. This implies that unique regions might be given priority when annotating mammalian genomes. Our documented pipeline for annotating unique regions in any mammalian genome is available from the repositorygithub.com/evolbioinf/auger; additional data for this study is available from the data-verse at doi.org/10.17617/3.4IKQAG.
Colorimetric detection methods of pH-sensing wound dressing for point-of-care wound diagnostics
Authors: Cherifi Katia , Toupchinejad Farnoush , Christodoulopoulos Katerina , Kizilkaya Aylin , Matoori Simon
Published: October 2024

Chronic lower extremity wounds like diabetic foot ulcers (DFUs) are a major complication of diabetes and the leading cause of lower limb amputations worldwide. Currently, DFUs are diagnosed through macroscopic evaluation, and molecular diagnostics are lacking for the disease staging, treatment selection, and evaluation of treatment success. There is a need for new diagnostic technologies combined with detection methods for point-of-care use. Preclinical and clinical data support the importance of wound pH as a biomarker in chronic wound healing, with DFUs typically exhibiting more alkaline pH values when compared to normal healing wounds. In a previous study, we developed a pH-sensing fluorescent bandage based on pyranine-loaded microparticles that were physically immobilized in an alginate hydrogel. Here, we present a second-generation pH-sensing bandage for colorimetric wound diagnostics. Pyranine was adsorbed at high concentrations onto microparticles to enable colorimetric signal detection. This approach leverages pyranine’s ability to change color in response to pH variations through proton exchange properties with the wound fluid. The colorimetric properties of our bandage enable signal detection by two methods suited for point-of-care use: a smartphone camera and a cost-effective homebuilt RGB detector. Analyzing the color intensity of the bandage with Red, Green and Blue absorbance values, it is possible to correlate the RGB absorbance to a pH value in the clinically-relevant range to 6.0 to 9.0in vitroandex vivo, as the B values decreased with the increase in pH levels, as associated with DFUs. These findings indicate the potential of colorimetric detection using smartphone cameras or home-built absorbance detectors for rapid wound diagnostics at the point-of-care.

Graphical Abstract

A pH-sensing bandage enables colorimetric detection of chronic wounds. The bandage absorbs wound exudate, triggering proton exchange with dye-loaded microparticles in an alginate matrix. Chronic wounds with high pH values induce strong fluorescence and yellow coloration. The signal is quantified through RGB colorimetry analysis using a smartphone camera or a homebuilt RGB detector, enabling point-of-care diagnostics for chronic wounds.
High-Resolution Genome-Wide Maps Reveal Widespread Presence of Torsional Insulation
Authors: Hall Porter M. , Mayse Lauren A. , Bai Lu , Smolka Marcus B. , Pugh B. Franklin , Wang Michelle D.
Published: October 2024

Torsional stress in chromatin plays a fundamental role in cellular functions, influencing key processes such as transcription, replication, and chromatin organization. Transcription and other processes may generate and be regulated by torsional stress. In the genome, the interplay of these processes creates complicated patterns of both positive (+) and negative (-) torsion. However, a challenge in generating an accurate torsion map is determining the zero-torsion baseline signal, which is conflated with chromatin accessibility. Here, we introduce a high-resolution method based on the intercalator trimethylpsoralen (TMP) to address this challenge. We describe a method to establish the zero-torsion baseline while preserving the chromatin state of the genome ofS. cerevisiae. This approach enables both high-resolution mapping of accessibility and torsional stress in chromatin in the cell. Our analysis shows transcription-generated torsional domains consistent with the twin-supercoiled-domain model of transcription and suggests a role for torsional stress in recruiting topoisomerases and in regulating 3D genome architecture via cohesin. Significantly, we reveal that insulator sequence-specific transcription factors decouple torsion between divergent promoters, whereas torsion spreads between divergent promoters lacking these factors, suggesting that torsion serves as a regulatory mechanism in these regions. Although insulators are known to decouple gene expression, our finding provides a physical explanation of how such decoupling may occur. This new method provides a potential path forward for using TMP to measure torsional stress in the genome without the confounding contribution of accessibility in chromatin.
Experiences of Parents and Solid Organ-transplanted Adolescents: A Qualitative Framework Analysis through Focus Groups. The TransplantKIDS Mental Health Project
Authors: Garrido-Bolton Jessica , de la Vega Rocío , Bravo-Ortiz María Fe , Fernández-Jiménez Eduardo
Published: October 2024

