bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence trends of type 2 diabetes treatment, dyslipidemia and hepatic steatosis in Northeast Germany
Authors: Bashir Aqsa , Völzke Henry , Henck Vivien , Schipf Sabine , Dörr Marcus , Nauck Matthias , Schmidt Carsten Oliver , Aghdassi Ali , Khattak Muhammad N K , Markus Marcello R P , Ittermann Till
Published: November 2024

Background

The investigation of prevalence trends of metabolic cardiovascular risk factors is important for appropriate planning of future health programs aiming to prevent cardiovascular morbidity and mortality. In a previous study, we demonstrated an increase in the prevalence of type 2 diabetes (T2D) between 2000 and 2010 in Northeast Germany. The purpose of this study is to investigate prevalence trends of T2D treatment, dyslipidemia and hepatic steatosis in Northeast Germany.

Methods

The baseline examinations of the first Study of Health in Pomerania (SHIP) project were carried out from 1997 to 2001 (SHIP-START-0, 4308 subjects). A second, independent random sample of the same region was enrolled between 2008 and 2012 (SHIP-TREND-0, 4420 subjects). All data were standardized with post-stratification weighting derived from the adult population of the German federal state of Mecklenburg-West Pomerania.

Results

The prevalence of metformin intake increased from 2.1% to 4.1% and insulin use from 2.0% to 2.8%. While the prevalence of statin intake increased from 6.8% to 12.2%, the prevalence of dyslipidemia decreased slightly from 49.0% in SHIP-START-0 to 45.5% in SHIP-TREND-0. The prevalence of hepatic steatosis increased from 29.7% to 37.3%. This increase was most prominently observed in women and younger age groups.

Conclusions

T2D, dyslipidemia and hepatic steatosis are common and increasing health problems among adults in Northeast Germany. Reassuring healthy diet and controlling obesity may result in prevention of above-mentioned health problems.
The Global Race for Talent: Brain Drain, Knowledge Transfer, and Growth
Authors: Prato Marta
Published: November 2024

How does inventors’ migration affect international talent allocation, knowledge diffusion, and productivity growth? To answer this question, I build a novel two-country innovation-led endogenous growth model, where heterogeneous inventors produce innovations, learn from others, and make dynamic migration and return decisions. Migrants interact with individuals at origin and destination, diffusing knowledge within and across countries. To quantify this framework, I construct a micro-level data set of migrant inventors on the U.S.-EU corridor from patent data and document that (i) gross migration is asymmetric, with brain drain (net emigration) from the EU to the United States; (ii) migrants increase their patenting by 33% a year after migration; (iii) migrants continue working with inventors at origin after moving, although less frequently; (iv) migrants’ productivity gains spill over to their collaborators at origin, who increase patenting by 16% a year when a co-inventor emigrates. I calibrate the model to match the empirical results and study the effect of innovation and migration policy. A tax cut for foreigners and return migrants in the EU that eliminates the brain drain increases EU innovation but lowers U.S. innovation and knowledge spillovers. The former effect dominates in the first 25 years, increasing EU productivity growth by 3%, but the latter dominates in the long run, lowering growth by 3%. On the migration policy side, doubling the size of the U.S. H1B visa program increases U.S. and EU growth by 4% in the long run, because it sorts inventors to where they produce more innovations and knowledge spillovers.
Inferring strain-level mutational drivers of phage-bacteria interaction phenotypes arising during coevolutionary dynamics
Authors: Lucia-Sanz Adriana , Peng Shengyun , Leung Chung Yin (Joey) , Gupta Animesh , Meyer Justin R , Weitz Joshua S
Published: November 2024

The enormous diversity of bacteriophages and their bacterial hosts presents a significant challenge to predict which phages infect a focal set of bacteria. Infection is largely determined by complementary—and largely uncharacterized—genetics of adsorption, injection, cell take-over, and lysis. Here we present a machine learning approach to predict phage–bacteria interactions trained on genome sequences of and phenotypic interactions among 51 Escherichia coli strains and 45 phage λ strains that coevolved in laboratory conditions for 37 days. Leveraging multiple inference strategies and without a priori knowledge of driver mutations, this framework predicts both who infects whom and the quantitative levels of infections across a suite of 2,295 potential interactions. We found that the most effective approach inferred interaction phenotypes from independent contributions from phage and bacteria mutations, accurately predicting 86% of interactions while reducing the relative error in the estimated strength of the infection phenotype by 40%. Feature selection revealed key phage λ and Escherchia coli mutations that have a significant influence on the outcome of phage–bacteria interactions, corroborating sites previously known to affect phage λ infections, as well as identifying mutations in genes of unknown function not previously shown to influence bacterial resistance. The method’s success in recapitulating strain-level infection outcomes arising during coevolutionary dynamics may also help inform generalized approaches for imputing genetic drivers of interaction phenotypes in complex communities of phage and bacteria.
The AMPK allosteric activator MK‐8722 improves the histology and spliceopathy in myotonic dystrophy type 1 (DM1) skeletal muscle
Authors: Ravel‐Chapuis Aymeric , Fahmi Chimène , Gobin Jonathan , Jasmin Bernard J.
Published: November 2024

