-
PLoS Computational Biology Jun 2024Therapeutic interventions are designed to perturb the function of a biological system. However, there are many types of proteins that cannot be targeted with...
Therapeutic interventions are designed to perturb the function of a biological system. However, there are many types of proteins that cannot be targeted with conventional small molecule drugs. Accordingly, many identified gene-regulatory drivers and downstream effectors are currently undruggable. Drivers and effectors are often connected by druggable signaling and regulatory intermediates. Methods to identify druggable intermediates therefore have general value in expanding the set of targets available for hypothesis-driven validation. Here we identify and prioritize potential druggable intermediates by developing a network perturbation theory, termed NetPert, for response functions of biological networks. Dynamics are defined by a network structure in which vertices represent genes and proteins, and edges represent gene-regulatory interactions and protein-protein interactions. Perturbation theory for network dynamics prioritizes targets that interfere with signaling from driver to response genes. Applications to organoid models for metastatic breast cancer demonstrate the ability of this mathematical framework to identify and prioritize druggable intermediates. While the short-time limit of the perturbation theory resembles betweenness centrality, NetPert is superior in generating target rankings that correlate with previous wet-lab assays and are more robust to incomplete or noisy network data. NetPert also performs better than a related graph diffusion approach. Wet-lab assays demonstrate that drugs for targets identified by NetPert, including targets that are not themselves differentially expressed, are active in suppressing additional metastatic phenotypes.
PubMed: 38935814
DOI: 10.1371/journal.pcbi.1012195 -
PloS One 2024The Youth Risk Behavior Survey (YRBS) among high school students includes standard questions about sexual identity and sex of sexual contacts, but these questions are...
PURPOSE
The Youth Risk Behavior Survey (YRBS) among high school students includes standard questions about sexual identity and sex of sexual contacts, but these questions are not consistently included in every state that conducts the survey. This study aimed to develop and apply a method to predict state-level proportions of high school students identifying as lesbian, gay, or bisexual (LGB) or reporting any same-sex sexual contacts in those states that did not include these questions in their 2017 YRBS.
METHODS
We used state-level high school YRBS data from 2013, 2015, and 2017. We defined two primary outcomes relating to self-reported LGB identity and reported same-sex sexual contacts. We developed machine learning models to predict the two outcomes based on other YRBS variables, and comparing different modeling approaches. We used a leave-one-out cross-validation approach and report results from best-performing models.
RESULTS
Modern ensemble models outperformed traditional linear models at predicting state-level proportions for the two outcomes, and we identified prediction methods that performed well across different years and prediction tasks. Predicted proportions of respondents reporting LGB identity in states that did not include direct measurement ranged between 9.4% and 12.9%. Predicted proportions of respondents reporting any same-sex contacts, where not directly observed, ranged between 7.0% and 10.4%.
CONCLUSION
Comparable population estimates of sexual minority adolescents can raise awareness among state policy makers and the public about what proportion of youth may be exposed to disparate health risks and outcomes associated with sexual minority status. This information can help decision makers in public health and education agencies design, implement and evaluate community and school interventions to improve the health of LGB youth.
Topics: Humans; Adolescent; Sexual and Gender Minorities; Male; Female; United States; Sexual Behavior; Surveys and Questionnaires; Machine Learning; Risk-Taking; Students
PubMed: 38935807
DOI: 10.1371/journal.pone.0304175 -
PLoS Computational Biology Jun 2024Spatial transcriptomics has gained popularity over the past decade due to its ability to evaluate transcriptome data while preserving spatial information. Cell...
Spatial transcriptomics has gained popularity over the past decade due to its ability to evaluate transcriptome data while preserving spatial information. Cell segmentation is a crucial step in spatial transcriptomic analysis, as it enables the avoidance of unpredictable tissue disentanglement steps. Although high-quality cell segmentation algorithms can aid in the extraction of valuable data, traditional methods are frequently non-spatial, do not account for spatial information efficiently, and perform poorly when confronted with the problem of spatial transcriptome cell segmentation with varying shapes. In this study, we propose ST-CellSeg, an image-based machine learning method for spatial transcriptomics that uses manifold for cell segmentation and is novel in its consideration of multi-scale information. We first construct a fully connected graph which acts as a spatial transcriptomic manifold. Using multi-scale data, we then determine the low-dimensional spatial probability distribution representation for cell segmentation. Using the adjusted Rand index (ARI), normalized mutual information (NMI), and Silhouette coefficient (SC) as model performance measures, the proposed algorithm significantly outperforms baseline models in selected datasets and is efficient in computational complexity.
PubMed: 38935799
DOI: 10.1371/journal.pcbi.1012254 -
PloS One 2024The elderly is commonly susceptible to depression, the symptoms for which may overlap with natural aging or other illnesses, and therefore miss being captured by routine...