Background

Solid organ transplantation is the optimal treatment for children and adolescents with end-stage organ failure. However, the biopsychosocial challenges faced jointly by the various types of solid organ recipients have received little attention from a multidimensional and qualitative approach in paediatric populations. This is the first study based on focus groups to identify the unmet care needs perceived by transplanted adolescents and parents throughout the pre-, peri-, and post-surgical phases of various types of solid organ transplantation.

Methods

Two focus groups were conducted with five adolescent transplant recipients and five parents, respectively, at the Children’s Hospital of La Paz University Hospital in Spain. The focus groups followed a biopsychosocial theoretical framework and used a semi-structured moderating guide. Participants were asked open-ended questions about aspects of healthcare that they would have liked to change or improve, followed by specific questions about biomedical, psychological, and social aspects that were not spontaneously addressed. The sessions were conducted using a video call, audio-recorded, and automatically transcribed. Thematic framework analysis was used to examine the data, involving familiarisation, identifying a thematic framework, indexing, charting, mapping, and interpretating.

Results

The findings revealed several unmet care needs, highlighting the importance of addressing social and psychological aspects of care throughout the transplantation process. Key issues common to both informant groups were inconveniences regarding the distance to the hospital and long waiting times for outpatient hospital visits, as well as the importance of peer support, humanised interaction with healthcare personnel, and mental health care during the whole process.

Conclusions

These findings will inform the design of future multifaceted prehabilitation interventions to prepare patients and parents for solid organ transplantation. This study highlights the importance of understanding the experiences and unmet needs of adolescent transplant recipients and their families in order to improve healthcare delivery and clinical outcomes.
Patient satisfaction: Insights from the regional referral hospitals in Bhutan
Authors: Dorji Kuenzang , Jamphel Kinga , Kelzang Jigme , Pelmo Ugyen , Nepal Hem Kumar , Zangpo Sonam , Wangdi Sonam , Galey Karma
Published: October 2024

Patient satisfaction is crucial for evaluating healthcare quality and guiding continuous quality improvement. Globally, patient satisfaction has been extensively studied; however, there is limited research on this topic in Bhutan, where the healthcare system is in the early stages of developing a quality-oriented culture. To address this gap, we aimed to evaluate patient satisfaction levels among different socio-demographic and clinical groups and identify the predictors of patient satisfaction in Bhutan.

We retrospectively analysed archived patient satisfaction data from two tertiary healthcare centres in Bhutan: Mongar Eastern Regional Referral Hospital and Gelephu Central Regional Referral Hospital. The routine survey was conducted throughout April 2024 using a modified version of the Patient Satisfaction Questionnaire 18. The data were analysed using descriptive statistics, one-way ANOVA, and binary logistic regression.

Our study revealed significant variations in patient satisfaction across socio-demographic and clinical groups. Ethnicity, occupation, and education level emerged as significant predictors of satisfaction. Sharchop and other ethnic groups; farmers, religious personnel, and other occupational groups; and illiterate individuals exhibited significantly higher satisfaction levels. While patient type, age, and marital status influenced satisfaction levels, they did not emerge as significant predictors when considering other variables. Overall, patient satisfaction in Bhutan was high, particularly in the financial domain; however, accessibility and convenience scored the lowest.

Our findings underscore the importance of addressing socio-demographic disparities in patient satisfaction. With anticipated changes in the socio-demographic characteristics of the Bhutanese population, satisfaction levels may decline. Therefore, healthcare policy and decision-makers should implement targeted interventions to address these shifts. To enhance overall satisfaction, healthcare policymakers should focus on improving accessibility and convenience. Strategies such as establishing dynamic limits on free services, exploring private sector engagement in high-end services, and strengthening the healthcare workforce are essential for sustainable and quality healthcare service delivery.
Prevalence and spectrum of germline BRCA1 and BRCA2 mutations in multiethnic cohort of breast cancer patients in Brunei Darussalam
Authors: Matusin Siti Nur Idayu , Mumin Nuramalina , Zainal Abidin Hazirah , Mohd Jaya Fatin Nurizzati , Lu Zen Huat , Haji Abdul Hamid Mas Rina Wati
Published: October 2024