Multiple signaling pathways have been reported to be altered in Myotonic Dystrophy type 1 (DM1) skeletal muscle, contributing to pathogenicity. In particular, previous work established that AMPK signaling, a key sensor of energy metabolism, is repressed in DM1 mouse muscle and that activating AMPK through exercise and/or with pharmacological activators is beneficial for the DM1 muscle phenotype. Here, we explored the effects of a newer, more specific allosteric AMPK activator acting directly on AMPK. We treated male and female HSALR mice for 1 and 4 weeks with a daily injection of the allosteric activator MK‐8722, the AMP mimetic AICAR, or vehicle. Our results show that 1 and 4 weeks of treatment with MK‐8722 improves alternative splicing toward wild‐type levels in male and female HSALR muscle. However, the effects of MK‐8722 were more modest compared to AICAR. In contrast, 4 weeks of treatment with MK‐8722 improved muscle histology to a greater extent than AICAR. As expected with AMPK activation, 4 weeks of treatment with MK‐8722 and AICAR promoted the expression of slower, more oxidative fibers. Finally, acute injections of MK‐8722 and AICAR triggered the rapid and transient increase in phospho‐AMPK in muscle. However, the peak of AMPK phosphorylation was lower with MK‐8722 compared to AICAR, thereby explaining the more modest effects of AMPK allosteric activation. Altogether, our data demonstrate that chronic activation of AMPK with specific pharmacological activators is beneficial for the DM1 muscle. They further indicate that at least a portion of the beneficial effects seen following the administration of these drugs occurs through AMPK.
Population health strategies for health equity in chronic kidney disease management
Authors: Brown Christopher O. , Pham Phuong-Chi , Shah Anuja , Dukkipati Ramanath , Shen Jenny , Elali Ibrahim , Dai Tiane , Raff Evan A. , Kalantar-Zadeh Kamyar
Published: November 2024

Purpose of review

Chronic kidney disease (CKD) is a widespread health issue, affecting one out of every 10 adults. This prevalence is even higher among vulnerable and underserved populations, including low-income individuals, racial and ethnic minorities, and immigrants. Urban areas such as New York City and Los Angeles County offer municipal safety-net healthcare systems for these groups.

Recent findings

Safety-net providers are essential to the healthcare landscape for vulnerable populations with chronic diseases including the Los Angeles County Health Services that exemplifies how effective population health strategies can be utilized to manage CKD and at-risk persons. These approaches focus on risk assessment, integrated practices, patient and care-partner education, cost reduction, and strategic partnerships. Kidney care tailored “Expected Practices” ensure that management strategies are equitable and based on clinical evidence. The eConsult system allows CKD patients’ primary care providers to efficiently consult nephrologists, facilitating timely specialty care appointments through “Precision Scheduling.” Priority goals include slowing CKD progression, equitable access to home dialysis, and preemptive kidney transplantation. As highlighted by Kalantar-Zadeh et al. in 2025 CJASN, advancing equitable kidney care through population health approaches support comprehensive and efficient CKD management, including diabetic kidney disease, in Los Angeles County's safety-net system.

With a large, underserved patient population affected by CKD, urban safety-net healthcare systems like those in Los Angeles County emphasize early detection, multidisciplinary management, shared decision-making, and equitable access to CKD. They prioritize equitable access to home dialysis modality choice and kidney transplantation, aiming to improve outcomes and the quality-of-life for diverse patient groups.
Network pharmacology and molecular docking analysis on the mechanism of Wensan tincture in the treatment of pulmonary nodules: A review
Authors: Zhang Jinzhi , Yang Jingqi , Li Guangxi
Published: November 2024

Network pharmacology and molecular docking methods were applied to elucidate the molecular mechanism of action of Wensan tincture (WST) in the treatment of pulmonary nodules. The Traditional Chinese Medicine Systems Pharmacology and the Traditional Chinese Medicine and Chemical Composition database were used to screen the active ingredients. Potential targets of WST were retrieved using Traditional Chinese Medicine Systems Pharmacology, SwissADME, and SwissTargetPrediction, while pulmonary nodule-associated targets were obtained from GeneCards and Online Mendelian Inheritance in Man databases. An active ingredient–target network was constructed using Cytoscape 3.9.1, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were conducted via the Database for Annotation, Visualization, and Integrated Discovery platform to identify core targets and signaling pathways. Molecular docking studies were performed using AutoDockTools. The results revealed 62 active ingredients and 344 corresponding targets within the tincture, alongside 1005 targets associated with pulmonary nodules. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that the potential therapeutic targets of WST include signal transducer and activator of transcription 3, mitogen-activated protein kinase-3, mitogen-activated protein kinase-1, Jun proto-oncogene, tumor protein 53, phosphoinositide-3-kinase regulatory subunit 1, heat shock protein 90 alpha family class A member 1, and AKT serine/threonine kinase 1. The primary pathways were the cancer pathway, mitogen-activated protein kinase signaling, advanced glycation end-products and their receptor signaling, epidermal growth factor receptor signaling, hypoxia-inducible factor-1 signaling, and the programmed cell death-ligand 1/programmed cell death protein 1 checkpoint pathways. Molecular docking demonstrated that quercetin exhibited the strongest binding affinity with mitogen-activated protein kinase-3, with a binding energy of −9.1 kcal/mol. Notably, key components of WST, such as quercetin, demonstrate considerable potential as drug candidates for the treatment of pulmonary nodules.
Causal relationships between immune cells, inflammatory cytokines, and pertussis: Bidirectional 2-sample Mendelian randomization study and mediation analysis
Authors: Lu Fu-Qing , Feng Hui-Mei , Wang Ji-Gan , Song Kun-Ling
Published: November 2024

