bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coupling of renal sodium and calcium transport: A modeling analysis
Authors: Hakimi Shervin , Dutta Pritha , Layton Anita T. 
Published: June 2023

AbstractCalcium (Ca2+) transport along the nephron occurs via specific transcellular and paracellular pathways, and is coupled to the transport of other electrolytes. Notably sodium (Na+) transport establishes an electrochemical gradient to drive Ca2+reabsorption. Hence, alterations in renal Na+handling, under pathophysiological conditions or pharmacological manipulations, can have major effects on Ca2+transport. An important class of pharmacological agent is diuretics, which are commonly prescribed for the management of blood pressure and fluid balance. The pharmacological targets of diuretics generally directly facilitate Na+transport, but also indirectly affect renal Ca2+handling. To better understand the underlying mechanisms, we have developed a computational model of electrolyte transport along the superficial nephron in the kidney of a male and female rat. Sex differences in renal Ca2+handling are represented. Model simulations predict in the female rat nephron lower Ca2+reabsorption in the proximal tubule and thick ascending limb, but higher reabsorption in the late distal convoluted tubule and connecting tubule, compared to the male nephron. The male rat kidney model yields a higher urinary calcium excretion than female, consistent with animal experiments. Additionally, we conducted simulations of inhibition of channels and transporters that play a major role in Na+and Ca2+transport. Model results indicate that along the proximal tubule and ascending thick ascending limb, Ca2+and Na+transport occurs in parallel, but those processes are dissociated in the distal convoluted tubule. Simulations also reveal sex-specific responses to different pharmacological manipulations.
Combinatorial chloride and calcium channelopathy in myotonic dystrophy
Authors: Cisco Lily A. , Sipple Matthew T. , Edwards Katherine M. , Thornton Charles A. , Lueck John D. 
Published: June 2023

AbstractMyotonic dystrophy type 1 (DM1) involves misregulated alternative splicing for specific genes. We used exon or nucleotide deletion to mimic altered splicing of genes central to muscle excitation-contraction coupling processes in mice. Mice with forced-skipping of exon 29 in CaV1.1 calcium channel combined with loss of ClC-1 chloride channel function showed a markedly reduced lifespan, whereas other combinations of splicing mimics did not affect survival. The Ca2+/Cl-bi-channelopathy mice exhibited myotonia, weakness, and impairment of mobility and respiration. Chronic administration of the calcium channel blocker verapamil rescued survival and improved force generation, myotonia, and respiratory function. These results suggest that Ca2+/Cl-bi-channelopathy contributes to muscle impairment in DM1 and is potentially mitigated by common clinically available calcium channel blockers.SummaryRepurposing of a calcium channel blocker extends life and mitigates muscle and respiratory dysfunction in a myotonic dystrophy type 1 Ca2+/Cl-bi-channelopathy mouse model.
Efficient multi-fidelity computation of blood coagulation under flow
Authors: Guerrero-Hurtado Manuel , Garcia-Villalba Manuel , Gonzalo Alejandro , Martinez-Legazpi Pablo , Kahn Andy M. , McVeigh Elliot , Bermejo J. , del Alamo Juan C. , Flores Oscar 
Published: June 2023