This is the first genetic study of its kind in Brunei Darussalam.  BRCA1 and BRCA2 genes are the most well-known and well described predictors of hereditary breast cancer due to their clinical importance. This study aimed to identify the prevalence and mutation spectrum of the BRCA1 and BRCA2 germline mutations among 120 unselected series of Brunei breast cancer patients.  We screened the entire coding region of BRCA1 and BRCA2 gene using Sanger sequencing and next-generation sequencing methods, and identified three pathogenic and one likely pathogenic mutations in the BRCA2 gene.  Of the 120 patients, 6 (5%) were BRCA2 carriers which confirm that BRCA2 carriers are more common in the Asian population compared to the Caucasian population.  One BRCA2 mutation observed only in the Chinese ethnicity of the Brunei breast cancer population contributes to the probability of the mutation being a founder effect in the Southern Chinese population.  Brunei BRCA2 carriers were more likely to have a positive family history of breast and/or ovarian cancers and have more than one family members in the first-degree relatives diagnosed with breast cancer.
Estimating the dietary and health impact of implementing mandatory front-of-package nutrient disclosures in the US: a policy scenario modeling analysis
Authors: Flexner Nadia , Zaltz Daniel , Greenthal Eva , Musicus Aviva A. , Ahmed Mavra , L’Abbe Mary R.
Published: October 2024

Background

Recognized as a cost-effective policy to promote healthier diets, mandatory front-of-package labeling (FOPL) identifying foods high in sodium, sugar, and saturated fat has been adopted and implemented in ten countries, and is currently under consideration in several others including the US. However, its potential impact on dietary intake and health have not yet been estimated in the US context.

Objectives

To estimate (1) the potential dietary impact of implementing mandatory nutrient-specific FOPL among US adults; and (2) the number of diet related non-communicable disease (NCD) deaths that could be averted or delayed due to estimated dietary changes.

Methods

Baseline and counterfactual dietary intakes of sodium, sugars, saturated fats, and calories were estimated among US adults (n=7,572) using both available days of 24h recall data from the 2017-2020 National Health and Nutrition Examination Survey (NHANES). The National Cancer Institute method was used to estimate usual intakes and distributions, adjusting for age, sex, misreporting status, weekend/weekday, and sequence of recall. To estimate counterfactual dietary intakes, we modeled reductions observed in experimental and observational studies that examined changes in sodium, sugars, saturated fat and calorie content of food and beverage purchases due to nutrient-specific ‘high in’ FOPL. This study used the Preventable Risk Integrated ModEl (PRIME) to estimate potential health impact.

Results

Estimated mean dietary reductions of 156 mg and 259 mg/day of sodium, 10.1 g and 7.2 g/day of sugars, 1.08 g and 4.49 g/day of saturated fats, and 38 kcal and 57 kcal/day of calories were observed under the two policy scenarios tested. Between 96,926 (95% UI 89,011-105,284) and 137,261 (95% UI 125,534-148,719) diet related NCD deaths, primarily from cardiovascular diseases (74%), could potentially be averted or delayed by implementing mandatory nutrient-specific FOPL in the US. Overall, more lives would be saved in males than females.

Conclusions

Findings suggest that implementing mandatory nutrient-specific FOPL in the US could significantly reduce sodium and total sugar intakes among US adults, resulting in a substantial number of NCD related deaths that could be averted or delayed. Our results can inform current food policy developments in the US regarding adoption and implementation of FOPL regulations.
Barriers to cataract surgeries as perceived by visually disabled 50 years and older cataract blind participants of Nepal survey for Rapid Assessment of Avoidable Blindness
Authors: Shah Ranjan , Mishra Sailesh Kumar , Khandekar Rajiv , Gogate Parikshit , Sapkota Yuddha Dhoj , Gurung Reeta , Shrestha Mohan Krishna , Mactaggart Islay , McCormick Ian , Shahi Brish Bahadur , Burton Matthew
Published: October 2024

Purpose

To identify the main barriers and determinants to cataract surgery as perceived by 50 years and older Nepali people with severe visual impairment & blind due to cataracts.