BACKGROUND
The elderly is commonly susceptible to depression, the symptoms for which may overlap with natural aging or other illnesses, and therefore miss being captured by routine screening questionnaires. Passive sensing data have been promoted as a tool for depressive symptoms detection though there is still limited evidence on its usage in the elderly. Therefore, this study aims to review current knowledge on the use of passive sensing data via smartphones and smartwatches in depressive symptom screening for the elderly.
METHOD
The search of literature was performed in PubMed, IEEE Xplore digital library, and PsycINFO. Literature investigating the use of passive sensing data to screen, monitor, and/or predict depressive symptoms in the elderly (aged 60 and above) via smartphones and/or wrist-worn wearables was included for initial screening. Studies in English from international journals published between January 2012 to September 2022 were included. The reviewed studies were further analyzed by a narrative analysis.
RESULTS
The majority of 21 included studies were conducted in Western countries with a few in Asia and Australia. Most studies adopted a cohort study design (n = 12), followed by cross-sectional design (n = 7) and a case-control design (n = 2). The most popular passive sensing data was related to sleep and physical activity using an actigraphy. Sleep characteristics, such as prolonged wakefulness after sleep onset, along with lower levels of physical activity, exhibited a significant association with depression. However, cohort studies expressed concerns regarding data quality stemming from incomplete follow-up and potential confounding effects.
CONCLUSION
Passive sensing data, such as sleep, and physical activity parameters should be promoted for depressive symptoms detection. However, the validity, reliability, feasibility, and privacy concerns still need further exploration.
Topics: Humans; Smartphone; Depression; Aged; Mass Screening; Wearable Electronic Devices; Sleep; Middle Aged; Exercise; Female
PubMed: 38935797
DOI: 10.1371/journal.pone.0304845 -
PloS One 2024Pre-Exposure Prophylaxis (PrEP) has demonstrated efficacy in preventing HIV infection. Female Bar Workers (FBWs) often act as informal sex workers, placing them at risk... (Randomized Controlled Trial)
Randomized Controlled Trial
Demonstrating service delivery models for effective initiation and retention on pre-exposure prophylaxis (PrEP) among female bar workers in Dar es Salaam, Tanzania: A double randomized intervention study protocol.
BACKGROUND
Pre-Exposure Prophylaxis (PrEP) has demonstrated efficacy in preventing HIV infection. Female Bar Workers (FBWs) often act as informal sex workers, placing them at risk of HIV infection. Despite expressing interest in PrEP, FBWs face barriers to accessing public-sector clinics where PrEP is delivered. We developed a study to compare the effectiveness of workplace-based PrEP provision to standard-of-care facility-based provision for PrEP initiation, retention and adherence among FBWs.
METHODS
In this double-randomized intervention study, FBWs aged 15 years and above will be screened, consented and initiated on PrEP (emtricitabine/tenofovir disoproxil), and followed for six months. Participants will be randomized at the bar level and offered PrEP at their workplace or at a health facility. Those who are initiated will be independently individually randomized to either receive or not receive an omni-channel PrEP champion intervention (support from an experienced PrEP user) to improve PrEP adherence. We expect to screen 1,205 FBWs to enroll at least 160 HIV negative women in the study. Follow-up visits will be scheduled monthly. HIV testing will be performed at baseline, month 1, 4 and 6; and TDF testing at months 2 and 6. Primary outcomes for this trial are: (1) initiation on PrEP (proportion of those offered PrEP directly observed to initiate PrEP); and (2) adherence to PrEP (detectable urine TDF drug level at 6-months post-enrollment). The primary outcomes will be analyzed using Intention-to-Treat (ITT) analyses.
DISCUSSION
Using a randomized trial design, we will evaluate two interventions aiming to reduce barriers to uptake and retention on PrEP among FBWs, a vulnerable population at risk of HIV acquisition and onward transmission. If these interventions prove effective in promoting PrEP among FBWs, they could assist in abating the HIV epidemic in Africa.
TRIAL REGISTRATION
Registered with German Clinical Trials Register (www.drks.de) on 29 April 2020; Registration number DRKS00018101.
Topics: Humans; Female; Pre-Exposure Prophylaxis; HIV Infections; Tanzania; Anti-HIV Agents; Sex Workers; Adult; Medication Adherence; Adolescent; Young Adult; Tenofovir
PubMed: 38935796
DOI: 10.1371/journal.pone.0304077 -
PloS One 2024Chronic enteropathies are a common cause of morbidity in dogs and are associated with disruption of the normal gastrointestinal mucosal barrier. The objective of this...
