bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simulation-based validation of a method to detect changes in SARS-CoV-2 reinfection risk
Authors: Lombard Belinda , Moultrie Harry , Pulliam Juliet R.C. , van Schalkwyk Cari 
Published: September 2023

AbstractBackgroundGiven the high global seroprevalence of SARS-CoV-2, understanding the risk of reinfection becomes increasingly important. Models developed to track trends in reinfection risk should be robust against possible biases arising from imperfect data observation processes.ObjectivesWe performed simulation-based validation of an existing catalytic model designed to detect changes in the risk of reinfection by SARS-CoV-2.MethodsThe catalytic model assumes the risk of reinfection is proportional to observed infections. Validation involved using simulated primary infections, consistent with the number of observed infections in South Africa. We then simulated reinfection datasets that incorporated different processes that may bias inference, including imperfect observation and mortality, to assess the performance of the catalytic model. A Bayesian approach was used to fit the model to simulated data, assuming a negative binomial distribution around the expected number of reinfections, and model projections were compared to the simulated data generated using different magnitudes of change in reinfection risk. We assessed the approach’s ability to accurately detect changes in reinfection risk when included in the simulations, as well as the occurrence of false positives when reinfection risk remained constant.Key FindingsThe model parameters converged in most scenarios leading to model outputs aligning with anticipated outcomes. The model successfully detected changes in the risk of reinfection when such a change was introduced to the data. Low observation probabilities (10%) of both primary- and re-infections resulted in low numbers of observed cases from the simulated data and poor convergence.LimitationsThe model’s performance was assessed on simulated data representative of the South African SARS-CoV-2 epidemic, reflecting its timing of waves and outbreak magnitude. Model performance under similar scenarios may be different in settings with smaller epidemics (and therefore smaller numbers of reinfections).ConclusionsEnsuring model parameter convergence is essential to avoid false-positive detection of shifts in reinfection risk. While the model is robust in most scenarios of imperfect observation and mortality, further simulation-based validation for regions experiencing smaller outbreaks is recommended. Caution must be exercised in directly extrapolating results across different epidemiological contexts without additional validation efforts.
Impact of bivalent BA.4/5 BNT162b2 COVID-19 vaccine on acute symptoms, quality of life, work productivity and activity levels among symptomatic US adults testing positive for SARS-CoV-2 at a national retail pharmacy
Authors: Fusco Manuela Di , Sun Xiaowu , Anatale-Tardiff Laura , Yehoshua Alon , Coetzer Henriette , Alvarez Mary B. , Allen Kristen E. , Porter Thomas M. , Puzniak Laura , Lopez Santiago M.C , Cappelleri Joseph C. 
Published: September 2023

ABSTRACTBackgroundEvidence on the impact of COVID-19 vaccination on symptoms, Health-Related Quality of Life (HRQoL), Work Productivity and Activity Impairment (WPAI) is scarce. We analyzed associations between bivalent BA.4/5 BNT162b2 and these patient-reported outcomes (PROs).MethodsSymptomatic US adults who tested positive for SARS-CoV-2 were recruited between 03/02-05/18/2023. PROs were assessed using a CDC-based symptom questionnaire, EQ-5D-5L, WPAI-GH, and PROMIS Fatigue, from pre-COVID to Week 4 following infection. Multivariable analysis using mixed models for repeated measures was conducted, adjusting for several covariates.ResultsThe study included 641 participants: 314 vaccinated with bivalent BA.4/5 BNT162b2 and 327 unvaccinated/not up-to-date. Mean (SD) age was 46.5 years (15.9), 71.2% were female, 44.2% reported prior infection, 25.7% had ≥1 comorbidity. The BA.4/5 BNT162b2 cohort reported fewer acute symptoms through Week 4, especially systemic and respiratory symptoms. All PROs were adversely affected, especially at Week 1; however, at that time point, the bivalent BA.4/5 BNT162b2 cohort reported better work performance, driven by less absenteeism, and fewer work hours lost. No significant differences were observed for HRQoL.ConclusionsCOVID-19 negatively impacted patient outcomes. Compared with unvaccinated/not up-to-date participants, those vaccinated with bivalent BA.4/5 BNT162b2 reported fewer and less persistent symptoms and improved work performance.Clinicaltrials.govNCT05160636
Within-host models unravelling the dynamics of dengue reinfections
Authors: Anam Vizda , Guerrero Bruno V. , Srivastav Akhil Kumar , Stollenwerk Nico , Aguiar Maíra 
Published: September 2023