Studies have shown that immune cells play an important role in the occurrence and development of pertussis, but the specific causal relationships are yet to be determined. Additionally, inflammatory cytokines, as regulators of immune responses, may mediate the relationship between immune cells and pertussis, and the specific mechanisms involved require further exploration. This study utilizes data from multiple large-scale genome-wide association studies, covering 731 types of immune cells and 91 types of inflammatory cytokines. The bidirectional 2-sample Mendelian randomization (MR) method is employed, with inverse-variance weighted as the main statistical approach, to assess the causal relationships between immune cells, inflammatory cytokines, and pertussis. Furthermore, a 2-step MR method is used to investigate the mediating role of inflammatory cytokines in the effect of immune cells on pertussis. Our study results indicate that 11 types of immune cells have a protective effect against pertussis, with the strongest protection observed from CD25 on CD28+ CD4+ cells (OR = 0.3533, CI = 0.1636–0.7627, P = .008). Conversely, 19 types of immune cells are positively associated with the risk of pertussis, with the strongest correlation found in CD3− lymphocyte %lymphocyte (OR = 3.6613, CI = 1.5012–8.299, P = .0043). Additionally, 3 inflammatory cytokines – IL-4, IL-18R1, and FGF-21 – show a causal relationship with pertussis. Our mediation MR results indicate that inflammatory cytokines do not act as mediators in the relationship between immune cells and pertussis. This study suggests a causal relationship between immune cells and pertussis, while inflammatory cytokines do not appear to be mediating factors in the pathway from immune cells to pertussis.
Partial nephrectomy versus radiofrequency ablation in patients with cT1a renal cell carcinoma: A surveillance, epidemiology, end results (SEER) analysis
Authors: Yang Bo , Zheng Yang , Zheng Mengqin , Wang Dong , Ren Shangqing , Tian Jingzhi
Published: November 2024

Radiofrequency ablation (RFA) has been proposed for T1a renal cell carcinoma (RCC). The present study compared partial nephrectomy (PN) with RFA for T1a RCC stratified by tumor sizes. We selected patients with RCC and underwent PN or RFA through the surveillance, epidemiology, end results (SEER) database. The Kaplan–Meier method and Cox proportional hazards regression model were conducted. Inverse probability of treatment weights was conducted for sensitivity analysis. We enrolled 15,692 patients in the unmatched cohort, 15,392 (98.1%) underwent PN, and 300 (1.9%) underwent RFA. For tumor ≦ 2 cm, PN was equal to RFA in terms of overall survival (OS) (P > .05) and cancer-specific survival (CSS) (P > .05). For tumor size 2 to 3 cm, PN is likely to have a better OS (P < .05)and comparable CSS (P > .05). For > 3 cm tumor, PN might be associated with higher OS (P < .05) and CSS (P < .05) compared with RFA. In conclusion, PN had a similar OS and CSS compared with RFA in tumor size ≦ 2 cm, RFA could be offered for elderly or patients with comorbidity. For > 2 cm tumors, RFA is not recommended. However, further randomized controlled trials are further required to validate our results.
Comparison of the effects on coagulation function and safety of bivalirudin and heparin in patients undergoing percutaneous coronary intervention: A randomized trial
Authors: Wang Yanan , Ren Xiaorong , Song Zhizhou , Wu Qi , Yang Youdong
Published: November 2024

Background:

To analyze the effects on coagulation function and safety of bivalirudin and heparin in patients undergoing percutaneous coronary intervention (PCI) and provide clinical evidence for their application.

Methods:

A total of 42 patients with coronary heart disease undergoing PCI treatment from July 2019 to January 2022 at Datong Third People’s Hospital in China were divided into 2 groups: the bivalirudin group and the heparin group. The former received perioperative administration of bivalirudin, while the latter received heparin. After 24 hours of treatment, blood indicators, coagulation functions, as well as cardiac, hepatic, and renal markers were evaluated. Additionally, Thrombolysis In Myocardial Infarction (TIMI) flow graded infarct-related vessel blood flow was assessed in both groups. Adverse cardiovascular and cerebrovascular events were monitored for a duration of 12 months.

Results:

The Activated clotting time (ACT), D-dimer (D-D), and prothrombin time (PT) levels in the bivalirudin group were significantly lower than those in the heparin group (P < .05). Both the bivalirudin and heparin groups showed significant improvement in TIMI flow grade after PCI (P < .05). The levels of Creatine Kinase-MB (CK-MB), N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) in the bivalirudin group were significantly lower than those in the heparin group (P < .05). There were no serious adverse cardiovascular and cerebrovascular events in either group.