AbstractClot formation is a crucial process that prevents bleeding, but can lead to severe disorders when imbalanced. This process is regulated by the coagulation cascade, a biochemical network that controls the enzyme thrombin, which converts soluble fibrinogen into the fibrin fibers that constitute clots. Coagulation cascade models are typically complex and involve dozens of partial differential equations (PDEs) representing various chemical species’ transport, reaction kinetics, and diffusion. Solving these PDE systems computationally is challenging, due to their large size and multi-scale nature.We propose a multi-fidelity strategy to increase the efficiency of coagulation cascade simulations. Leveraging the slower dynamics of molecular diffusion, we transform the governing PDEs into ordinary differential equations (ODEs) representing the evolution of species concentrations versus blood residence time. We then Taylor-expand the ODE solution around the zero-diffusivity limit to obtain spatiotemporal maps of species concentrations in terms of the statistical moments of residence time,, and provide the governing PDEs for. This strategy replaces a high-fidelity system ofNPDEs representing the coagulation cascade ofNchemical species byNODEs andpPDEs governing the residence time statistical moments. The multi-fidelity order(p) allows balancing accuracy and computational cost, providing a speedup of overN/pcompared to high-fidelity models.Using a simplified coagulation network and an idealized aneurysm geometry with a pulsatile flow as a benchmark, we demonstrate favorable accuracy for low-order models ofp= 1 andp= 2. These models depart from the high-fidelity solution by under 16% (p= 1) and 5% (p= 2) after 20 cardiac cycles.The favorable accuracy and low computational cost of multi-fidelity models could enable unprecedented coagulation analyses in complex flow scenarios and extensive reaction networks. Furthermore, it can be generalized to advance our understanding of other systems biology networks affected by blood flow.
Androgenic Steroids Induce Pathologic Scarring in a Preclinical Swine Model Via Dysfunctional Extracellular Matrix Deposition
Authors: Reiche Erik , Keller Patrick R , Soares Vance , Schuster Calvin R , Rahmayanti Siti , Mroueh Jessica , Mroueh Vanessa , Billaud Marie , Hu Sophia , Hoover-Watson Hunter , Lian Christine G , Tan Yu , Doloff Joshua C , Newell-Fugate Annie E , Coon Devin 
Published: June 2023

AbstractBackgroundHypertrophic scarring is a major source of morbidity for surgery patients. Sex hormones are not classically considered to be modulators of scarring. However, based on clinical observations of increased frequency of hypertrophic scarring in patients on testosterone, we hypothesized that androgenic steroids induce abnormal scarring and developed a preclinical swine model to explore these effects.MethodsA total of six male (XY) and female (XX) mini-swine underwent castration and were randomly assigned to no testosterone (noT) or biweekly testosterone therapy (+T). Ten dorsal excisional wounds were created on each pig. To mimic a chronic wound, a subset of wounds were re-excised at two weeks. Scars (POD42) and chronic wounds (POD28) were harvested six weeks after initial wounding for analysis via histology, RNA-seq, and mechanical testing.ResultsHistologic analysis of POD42 scars from +T swine showed increased mean fibrosis area (16mm2noT, 28mm2+T; p=0.007) and thickness (0.246mm2noT, 0.406mm2+T; p<0.001) compared to noT swine. Scars in XX+T and XY+T pigs had greater tensile burst strength (p=0.024 and p=0.013 respectively) compared to scars in noT swine. Color deconvolution analysis showed greater deposition of type I and type III collagen as well as increased type I to type III collagen ratio in +T scars. Dermatopathologist scores of POD42 scars show +T exposure was associated with worse overall scarring scores compared to controls (p<0.05). On RNAseq, gene ontology analysis showed testosterone exposure was associated with significant upregulation of cellular metabolism and immune response gene sets. Pathway analysis showed testosterone upregulated Reactome pathways related to keratinization and formation of collagen and laminin.ConclusionWe developed a novel preclinical porcine model to study the effects of the sex hormone testosterone on scarring. Testosterone induces early proliferation of excessive granulation tissue, which eventually leads to increased scar tissue. T also appears to increase the physical strength of scars via supraphysiologic deposition of collagen and other ECM factors. The increase in burst strength observed for both XX and XY suggests that hormonal administration has a stronger influence on mechanical properties than chromosomal sex. Antiandrogen topical therapies may be a promising future area of research.
Evaluating the Risk of Conflict on Recent Ebola Outbreaks in Guinea and the Democratic Republic of the Congo
Authors: Charnley Gina E C , Green Nathan , Kelman Ilan , Malembaka Espoir B , Gaythorpe Katy A M 
Published: June 2023