Methods

This was part of the Rapid Assessment for Avoidable Blindness (RAAB), held in all provinces of Nepal from 2018 to 2021. Cataract blindness was defined as a person having the best-corrected vision, <6/60 in the better eye, and an unoperated cataract, which was the principal cause of visual disability. The participants were interviewed using a pretested questionnaire with seven known barriers. The demographic information was correlated with the barrier score.

Results

We surveyed 718 cataract blinds. Two-thirds of the participants were females. Four in ten were aged 50 to 59 years. The main barriers perceived were ’need is not felt’ (237; 33%), cost associated with surgery (218; 30%), lack of access (93; 13%), fear of surgery (88; 12%), nobody to accompany (40; 6%), unaware of surgery (18; 3%), and treatment denied (24; 3%). The barriers were not significantly different in females than in males. (P = 0.85). The provincial variations of barriers were significant. (P <0.001). High cost was a perceived barrier in all provinces except Gandaki. Access to treatment was a barrier in the Gandaki province (38%). One in four participants in the Madhesh and Bagmati provinces feared surgery. Nearly half of the cataract blind in the Madhesh and Lumbini province did not feel ‘need for restoring vision’.

Conclusions

To improve cataract surgery uptake, identified barriers, like lack of awareness, low visual need, and high cost must be addressed. The strategies could be devised according to provincial barriers but similar to both genders and all 50 years and older cataract blind. Offering low-cost cataract surgery, financial assistance and health promotion to improve awareness and remove fear were recommended.
Knowledge and Willingness towards Human Papillomavirus Vaccination among the Parents and School Teachers of Eligible Girls in Dhaka, Bangladesh: A School-Based Cross-Sectional Study
Authors: Sultana Samina , Nishan MD Nahid Hassan , Akter Aklima , Rahman Dalia , Yesmin Fowzia , Hawlader Mohammad Delwer Hossain
Published: October 2024

Abstracts

Background

Cervical cancer ranks as the common prevalent cancer, among women worldwide especially impacting low-resource countries. In Bangladesh, this accounts for 12% of all cancer cases. The development of cancer is closely linked to Human Papillomavirus (HPV) infection. Despite the availability of HPV vaccines, their uptake remains limited in Bangladesh. Thus, this research aims to assess the knowledge and willingness of parents and school teachers regarding HPV vaccination for eligible girls in Bangladesh.

Methodology

This study involved 406 parents and school teachers of girls aged 9-14 years from Dhaka city. A cross-sectional study design was used. Data collection was done through a questionnaire administered by interviewers after pre-testing and refinement for clarity and reliability. Analysis was carried out using Stata 17 software. Chi-square tests and logistic regression were used to uncover associations and predictors related to knowledge levels and willingness.

Results

Findings revealed that a majority of participants (64.04%) exhibited an understanding of HPV and cervical cancer yet a high percentage (98.28%) expressed willingness to engage in HPV vaccination initiatives. participants with primary (AOR=3.306, p<0.005), secondary (AOR=8.806, p<0.001), and higher education (AOR=5.059, p<0.001), as well as those from upper-middle-income groups (AOR=3.038, p<0.001), had significantly higher knowledge of HPV and cervical cancer.

Conclusion

The research emphasizes lack of knowledge regarding HPV and its vaccination among parents and educators in Bangladesh despite a willingness to vaccinate. These results emphasize the importance of tailored initiatives and better access, to health information to increase HPV vaccine acceptance and lower the incidence of cervical cancer.
Geometric Deep Learning Methods for Improved Generalizability in Medical Computer Vision: Hyperbolic Convolutional Neural Networks in Multi-Modality Neuroimaging
Authors: Ayubcha Cyrus , Sajed Sulaiman , Omara Chady , Veldman Anna B. , Singh Shashi Bhushan , Lokesha Yashas Ullas , Liu Alex , Aziz-Sultan Mohammad Ali , Smith Timothy R. , Beam Andrew
Published: October 2024

Objective

This study investigates the potential advantages of hyperbolic convolutional neural networks (HCNNs) over traditional convolutional neural networks (CNNs) in neuroimaging tasks.