Conclusion:

Bivalirudin has a slightly superior impact on coagulation function and safety profile in patients undergoing PCI compared to heparin, and the preventive effect of both on postoperative cardiovascular events is similar.
Identification and validation of ion channels-related mRNA prognostic signature for glioblastomas
Authors: Huang Chao , Yu Xue-Bin , Zhou Yong-Zhi , Bao Wu-Qiao
Published: November 2024

Glioblastomas (GBM) is a kind of malignant brain tumor with poor prognosis. Identifying new biomarkers is promising for the treatment of GBM. The mRNA-seq and clinical data were obtained from The Cancer Genome Atlas and the Chinese Glioma Genome Atlas databases. The differentially expressed genes were identified using limma R package. The prognosis-related genes were screened out and a risk model was constructed using univariate, least absolute shrinkage and selection operator, and multivariate Cox analysis. Receiver operating characteristic curve was used to assess the efficiency of model. Kaplan–Meier survival curve was applied for the survival analysis. Mutation analysis was conducted using maftools package. The effect of immunotherapy was analyzed according to TIDE score, and the drug sensitivity analysis was performed. The Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis enrichment analyses were performed for the functional analysis. The regulatory network was constructed by STRING and Cytoscape software. RT-qPCR was performed to validate the expression of 3 hub genes in vitro. A risk model was constructed based on 3 ion channels related genes (gap junction protein beta 2 [GJB2], potassium voltage-gated channel subfamily h member 6 [KCNH6], and potassium calcium-activated channel subfamily n member 4 [KCNN4]). The risk score and hub genes were positively correlated with the calcium signaling pathway. Patients were divided into 2 groups based on the risk score calculated by 3 signatures. The infiltration levels of T cell, B lineage, monocytic lineage, and neutrophils were increased in high risk group, while TIDE score was decreased. IC50 of potential drugs for GBM treatment was elevated in the high risk group. Furthermore, GJB2, KCNH6, and KCNN4 were oncogenic, and GJB2 and KCNN4 were upregulated, while KCNH6 was downregulated in high risk group and GBM cells. The regulatory network showed that KCNH6 was targeted by more miRNA and transcription factors and KCNN4 interacted with more drugs. We constructed a three-signature risk model, which could effectively predict the prognosis of GBM development. Besides, KCNH6 and KCNN4 were respectively considered as the targets of molecular targeted treatment and chemotherapy.
Assessing coronavirus disease 2019 pandemic impacts on the health of people who inject drugs using a novel data sharing model
Authors: Bradley Heather , Luisi Nicole , Carter Anastasia , Pigott Terri D. , Abramovitz Daniela , Allen Sean T. , Asher Alice , Austin Chelsea , Bartholomew Tyler S. , Baum Marianna , Board Amy , Boodram Basmattee , Borquez Annick , Brookmeyer Kathryn A. , Buchacz Kate , Burnett Janet , Cooper Hannah L.F. , Crepaz Nicole , Debeck Kora , Feinberg Judith , Fong Chunki , Freeman Edward , Furukawa Nathan Woo , Genberg Becky , Gorbach Pamina , Hagan Holly , Hayashi Kanna , Huriaux Emalie , Hurley Hermione , Keruly Jeanne , Kristensen Kathleen , Lai Shenghan , Martin Natasha K. , Mateu-Gelabert Pedro , Mcclain Gregory M. , Mehta Shruti , Mok Wing Yin , Reynoso Marley , Strathdee Steffanie , Torigian Nicole , Weng Chenziheng Allen , Westergaard Ryan , Young April , Des Jarlais Don C.
Published: November 2024

Objective:

Using an innovative data sharing model, we assessed the impacts of the COVID-19 pandemic on the health of people who inject drugs (PWID).

Design:

The PWID Data Collaborative was established in 2021 to promote data sharing across PWID studies in North America. Contributing studies submitted aggregate data on 23 standardized indicators during four time periods: prepandemic (March 2019 to February 2020), early-pandemic (March 2020 to February 2021), mid-pandemic (March 2021 to February 2022), and late pandemic (March 2022 to February 2023).

Methods:

We present study-specific and meta-analyzed estimates for the percentage of PWID who took medications for opioid use disorder, received substance use treatment, shared syringes or injection equipment, had a mental health condition, had been incarcerated, or had experienced houselessness. To examine change over time across indicators, we fit a random effects meta-regression model to prevalence estimates using time as a moderator.

Results:

Thirteen studies contributed estimates to the Data Collaborative on these indicators, representing 6213 PWID interviews. We observed minimal change across prevalence of the six indicators between the prepandemic (March 2019 to February 2020) and three subsequent time periods, overall or within individual studies. Considerable heterogeneity was observed across study-specific and time-specific estimates.

Conclusion:

Limited pandemic-related change observed in indicators of PWID health is likely a result of policy and supportive service-related changes and may also reflect resilience among service providers and PWID themselves. The Data Collaborative is an unprecedented data sharing model with potential to greatly improve the quality and timeliness of data on the health of PWID.
Molecular Ultrasound Imaging With Clinically Translatable cRGD-Coated Microbubbles to Assess αvβ3-Integrin Expression in Inflammatory Bowel Disease
Authors: Qi Jinwei , Chen Junlin , von Stillfried Saskia , Kozcera Patrick , Shi Yang , Rix Anne , Kiessling Fabian
Published: November 2024

Objectives

Inflammatory bowel disease (IBD) subdivides into Crohn disease (CD) and ulcerative colitis (UC), and is characterized by unpredictable periods of inflammation and results in significant patient suffering and even death. Conventional diagnostic methods, for example, colonoscopy, computed tomography, or magnetic resonance imaging, have limitations such as invasiveness, patient discomfort, and limited sensitivity and accuracy. Therefore, we propose ultrasound molecular imaging (USMI) to detect and characterize IBD. First, we evaluated integrin-αvβ3 as a biomarker of IBD in human samples and then used clinically translatable cyclic Arg-Gly-Asp-D-Phe-Lys (cRGDfK)–coupled poly(butyl)cyanoacrylate microbubbles (cRGD-MB) to assess IBD in mice.