Chronic enteropathies are a common cause of morbidity in dogs and are associated with disruption of the normal gastrointestinal mucosal barrier. The objective of this prospective study was to determine the association between measures of gastrointestinal dysbiosis and plasma concentrations of glucagon-like peptide-2, a hormone responsible for normal mucosal structure, in dogs with chronic enteropathies. Fecal 16S V4 rRNA gene sequencing and quantitative PCR via the dysbiosis index was performed on 16 healthy controls and 18 dogs with chronic enteropathy prior to and 1 month after initiation of individualized therapy. Fasting and post-prandial plasma GLP-2 concentrations were measured via ELISA in healthy dogs and chronic enteropathy dogs at both time points. Alpha and beta diversity indices, as well as bacterial population abundances were compared between groups and time-points. Principal component analysis combined with least squares regression was used to identify taxa contributing to glucagon-like peptide-2 variance among groups. While the dysbiosis index did not differ between healthy dogs and dogs with chronic enteropathy, 16S V4 genomic sequencing identified 47 operational taxonomic units that differed between the groups, all but 2 of which resolved following chronic enteropathy treatment. Principal component analysis identified 6 families and 19 genera that contributed to differences in glucagon-like peptide-2 concentrations between groups. Dysbiosis associated with chronic enteropathies in dogs may contribute to the observed lower plasma glucagon-like peptide-2 concentrations. Further research into mechanisms of microbiota impact on the enteroendocrine system is needed. Association between glucagon-like peptide-2 secretion and microbiome indices may help to guide research into future treatment strategies for dogs with chronic enteropathy.
Topics: Dogs; Animals; Glucagon-Like Peptide 2; Dysbiosis; Dog Diseases; Female; Male; Gastrointestinal Microbiome; Chronic Disease; Prospective Studies; Feces; RNA, Ribosomal, 16S; Intestinal Diseases
PubMed: 38935795
DOI: 10.1371/journal.pone.0305711 -
PloS One 2024Sickle cell disease (SCD) decreases the oxygen-carrying capacity of red blood cells. Children with SCD have reduced/restricted cerebral blood flow, resulting in...
Sickle cell disease (SCD) decreases the oxygen-carrying capacity of red blood cells. Children with SCD have reduced/restricted cerebral blood flow, resulting in neurocognitive deficits. Hydroxyurea is the standard treatment for SCD; however, whether hydroxyurea influences such effects is unclear. A key area of SCD-associated neurocognitive impairment is working memory, which is implicated in other cognitive and academic skills. The neural correlates of working memory can be tested using n-back tasks. We analyzed functional magnetic resonance imaging (fMRI) data of patients with SCD (20 hydroxyurea-treated patients and 11 controls, aged 7-18 years) while they performed n-back tasks. Blood-oxygenation level-dependent (BOLD) signals were assessed during working memory processing at 2 time points: before hydroxyurea treatment and ~1 year after treatment was initiated. Neurocognitive measures were also assessed at both time points. Our results suggested that working memory was stable in the treated group. We observed a treatment-by-time interaction in the right cuneus and angular gyrus for the 2- >0-back contrast. Searchlight-pattern classification of the 2 time points of the 2-back tasks identified greater changes in the pattern and magnitude of BOLD signals, especially in the posterior regions of the brain, in the control group than in the treated group. In the control group at 1-year follow-up, 2-back BOLD signals increased across time points in several clusters (e.g., right inferior temporal lobe, right angular gyrus). We hypothesize that these changes resulted from increased cognitive effort during working memory processing in the absence of hydroxyurea. In the treated group, 0- to 2-back BOLD signals in the right angular gyrus and left cuneus increased continuously with increasing working memory load, potentially related to a broader dynamic range in response to task difficulty and cognitive effort. These findings suggest that hydroxyurea treatment helps maintain working memory function in SCD.
Topics: Humans; Hydroxyurea; Anemia, Sickle Cell; Memory, Short-Term; Child; Adolescent; Male; Female; Magnetic Resonance Imaging; Antisickling Agents; Brain; Case-Control Studies
PubMed: 38935785
DOI: 10.1371/journal.pone.0296196 -
PLoS Computational Biology Jun 2024As the spatial arrangement of trees planted along streets in cities makes their bases potential ecological corridors for the flora, urban tree bases may be a key...