Materials and Methods

We conducted a comparative analysis of HCNNs and CNNs across various medical imaging modalities and diseases, with a focus on a compiled multi-modality neuroimaging dataset. The models were assessed for performance parity, robustness to adversarial attacks, semantic organization of embedding spaces, and generalizability. Zero-shot evaluations were also performed with ischemic stroke non-contrast CT images.

Results

HCNNs matched CNN performance on less complex settings and demonstrated superior semantic organization, and robustness to adversarial attacks. While HCNNs equaled CNNs in out-of-sample datasets identifying Alzheimer’s disease, in zero-shot evaluations, HCNNs outperformed CNNs and radiologists.

Discussion

HCNNs deliver enhanced robustness and organization in the neuroimaging data. This likely underlies why while HCNNs perform similarly to CNNs with respect to in-sample tasks, they confer improved generalizability. Nevertheless, HCNNs encounter efficiency and performance challenges with larger, complex datasets. These limitations underline the need for further optimization of HCNN architectures.

Conclusion

HCNNs present promising improvements in generalizability and resilience for medical imaging applications, particularly in neuroimaging. Despite challenges with larger datasets, HCNNs enhance performance under adversarial conditions and offer better semantic organization, suggesting valuable potential in generalizable deep learning models in medical imaging and neuroimaging diagnostics.
Chronic fatigue syndrome, depression, and anxiety symptoms due to relapsing-remitting multiple sclerosis are associated with reactivation of Epstein-Barr virus and Human Herpesvirus 6
Authors: Maes Michael , Almulla Abbas F. , Vojdani Elroy , Dzhambazova Elizabet , Stoyanov Drozdstoj , Zhang Yingqian , Vojdani Aristo
Published: October 2024

Relapsing-remitting multiple sclerosis (RRMS) is defined by elevated IgG/IgA/IgM responses targeting Epstein-Barr Virus (EBV) nuclear antigen 1 (EBNA) and deoxyuridine-triphosphatases (dUTPases) of Human herpsesvirus-6 (HHV-6) and EBV. These responses suggest that the viruses are being replicated and reactivated. An increased prevalence of chronic fatigue syndrome, depression, and anxiety is associated with signs of immune activation in RRMS. Nevertheless, there is a lack of data regarding the association between viral reactivation and neuropsychiatric symptoms of RRMS. This study investigated the IgG/IgA/IgM responses to EBNA, and EBV and HHV-6-dUTPases, in 58 remitted RRMS patients and 63 normal controls. The McDonald criteria were employed to establish the diagnosis of MS. The Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Severity Score were employed to evaluate disabilities caused by RRMS. We evaluated the scores of the Hamilton Depression (HAMD) and Anxiety (HAMA) Rating Scales, and Fibro-Fatigue (FF) scale. One latent construct was extracted from the EDSS, MSSS, FF, HAMD, and HAMA scores. We discovered that the combined effects of IgG and IgM-HHV-6-dUTPAses accounted for 63.7% of the variance in this construct. Furthermore, the total FF, HAMA, and HAMD scores were substantially associated with the IgG and IgM-HHV-6-dUTPAses, accounting for approximately 38.7% to 51.0% of the variance. The three neuropsychiatric rating scale scores were also significantly correlated with IgA reactivity directed to both dUTPases and IgG/IgA/IgM to EBNA. In conclusion, the reactivation and replication of HHV-6 and EBV significantly contributes to chronic fatigue syndrome, as well as symptoms of depression and anxiety due to RRMS.
Beyond Traditional Assessments of Cognitive Impairment: Exploring the Potential of Spatial Navigation Tasks
Authors: Colombo Giorgio , Minta Karolina , Thrash Tyler , Grübel Jascha , Wiener Jan , Avraamides Marios , Hölscher Christoph , Schinazi Victor R.
Published: October 2024

INTRODUCTION

Alzheimer’s disease affects spatial abilities that are often overlooked in standard cognitive screening tools. We assessed whether the spatial navigation tasks in the Spatial Performance Assessment for Cognitive Evaluation (SPACE) can complement existing tools such as the Montreal Cognitive Assessment (MoCA).