Materials and Methods

Vascular integrin-αvβ3 expression in human colon tissue samples (healthy, CD and UC, n = 10 per group) was analyzed by immunofluorescence staining. In mice, acute colitis was induced by administration of 4% dextran sodium sulfate in drinking water for 5 days. On day 7, USMI with cRGD-MB was performed in colitis (n = 6) and healthy (n = 5) mice. The signal of bound cRGD-MB was assessed by the destruction-replenishment method. Ex vivo analysis of mouse colon tissue was performed to assess the degree of colitis by hematoxylin-eosin staining and the vascular expression of integrin-αv by immunofluorescence.

Results

Human samples showed a significantly higher vascular integrin-αvβ3 expression in CD and UC tissue, when compared with healthy samples (P < 0.005). In mice, a higher binding of cRGD-MB to inflamed colon was detected by USMI compared with healthy controls (P < 0.005). Immunofluorescence staining confirmed these findings, showing stronger integrin-αv expression in acute colitis, with a good correlation between USMI signal intensity and integrin-αv expression (r = 0.8, P = 0.0016).

Conclusions

Integrin-αvβ3 on vessels is a suitable marker for IBD. USMI using cRGD-MB accurately detects this marker and correlates well with histology. These encouraging results support clinical translation of this imaging method as a noninvasive and cost-effective monitoring tool.
Clinical Validation of Metabolite Markers for Early Lung Cancer Detection
Authors: Zhang Lun , Zheng Jiamin , Ahmed Rashid , Haince Jeff , Torres-Calzada Claudia , Mandal Rupasri , Maksymuik Andrew , Tappia Paramjit S. , Joubert Philippe , Rolfo Christian D. , Wishart David S.
Published: November 2024

Non-small cell lung cancer (NSCLC), comprising 85% of lung cancers, is a leading cause of cancer mortality. Early detection enhances survival, but current screening methods are limited. This retrospective study used targeted mass spectrometry-based metabolomics on 680 plasma samples from NSCLC patients and controls (discovery cohort) and 216 samples (validation cohort). Logistic regression models with a subset of ten metabolites achieved over 90% area under the ROC curve (AUROC) for distinguishing patients from controls, including early-stage disease. Incorporating smoking history improved model performance. In the discovery cohort, AUROCs were 93.6% (all stages), 93.7% (Stage I and II), and 93.9% (Stage I). Validation confirmed the high sensitivity and specificity of the models. This study demonstrates that metabolomic biomarkers provide a minimally invasive, sensitive, and specific tool for early NSCLC detection, potentially improving screening and patient outcomes. Future studies should validate these biomarkers in diverse populations.

Statement of significance

This study identifies plasma metabolite biomarkers that enable sensitive and specific early detection of NSCLC using minimally invasive blood sampling. Achieving over 90% area under the ROC curve for early-stage patients, the findings promise to improve lung cancer screening methods and enhance early interventions and patient outcomes.
Perspectives of Key Stakeholders on Integrating Wearable Sensor Technology into Rehabilitation Care: A Mixed-Methods Analysis
Authors: Miller Allison E. , Holleran Carey L. , Bland Marghuretta D. , Fitzsimmons-Craft Ellen E. , Newman Caitlin A. , Maddox Thomas M. , Lang Catherine E.
Published: November 2024

Introduction

Rehabilitation is facing a critical practice gap: Patients seek out rehabilitation services to improve their activity in daily life, yet recent work demonstrates that rehabilitation may be having a limited impact on improving this outcome due to lack of objective data on patients’ activity in daily life. Remote monitoring using wearable sensor technology is a promising solution to this address this gap. The purpose of this study was to understand patient and clinician awareness of the practice gap and preferences for integrating wearable sensor technology into rehabilitation care.

Methods

This study used a mixed-methods approach consisting of surveys and 1:1 interviews with clinicians (physical and occupational therapists or assistants) employed at an outpatient rehabilitation clinic within an academic medical center and patients seeking care at this clinic. Data were analyzed using descriptive statistics and thematic analysis.

Results

Data saturation was reached from recruiting nineteen clinicians and ten patients. Both clinicians and patients recognized the importance of measuring activity outside the clinic and viewed wearable sensor technology as an objective measurement tool. Most clinicians (63%) preferred continuous (vs. intermittent) monitoring within a care episode and most patients (60%) were willing to sync their sensor data as often as instructed by their provider. To maximize integration into clinical workflows, clinicians voiced a preference for availability of sensor data in the electronic health record.

Conclusions

Clinicians and patients value the use of wearable sensor technology to improve measurement of activity outside the clinic environment and expressed preferences for how this technology could best be integrated into routine rehabilitation care.
Undergraduate students with and without mental health concerns have different perceptions of disclosing mental health challenges to instructors
Authors: Sizemore J. Michael , Von der Mehden Bailey , Schussler Elisabeth E.
Published: November 2024