As the spatial arrangement of trees planted along streets in cities makes their bases potential ecological corridors for the flora, urban tree bases may be a key contributor to the overall connectivity of the urban ecosystem. However, these tree bases are also a highly fragmented environment in which extinctions are frequent. The goal of this study was to assess the plant species' ability to survive and spread through urban tree bases. To do so, we developed a Bayesian framework to assess the extinction risk of a plant metapopulation using presence/absence data, assuming that the occupancy dynamics was described by a Hidden Markov Model. The novelty of our approach is to take into account the combined effect of low-distance dispersal and the potential presence of a seed bank on the extinction risk. We introduced a metric of the extinction risk and examined its performance over a wide range of metapopulation parameters. We applied our framework to yearly floristic inventories carried out in 1324 tree bases in Paris, France. While local extinction risks were generally high, extinction risks at the street scale varied greatly from one species to another. We identified 10 plant species that could survive and spread through urban tree bases, and three plant traits correlated with the extinction risk at the metapopulation scale: the maximal height, and the beginning and end of the flowering period. Our results suggest that some plant species can use urban tree bases as ecological corridors despite high local extinction risks by forming a seed bank. We also identified other plant traits correlated with the ability to survive in tree bases, related to the action of gardeners. Moreover, our findings demonstrate that our Bayesian estimation framework based on percolation theory has the potential to be extended to more general metapopulations.
PubMed: 38935782
DOI: 10.1371/journal.pcbi.1012191 -
PloS One 2024Dairy production in the UK has undergone substantial restructuring over the last few decades. Farming intensification has led to a reduction in the total numbers of...
Dairy production in the UK has undergone substantial restructuring over the last few decades. Farming intensification has led to a reduction in the total numbers of farms and animals, while the average herd size per holding has increased. These ever-changing circumstances have important implications for the health and welfare of dairy cows, as well as the overall business performance of farms. For decision-making in dairy farming, it is essential to understand the underlying causes of the inefficiencies and their relative impact. The investigation of yield gaps regarding dairy cattle has been focused on specific causes. However, in addition to the risk of overestimating the impact of a specific ailment, this approach does not allow understanding of the relative contribution to the total, nor does it allow understanding of how well-described that gap is in terms of underlying causes. Using the English and Welsh dairy sectors as an example, this work estimates the Loss Gap-composed of yield losses and health expenditure - using a benchmarking approach and scenario analysis. The Loss Gap was estimated by comparing the current performance of dairy herds as a baseline with that of scenarios where assumptions were made about the milk production of cows, production costs, market prices, mortality, and expenditure related to health events. A deterministic model was developed, consisting of an enterprise budget, in which the cow was the unit, with milking herd and young stock treated separately. When constraining milk production, the model estimated an annual Loss Gap of £148 to £227 million for the whole sector. The reduction in costs of veterinary services and medicines, alongside herd replacement costs, were important contributors to the estimate with some variation between the scenarios. Milk price had a substantial impact in the estimate, with revenue from milk yield representing more than 30% of the Loss Gap, when milk price was benchmarked against that of the top performing farms. This framework provides the boundaries for understanding the relative burden from specific causes in English and Welsh dairy cattle, ensuring that the sum of the estimated losses due to particular problem does not exceed the losses from all-causes, health or non-health related.
Topics: Animals; Cattle; Dairying; Female; Milk; Lactation
PubMed: 38935774
DOI: 10.1371/journal.pone.0306314 -
PloS One 2024Expert opinion is widely used in clinical guidelines. No research has ever been conducted investigating the use of expert opinion in international infectious disease... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Expert opinion is widely used in clinical guidelines. No research has ever been conducted investigating the use of expert opinion in international infectious disease guidelines. This study aimed to create an analytical map by describing the prevalence and utilization of expert opinion in infectious disease guidelines and analyzing the methodological aspects of these guidelines.
METHODS
In this meta-epidemiological study, systematic searches in PubMed and Trip Medical Database were performed to identify clinical guidelines on infectious diseases, published between January 2018 and May 2023 in English, by international organizations. Data extracted included guideline characteristics, expert opinion utilization, and methodological details. Prevalence and rationale of expert opinion use were analyzed descriptively. Methodological differences between groups were analyzed with Chi-square and Mann-Whitney U Test.
RESULTS
The analysis covered 66 guidelines with 2296 recommendations, published/endorsed by 136 organizations. Most guidelines (79%) used systematic literature searches, 42% provided search strategies, and 38% presented screening flow diagrams and conducted risk of bias assessments. 48.5% of the guidelines allowed expert opinion, most of which included expert opinion as part of the evidence hierarchy within the grading system. Guidelines allowing expert opinion, compared to those which do not, issued more recommendations per guideline (48.82 vs.19.13, p<0.001), and reported fewer screening flow diagrams (25% vs. 65%, p = 0.002), and less risk of bias assessments (19% vs.78%, p<0.001).
CONCLUSIONS
Expert opinion is utilized in half of assessed guidelines, often integrated into the evidence hierarchy within the grading system. Its utilization varies considerably in methodology, form, and terminology between guidelines. These findings highlight a pressing need for additional research and guidance, to improve and advance the standardization of infectious disease guidelines.
Topics: Humans; Expert Testimony; Communicable Diseases; Practice Guidelines as Topic; Epidemiologic Studies
PubMed: 38935698
DOI: 10.1371/journal.pone.0306098