METHODS

348 participants aged 21-76 completed the MoCA, SPACE, and sociodemographic- health questionnaires. Regressions were used to predict MoCA scores with risk factors and SPACE tasks as predictors. We also conducted a factor analysis to investigate the relationships among SPACE tasks and the MoCA.

RESULTS

Regressions revealed significant effects of age, gender, and SPACE tasks. No risk factors for dementia predicted MoCA scores. The factor analysis revealed that MoCA and perspective taking contributed to a separate factor from other navigation tasks in SPACE. Normative data for SPACE are provided.

DISCUSSION

Our findings highlight the importance of navigation tasks for cognitive assessment and the early detection of cognitive impairment.
Curative levels of endogenous gene replacement achieved in non-human primate liver using programmable genomic integration
Authors: Xie Jenny , Dunyak Maike Thamsen , Hanna Patrick , Nan Angela X. , Estes Brett , Cochrane Jesse C. , Wu Shuai , Wang Jie , McGinnis Connor , Wang Qiang , Pokharel Rejina , Paudel Dev , Zhang Jason , Li Dan , Amin Parth , Narayan Siddharth , Hsia Angela , Hazelbaker Dane Z. , Shi Xiarong , Packer Meredith , Duke Brian , Dickerson Ryan , Piard Charlotte , Meagher Martin , Gatlin Jason , Svenson Sonke , Monsef Adrianne , Bourdeau Raymond W. , Lam Kieu , Reid Steve , Kazemian Mohammad , Chander Nisher , Holland Richard , Heyes James , Mukherjee Swati , Kumar Sandeep , O’Connell Daniel J. , Finn Jonathan D.
Published: October 2024

The ability to efficiently place a large piece of DNA in a specific genomic location has been a goal for the gene therapy field since its inception; however, despite significant advances in gene editing technology, this had yet to be achieved. Here we describe two methods of programmable genomic integration (PGI) that overcome some of the limitations of current approaches. Using a combination of clinically validated delivery technologies (LNP, AAV), we demonstrate the ability to specifically integrate large (>2 kb) DNA sequences into endogenous introns in the liver of non-human primates (NHP). PGI was effective across multiple genomic locations and transgenes, and insertion led to expression from the endogenous promoter. PGI was highly efficient, achieving expression in >50% of liver cells after a single course of treatment, which would be curative for most monogenic recessive liver diseases. This is the first report of clinically curative level of gene insertion at endogenous loci in NHP.
Deciphering RNA regulation with a foundation language model
Authors: Zhou Hanwen , Hu Yue , Zheng Yulong , Li Jiefu , Peng Jielong , Zhang Guoqing , Wang Zefeng
Published: October 2024

RNAs are widely regulated in cellular processes by theircis-regulatory elements andtrans-acting RNA binding proteins, the information of which is encoded in RNA sequences spanning evolutionary diversity. Deciphering the rules underlying RNA regulation can provide new insights into molecular mechanisms and RNA therapies. The large language models have demonstrated their efficacy in the analysis of human languages and protein sequences. Considering the similarities in semantic and syntactic features between RNA sequences and human language, we developed LAMAR, a foundationlanguagemodel for RNAregulation, aimed at capturing the intrinsic characteristics of RNA sequences. The model was first pretrained on approximately 15 million sequences of genes and transcripts from 225 mammals and 1569 viruses. By leveraging LAMAR as a foundational platform, we fine-tuned the pretrained model with labeled datasets across various tasks. The resulting fine-tuned model outperformed the best benchmark by up to 9% for predicting mRNA translation efficiency, and improved by 7% for predicting the RNA half-life. We further applied LAMAR to predict the splice sites of pre-mRNAs and internal ribosome entry sites driving cap-independent translation, the performances of which were comparable with the state-of-the-art methods. The results indicated that our foundation language model is applicable for comprehensive regulatory analysis of RNA, providing new clues into molecular cell biology and disease.

The code is available athttps://github.com/rnasys/LAMAR.