A significant proportion of undergraduates report having mental health concerns (MHC), which are associated with reduced academic success. Students with MHC are encouraged to seek help from their instructors but may not because of perceived negative reactions by instructors and peers. This suggests stigma about MHC may differentially impact disclosure perceptions of students with MHC compared with their peers, yet the perceptions of both groups have been unexplored. This study surveyed students with and without MHC in the same classes about their hypothetical disclosure of MHC. Students in several introductory biology classes were asked whether they identified as having MHC, whether they would or would not hypothetically disclose MHC to an instructor, and why. Thematic analysis identified reasons underlying their disclosure choices, which were sorted into the three beliefs of the Theory of Planned Behavior: attitudes, subjective norms, and behavioral control. Of the 803 respondents, 50% self-identified as having MHC. Students with MHC were less likely to say they would disclose their MHC to an instructor than students without MHC. Students with and without MHC who said ‘yes’ to disclosure gave similar reasons aligned with attitude beliefs. Students with MHC who said ‘no’ to disclosure perceived that the instructor wouldn’t care (attitude beliefs). Students without MHC who said ‘no’ to disclosure talked more about keeping their MHC private (subjective norms beliefs). Students without MHC who said ‘it depends’ talked more about impact on their course performance (attitude) than students with MHC. This research indicated that students with and without MHC do perceive disclosure differently and suggested that students with MHC focus more on negative instructor reactions, while those without MHC focus on privacy and performance. These differential perceptions may contribute to students with MHC seeing disclosure as a negative social cost versus a positive academic benefit.
Sexual dimorphism of MASLD-driven bone loss
Authors: Goldscheitter Galen M , Seneshaw Mulugeta , Mirshahi Faridoddin , Buettmann Evan G , Genetos Damian C , Sanyal Arun J , Donahue Henry J
Published: November 2024

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is highly prevalent with major risk of progression to Metabolic Dysfunction-Associated Steatohepatitis (MASH) and Hepatocellular Carcinoma (HCC). Recently, osteoporosis and bone fracture have emerged as sexually-dimorphic comorbidities of MASLD yet the mechanisms of this bone loss are unknown. Herein, we address these knowledge gaps using DIAMOND mice which develop MASLD, MASH, and HCC via Western diet exposure. We examined the skeletal phenotype of male DIAMOND mice after 16, 36, and 48 weeks of exposure to Western or control diet. At 16 weeks, male DIAMOND mice with MASLD lose trabecular bone but retain mechanical bone integrity. At 48 weeks, males lose cortical bone and mechanical integrity, indicating severe skeletal weakening. Female DIAMOND mice were protected from cortical and trabecular MASLD-associated bone loss and skeletal fragility at all timepoints. Using NicheNet, a publicly available database of hepatic mRNA expression in DIAMOND mice, and a PTH-induced model of bone loss, we suggestCtgf, Rarres2, Anxa2, Fgf21,andMmp13are liver-secreted ligands inducing bone resorption. This study is the first preclinical investigation of bone loss in MASLD, and the first to suggest the role ofCtgf, Rarrest2, Anxa2, Fgf21,andMmp13as drivers of this pathology.
CASTER-DTA: Equivariant Graph Neural Networks for Predicting Drug-Target Affinity
Authors: Kumar Rachit , Romano Joseph D. , Ritchie Marylyn D.
Published: November 2024

Accurately determining the binding affinity of a ligand with a protein is important for drug design, development, and screening. With the advent of accessible protein structure prediction methods such as AlphaFold, several approaches have been developed that make use of information determined from the 3D structure for a variety of downstream tasks. However, methods for predicting binding affinity that do consider protein structure generally do not take full advantage of such 3D structural protein information, often using such information only to define nearest-neighbor graphs based on inter-residue or inter-atomic distances. Here, we present a joint architecture that we call CASTER-DTA (Cross-Attention with Structural Target Equivariant Representations for Drug-Target Affinity) that makes use of an SE(3)-equivariant graph neural network to learn more robust protein representations alongside a standard graph neural network to learn molecular representations, and we further augment these representations by incorporating an attention-based mechanism by which individual residues in a protein can attend to atoms in a ligand and vice-versa to improve interpretability. In this manner, we show that using equivariant graph neural networks in our architecture enables CASTER-DTA to approach and exceed state-of-the-art performance in predicting drug-target affinity without the inclusion of external information, such as protein language model embeddings. We do so on the Davis and KIBA datasets, common benchmarks for predicting drug-target affinity. We also discuss future steps to further improve performance.
The G protein inhibitor YM-254890 is an allosteric glue
Authors: Trent Tony , Miller Justin J. , Bowman Gregory R
Published: November 2024

Given the prominence of G protein coupled receptors (GPCRs) as drug targets, targeting their immediate downstream effectors, G proteins, could be of immense therapeutic value. The discovery that the natural product YM-254890 (YM) can arrest uveal melanoma by specifically inhibiting constitutively active Gq/11without impacting other G protein families demonstrates the potential of this approach. However, efforts to find other G protein family-specific inhibitors have had limited success. Better understanding the mechanism of YM could facilitate efforts to develop other highly specific G protein inhibitors. We hypothesized that differences between the conformational distributions of various G proteins play an important role in determining he specificity of inhibitors like YM. To explore this hypothesis, we built Markov state models (MSMs) from molecular dynamics simulations of the Gα subunits of three different G proteins, as YM predominantly contacts Gα. We also modeled the heterotrimeric versions of these proteins where Gα is bound to the Gβγ heterodimer. We find that YM-sensitive Gα proteins have a higher probability of adopting YM-bound-like conformations than insensitive variants. There is also strong allosteric coupling between the YM- and Gβγ-binding interfaces of Gα. This allostery gives rise to positive cooperativity, wherein the presence of Gβγ enhances preorganization for YM binding. We predict that YM acts as an “allosteric” glue that allosterically stabilizes the complex between Gα and Gβγ despite the minimal contacts between YM and Gβγ.
Epstein-Barr viral product-containing exosome facilitates LIF-associated immunosuppressive polarization of macrophage in nasopharyngeal carcinoma
Authors: Liu Tzu-Tung , Sui Yun-Hua , Jiang Shih-Sheng , Tsai Fang-Yu , Chang Kai-Ping , Tsang Ngan-Ming , Lee Meng-Hsin , Huang Chen-Han , Liu Shu-Chen
Published: November 2024