AbstractBackgroundReducing Ebola virus transmission relies on the ability to identify cases and limit contact with infected bodily fluids through biosecurity, safe sex practices, safe burial and vaccination. Armed conflicts can complicate outbreak detection and interventions due to widespread disruption to governments and the populations. Guinea and the Democratic Republic of the Congo (DRC) have historically reported the largest and the most recent Ebola virus outbreaks. Understanding if conflict played a role in these outbreaks may help in identifying key risks factors to improve disease control.MethodsWe used data from a range of publicly available data sources for both Ebola virus cases and conflict events from 2018 to 2021 in Guinea and the DRC. We fitted these data to conditional logistic regression models using the Self-Controlled Case Series methodology to evaluate the magnitude in which conflict increased the risk of reported Ebola virus cases in terms of incidence rate ratio. We re-ran the analysis sub-nationally, by conflict sub-event type and tested any lagged effects.ResultsConflict was significantly associated with an increased risk of reported Ebola virus cases in both the DRC and Guinea in recent outbreaks. The effect was of a similar magnitude at 1.88- and 1.98-times increased risk for the DRC and Guinea, respectively. The greatest effects (often higher than the national values) were found in many conflict prone areas and during protest/riot-related conflict events. Conflict was influential in terms of Ebola virus risk from 1 week following the event and remained important by 10 weeks.ConclusionExtra vigilance is needed following protests and riot-related conflict events in terms of Ebola virus transmission. These events are highly disruptive, in terms of access to transportation and healthcare and are often in urban areas with high population densities. Additional public health messaging around these types of conflict events, relating to the risks and clinical symptoms may be helpful in reducing transmission. Future work should aim to further understand and quantify conflict severity and intensity, to evaluate dose-response relationships in terms of disease risk.
Provider-led community Antiretroviral Therapy distribution in Malawi: Retrospective cohort study of retention, viral load suppression, and costs
Authors: Songo John , Whitehead Hannah , Nichols Brooke , Makwaya Amos , Njala Joseph , Phiri Sam , Hoffman Risa M. , Dovel Kathryn , Phiri Khumbo , van Oosterhout Joep J. 
Published: June 2023

AbstractBackgroundOutcomes of community antiretroviral therapy (ART) distribution (CAD), in which provider–led ART teams deliver integrated HIV services at health posts in communities, have been mixed in sub-Saharan African countries. CAD outcomes and costs relative to facility-based care have not been reported from Malawi.MethodsWe performed a retrospective cohort study in two Malawian districts (Lilongwe and Chikwawa districts), comparing CAD with facility-based ART care. We selected an equal number of clients in CAD and facility-based care who were aged >13 years, had an undetectable viral load (VL) result in the last year and were stable on first-line ART for ≥1 year. We compared retention in care (alive and no period of ≥60 days without ART) using Kaplan-Meier survival analysis and Cox regression and maintenance of VL suppression (<1,000 copies/mL) during follow-up using logistic regression. We also compared costs (in US$) from the health system and client perspectives for the two models of care. Data were collected in October and November 2020.Results700 ART clients (350 CAD, 350 facility-based) were included. The median age was 43 years (IQR 36-51), median duration on ART was 7 years (IQR 4-9), and 75% were female. Retention in care did not differ significantly between clients in CAD (89.4% retained) and facility-based care (89.3%), p=0.95. No significant difference in maintenance of VL suppression were observed between CAD and facility-based care (aOR: 1.24, 95% CI: 0.47-3.20, p=0.70). CAD resulted in slightly higher health system costs than facility-based care: $118/year vs. $108/year per person accessing care; and $133/year vs. $122/year per person retained in care. CAD decreased individual client costs compared to facility-based care: $3.20/year vs. $11.40/year per person accessing care; and $3.60/year vs. $12.90/year per person retained in care.ConclusionClients in provider-led CAD care in Malawi had very good retention in care and VL suppression outcomes, similar to clients receiving facility-based care. While health system costs were somewhat higher with CAD, costs for clients were reduced substantially. More research is needed to understand the impact of other differentiated service delivery models on costs for the health system and clients.
Intrinsic functional brain connectivity changes following aerobic exercise, computerized cognitive training and their combination in healthy late-middle-aged adults: the Projecte Moviment
Authors: Dimitriadis Stavros I. , Castells-Sánchez Alba , Roig-Coll Francesca , Dacosta-Aguayo Rosalía , Lamonja-Vicente Noemí , Torán-Monserrat Pere , García-Molina Alberto , Monte-Rubio Gemma , Stillman Chelsea , Perera - Lluna Alexandre , Mataró Maria 
Published: June 2023