Nasopharyngeal carcinoma (NPC) is characterized by Epstein-Barr virus (EBV) infection and severe immune cell infiltration. How tumor-derived EBV or viral products regulate macrophage polarization within NPC microenvironment remains to be explored. Here, we investigated the exosome-mediated intercellular communications between EBV+NPC cells and tumor-associated macrophages (TAMs). We demonstrate that leukemia inhibitory factor (LIF) expression correlates with poorer metastasis/recurrence-free survival in NPC patients. Immunohistochemical analyses revealed that LIF is highly expressed by both tumor cells and macrophages. The uptake of NPC-derived exosomes by human monocyte-derived macrophages induced an immunosuppressive polarization and enhanced LIF expression, exhibiting a reduced cytotoxicity against primary cancer cells. Blocking LIF suppressed the pro-tumor functions mediated by tumor-derived exosomes, in bothin vitroandin vitrozebrafish xenografts model. Furthermore, single-cell transcriptomic analysis (scRNA-seq) suggested that tumor- derived exosomes remodeled the NPC microenvironment by increasing the proportion of a pro-tumoral TAM subtype, CCL18-MΦ. Intercellular analysis revealed that exosome-treated macrophages could modulate T cell cytotoxicity and promoting Treg-mediated immunosuppression. Collectively, EBV shapes the tumor microenvironment by driving macrophage toward an immunosuppressive phenotype via exosome cargos, facilitating a pro-tumoral niche and contribute to NPC progression.
Atheroprone Flow Activates SMAD-FOXO1 to drive Endothelial-to-Mesenchymal Transition and Atherosclerosis
Authors: Mendez Paul-Lennard , Raaz Lion , Jatzlau Jerome , Xiao Yunyun , Vrancaert Pieter , Ksiazkiewicz Jakub , Wallentin Jakob , Trumpp Michael , Scharnitzki Stefanie , Mundlos Stefan , Luttun Aernout , Zwijsen An , Itoh Fumiko , Knaus Petra
Published: November 2024

Background

Cardiovascular diseases are the leading cause of death worldwide with atherosclerosis as the main underlying pathology. A hallmark of atherosclerotic lesion formation is endothelial-to-mesenchymal transition (EndoMT) triggered by perturbed blood flow patterns at arterial bifurcations and curvatures. SMAD transcription factors (TFs), activated by bone morphogenetic protein (BMP) 9/10 or transforming growth factor beta (TGFβ) signaling, are indispensable for endothelial homeostasis. Yet, they also play a significant role in stimulating EndoMT. How different interacting co-factors mediate the shift towards a pathological SMAD response remains elusive.

Methods

We generated endothelial cell (EC)-specific SMAD1/5 or SMAD2/3 knock-out mice and performed assay for transposase accessible chromatin sequencing (ATAC-Seq) of EC nuclei from regions of atheroprone (aortic arch) and atheroprotective (descending thoracic aorta) flow to identify transcriptional co-regulators of SMADs. We validated this using single-cell (sc)ATAC-Seq and immunofluorescence staining data from wild-type mice. To assess conservation of our findings for the human situation, we performed co-immunoprecipitation and proximity ligation assays in human aortic ECs (HAoECs). We exposed HAoECs to pathological or physiological (i.e. oscillatory or pulsatile) flow and performed ATAC- and RNA-Seq. Next, transcriptomic and chromatin accessibility data were integrated and motif enrichment and TF footprinting analysis were performed. Finally, we used siRNA-mediated approaches, TF inhibition, and luciferase-based reporter gene assays to analyze the transcriptional response of target TFs and explored their presence in plaques of atheroprone low-density lipoprotein receptor-deficient mice.

Results

We observed enrichment of FOXO TF family motifs in DNA loci with increased accessibility in response to atheroprone flowin vitroandin vivo. These motifs were associated with genes displaying enhanced mRNA expression. We observed that FOXO motifs are enriched in peaks lost upon EC-specific SMAD KO in mice. We identified SMADs and FOXO1 as interacting partners that form complexes upon atheroprone flow stimulation. Inhibitor experiments revealed that FOXO1 and SMADs mediate EndoMT upon atheroprone flow exposure by upregulatingSNAI2.

Conclusion

We identified SMAD/FOXO1 complexes that mediate EndoMT in response to atheroprone flow. Targeting this interaction can potentially reduce atherosclerotic burden by interfering with pathological flow-induced EndoMT and thus disease progression.
Distinct medical and substance use histories associate with cognitive decline in Alzheimer’s Disease
Authors: Mansel Clayton , Mazzotti Diego R. , Townley Ryan , Sardiu Mihaela E , Swerdlow Russell H. , Honea Robyn A , Veatch Olivia J
Published: November 2024

INTRODUCTION

Phenotype clustering reduces patient heterogeneity and could be useful when designing precision clinical trials. We hypothesized that the onset of early cognitive decline in patients would exhibit variance predicated on the clinical history documented prior to an Alzheimer’s Disease (AD) diagnosis

METHODS

Self-reported medical and substance use history (i.e., problem history) was used to cluster participants from the National Alzheimer’s Coordinating Centers (NACC) into distinct subtypes. Linear mixed effects modeling was used to determine the effect of problem history subtype on cognitive decline over two years.

RESULTS

2754 individuals were partitioned into three subtypes: minimal (n = 1380), substance use (n = 1038), and cardiovascular (n = 336) subtypes. The cardiovascular problem history subtype had significantly worse cognitive decline over a two-year follow-up period (p = 0.013).

DISCUSSION

Our study highlights the need to account for problem history to reduce heterogeneity of outcomes in AD clinical trials.
Process evaluation of pragmatic cluster randomized trials of digital adherence technologies for tuberculosis treatment support: a mixed methods study in five countries
Authors: Madden N. , Tadesse A. , Leung A. , Gonçalves Tasca B. , Alacapa J. , Deyanova N. , Ndlovu N. , Mokone N. , Onjare B , Mganga A. , van Kalmthout K. , Jerene D. , Fielding K.
Published: November 2024

Background

Digital adherence technologies (DATs) could improve the person-centredness of TB treatment. Acceptability of DATs is high, though evidence of their effectiveness is varied. Our objective was to understand the fidelity of DAT interventions within five cluster-randomized trials.

Methods

Two DATs (smart pill box, medication labels) were assessed, with real-time adherence data made available to healthcare providers (HCPs) on a digital platform in Ethiopia, the Philippines, South Africa, Tanzania, and Ukraine. The process evaluation framework assessed four components: inputs, processes, outputs, and outcomes. Fidelity of the most important intervention components was evaluated by quantitative indicators, with analysis conducted by country and DAT type. Content analysis of qualitative sub-studies supplemented some indicators.

Results

Engagement with DATs was high among persons with TB (PwTB). Pillbox users showed high levels of sustained engagement, with digitally recorded doses ranging from 82% to 91%. Sole ownership of a mobile phone was highest in South Africa (90%) and lowest in the Philippines (63%). Differences were also observed in the frequency of logins by HCPs to the adherence platform and the type of device used. In the Philippines and Ukraine, >50% of logins were from mobile phones. In Ethiopia, Tanzania, and Ukraine there was at least one login to the platform on 71% of weekdays per facility, compared with the Philippines and South Africa at 42% and 52%, respectively. A feeling of connection between PwTB and their HCP was reported by over 95% of participants surveyed in Ethiopia and Tanzania, this was 84% in South Africa and 76% Philippines, a finding underpinned by qualitative data.

Conclusion

We observed varying levels of intervention fidelity between countries. Timeliness and intensity of utilization of real-time data, and taking required actions are impacted by staff and health system capacity. Acceptance of DATs is high; therefore, future work should focus on identifying optimal intervention strategies.
Associations between weather andPlasmodium vivaxmalaria in an elimination setting in Peru: a distributed lag analysis
Authors: Barratt Heitmann Gabriella , Wu Xue , Nguyen Anna T. , Altamirano-Quiroz Astrid , Fine Sydney , Fernandez-Camacho Bryan , Barja Antony , Cava Renato , Soto-Calle Verónica , Rodriguez Hugo , Carrasco-Escobar Gabriel , Bennett Adam , Llanos-Cuentas Alejandro , Mordecai Erin A. , Hsiang Michelle S. , Benjamin-Chung Jade
Published: November 2024

Background

Plasmodium vivax(Pv) is the predominant malaria species in countries approaching elimination. In the context of climate change, understanding environmental drivers of transmission can guide interventions, yet evidence is limited, particularly in Latin America.

Objectives

We estimated the association between temperature and precipitation andPvmalaria incidence in a malaria elimination setting in Peru.

Methods

We analyzed malaria incidence data from 2021-2023 from 30 communities in Loreto, Peru with hourly weather data from the ERA5 dataset and land cover data from MapBiomas. Predictors included average weekly minimum and maximum temperature, high heat (>90th percentile mean temperature), total weekly precipitation, and heavy rain (>90th percentile total precipitation). We fit non-linear distributed lag models for continuous weather predictors and generalized additive models for binary predictors and the lookback period was 2—16 weeks. Temperature models adjusted for total precipitation; precipitation models adjusted for maximum temperature. We performed subgroup analyses by season, community type, and distance to forest edge.

Results

The median vs. lowest values of weekly average minimum temperature was associated with 2.16 to 3.93-fold higher incidence 3-16 weeks later (5-week lag incidence ratio (IR) =3.93 [95% CI 2.18, 7.09]); for maximum temperature, the association was hump-shaped across lags, with protective associations at 1-2 and 15-16 week lags and 1.07-1.66-fold higher incidence at 6-13 week lags. High heat (>27.5°C) was associated with 1.23 to 1.37-fold higher incidence at 5--9 week lags (9-week lag IR = 1.25 [1.02, 1.53]). Associations between total precipitation and malaria incidence were hump-shaped across lags, with the strongest positive association at 750 mm of precipitation at a 9-week lag (IR=1.56; [1.27, 1.65]). Heavy rain (>186mm) was associated with 1.22–1.60-fold higher incidence at 2–10 week lags (9-week lag IR=1.23 [1.02, 1.49]).

Discussion

Higher temperatures and precipitation were generally associated with higher malaria incidence over 1–4 months.