AbstractLifestyle interventions have positive neuroprotective effects in aging. However, there are still open questions about how changes in resting-state functional connectivity (rsFC) contribute to cognitive improvements. The Projecte Moviment is a 12-weeks randomized controlled trial of a multimodal data acquisition protocol that investigated the effects of aerobic exercise (AE), computerized cognitive training (CCT), and their combination (COMB). An initial list of 109 participants was recruited from which a total of 82 participants (62% female; age = 58.38 ± 5.47) finished the intervention with a level of adherence > 80%. We report intervention-related changes in rsFC, and their potential role as mediators of cognitive benefits. For the AE group, we revealed a limited network of 11 connections showing an increased rsFC that involved mainly the anterior default mode network (aDMN), the posterior default mode network (pDMN : left middle temporal gyrus, and right precuneus), and a decreased rsFC that involved the pDMN (left fusiform gyrus (pDMN), right middle temporal gyrus (pDMN), left and right precentral gyrus), the hippocampus, bilateral supplementary motor areas, and the right thalamus. For the CCT group, we untangled a limited network of 6 connections as a combination of increased and decreased rsFC between brain areas located mainly in the aDMN and pDMN. In the COMB group, we revealed an extended network of 33 connections that involved an increased and decreased rsFC within and between the aDMN/pDMN and a reduced rsFC between the bilateral supplementary motor areas and the right thalamus. No global and especially local rsFC changes due to any intervention mediated the cognitive benefits detected in the AE and COMB groups. Projecte Moviment provides evidence of the clinical relevance of lifestyle interventions and the potential benefits when combining them.
LncRNA antigens- a novel resource to improve immunotherapy efficacy predictions in Melanoma
Authors: Malik Sumaira , Golden Aaron 
Published: June 2023

AbstractBackgroundICI (immune checkpoint inhibitor) therapy is one of the most promising treatments for melanoma. ICI response however varies among patients, emphasizing the importance of identifying genomic biomarkers to predict likely therapeutic efficacy in advance of treatment. We hypothesised that a lncRNA based immunogencity (lnc-IM) score could be used to predict individual response to ICI treatment, and that this could complement the existing criterion for ICI selection based on tumor mutation burden (TMB).MethodologyThe TCGA-SKCM (n=101) and the ICI treated UCLA (n=25), MSKCC (n=16) and DFCI (n=40) melanoma cohorts were used in this study, involving both clinical and transcriptomic data. Each patient was assigned an lnc-IM score based on the number of lncRNA sORF derived peptides predicted to be presented by their tumor’s MHC-I genotype. For the ICI treated cohorts, a combined antigen score was defined as a sum of neo-antigen load (derived from TMB) and lnc-IM score. A logistic regression-based classifier was used to predict ICI responses based on these combined antigen scores.ResultsSurvival analysis showed improved overall survival among patients with low lnc-IM scores (HR= 0.39, p=0.009) in the TCGA-SKCM cohort. We also observed a negative association between tumor immune cell concentration and lnc-IM scores, with low lnc-IM groups showing higher anti-tumor immune cell concentrations . Using the ICI treated cohorts, we demonstrated that a classifier based on combined antigen scoring improved the prediction of immunotherapy outcomes as compared to using TMB alone, yielding an area under the curve (AUC) of 0.71 with an accuracy of 0.54 and recall of 1. We also demonstrated a reduced rate of false negatives (14%) by using a combined antigen score as compared to the use of TMB alone (33%) in ICI treated cohorts.ConclusionOur findings suggest that the use of combined antigen scores (using lnc-IM scores along with TMB derived neoantigen load) have potential in improving immunotherapy efficacy predictions. Prospective validation in larger cohort sizes is warranted.KEY MESSAGES:What is already known on this topicPrevious studies have established actionable associations between TMB neoantigen load and immunotherapy responses.What this study addsThis study introduces lnc-IM scores as a novel metric that predicts patients antigen load based on translatable lncRNAs expression. These lnc-IM scores when combined with TMB associated neoantigen load indicate an improvement in immunotherapy efficacy predictions.How this study might affect research, practice or policyFuture research is needed to further validate lnc-IM scores as a predictive biomarker for immunotherapy response in various cancer types. The use of lnc-IM scores can empower clinicians to make more informed decisions about administering immunotherapy treatments, improvingpatient outcomes.
CURRENT TRENDS IN HOSPICE CARE USAGE FOR DIALYSIS PATIENTS IN THE USA
Authors: Soipe Ayorinde I , Leggat John E , Abioye Ajibola I , Devkota Kriti , Oke Fausat , Bhuta Kunal , Omotayo Moshood O 
Published: June 2023

ABSTRACTBackgroundThis study examined the predictors and latest trends in hospice utilization, adequate duration of hospice care, and dialysis discontinuation without hospice enrollment among patients with end stage renal disease (ESRD).MethodsData from the United States Renal Data System (USRDS) for ESRD patients who died between January 1, 2012, and December 31, 2019, were analyzed. Chi-square and logistic regression were used to evaluate associations between outcomes of interest and predictors while Joinpoint regression was used to examine trends.ResultsAmong 803,049 patients, the median (IQR) age was 71 (17) years, 57% were male, 27% enrolled in hospice, 8% discontinued dialysis before death without hospice enrollment, and 7% remained in hospice for ≥15 days. Patients older than 64 years (adjusted odds ratio [aOR]: 2.75, 95% CI: 2.71-2.79) and white race (aOR: 1.79, 95% CI: 1.77-1.81) were more likely to enroll in hospice. White patients (aOR: 0.75, 95% CI: 0.73-0.76) and those who never received a kidney transplant (aOR: 0.75, 95% CI: 0.73-0.78) were less likely to have adequate duration of hospice care. Hospice enrollment and standardized duration of hospice care increased over time, with an average annual percentage change (AAPC) of 1.1% (95% CI:0.6 – 1.6) and 5% (95% CI:2.6 – 7.4) respectively.ConclusionsApproximately one in every four ESRD patients who died between 2012 and 2019 had a history of hospice enrollment, while one in every 12 discontinued dialysis before death without hospice enrollment. There was an upward trend in the standardized duration of hospice care.
Evaluating ChatGPT-4 in Otolaryngology–Head and Neck Surgery Board Examination using the CVSA Model
Authors: Long Cai , Lowe Kayle , Santos André dos , Zhang Jessica , Alanazi Alaa , O’Brien Daniel , Wright Erin , Cote David 
Published: June 2023

AbstractBackgroundChatGPT is among the most popular Large Language Models (LLM), exhibiting proficiency in various standardized tests, including multiple-choice medical board examinations. However, its performance on Otolaryngology–Head and Neck Surgery (OHNS) board exams and open-ended medical board examinations has not been reported. We present the first evaluation of LLM (ChatGPT-4) on such examinations and propose a novel method to assess an artificial intelligence (AI) model’s performance on open-ended medical board examination questions.MethodsTwenty-one open end questions were adopted from the Royal College of Physicians and Surgeons of Canada’s sample exam to query ChatGPT-4 on April 11th, 2023, with and without prompts. A new CVSA (concordance, validity, safety, and accuracy) model was developed to evaluate its performance.ResultsIn an open-ended question assessment, ChatGPT-4 achieved a passing mark (an average of 75% across three trials) in the attempts. The model demonstrated high concordance (92.06%) and satisfactory validity. While demonstrating considerable consistency in regenerating answers, it often provided only partially correct responses. Notably, concerning features such as hallucinations and self-conflicting answers were observed.ConclusionChatGPT-4 achieved a passing score in the sample exam, and demonstrated the potential to pass the Canadian Otolaryngology–Head and Neck Surgery Royal College board examination. Some concerns remain due to its hallucinations that could pose risks to patient safety. Further adjustments are necessary to yield safer and more accurate answers for clinical implementation.