AbstractDengue fever is a major public health concern in tropical regions, caused by four distinct serotypes. Sequential infection with a different serotype increases the risks of severe disease through antibody-dependent enhancement (ADE). Huge modeling efforts have focused on primary and heterologous secondary infections, while the dynamics of homologous secondary infections were overlooked due to the assumption of lifelong immunity preventing reinfections by the same serotype.Recent findings challenge the current understanding of dengue immunity. To explore immunological responses in various dengue infection scenarios, we use a within-host modeling framework that considers individual immunological variations. These models are validated using empirical data. In addition to successfully capturing primary and heterologous secondary infection dynamics facilitated by ADE, this framework provides, for the first time, insights into homotypic reinfection dynamics and discusses its relevance in dengue transmission at the population level, with potential implications for disease prevention and control strategies.
Methylenetetrahydrofolate reductase polymorphic variants in rectal cancer: significance for cancer risk and response to chemoradiotherapy
Authors: Stanojevic Aleksandra , Spasic Jelena , Marinkovic Mladen , Stojanovic-Rundic Suzana , Jankovic Radmila , Djuric Ana , Zoidakis Jerome , Fijneman Remond J.A. , Castellvi-Bel Sergi , Cavic Milena 
Published: September 2023

AbstractBackgroundMethylenetetrahydrofolate reductase (MTHFR) small nucleotide polymorphisms (SNPs) have been suggested as risk, prognostic, and predictive factors for colorectal cancer in various populations, but have not been validated so far. The aim of this study was to analyze the association ofMTHFRC677T (rs1801133) and A1298C (rs1801131) small nucleotide polymorphisms with the risk of rectal cancer as well as the response to neoadjuvant chemoradiotherapy (nCRT) based on 5-Fluorouracil (5- FU)/leucovorin (LV) in the locally advanced setting.Patients and methodsA total of 102 patients with locally advanced rectal cancer (LARC) and 119 healthy controls were included in this case-control study. Restriction fragment length polymorphism analysis (PCR-RFLP) was used forMTHFRgenotypingResultsUsing dominant and recessive models, it was found that theMTHFR667C allele and the 1298A allele were significantly associated with rectal cancer as low-penetrant factors. Combined genotype analysis highlighted the protective role of the 677CT/1298AC genotype and increased risk for rectal cancer development for carriers of 677CC/1298AA. Haplotype analysis indicated that carriers of haplotype 677C/1298A have an increased risk for rectal cancer development while the haplotype 677T/1298A has a protective role. No significant association with response to chemoradiotherapy was foundConclusionOur data point toMTHFR667C allele and 1298A alleles as low-penetrant risk factors for rectal cancer in our population. To the best of our knowledge, this is the first study of this type performed on the Slavic population in the Western Balkan area which might be useful for future meta-analyses and the construction of genetic cancer risk prediction panels, as various population-based factors might also be significant in this setting.
Sleep and circadian biomarkers of postoperative delirium: protocol for a prospective, observational cohort study
Authors: Sugg Elizabeth , Gleeson Elizabeth , Baker Sarah N. , Li Peng , Gao Chenlu , Mueller Ariel , Deng Hao , Shen Shiqian , Franco Garcia Esteban , Saxena Richa , Musiek Erik , Akeju Oluwaseun , Xie Zhongcong , Hu Kun , Gao Lei 
Published: September 2023

ABSTRACTSurgical patients over 70 experience postoperative delirium (POD) complications in up to 50% of procedures. Sleep/circadian disruption has emerged as a potential risk factor for POD in epidemiological studies. However, the relationship remains unclear in a clinical setting. This protocol presents a single-site, prospective, noninvasive observational study designed to examine the relationship between sleep/circadian regulation and POD and how this association is influenced by AD pathology and genetic risk for AD. This novel approach for understanding modifiable risk factors of POD and cognitive decline after surgery could assist with establishing treatments and preventative measures for POD in the future.
Remnant cholesterol associated with all-cause mortality in oldest-old acute coronary syndrome patients: a cohort study
Authors: Zhou Boning , Gao Ling , Zhang Xin , Shen Jian , Li Ying , Jiao Yang , Wang Jian , Hou Xiaoling , Su Yongkang , Fu Zhenhong 
Published: September 2023

AbstractBackgroundPrevious studies showed that remnant cholesterol(RC) partially explained the residual risk of cardiovascular disease. We tried to test the hypothesis that remnant cholesterol is a risk factor for all-cause mortality in oldest-old(>80 years old) patients with acute coronary syndrome(ACS).Methods662 oldest-old patients with acute coronary syndrome and undergoing coronary angiography were finally included in our study. Remnant cholesterol(RC) was calculated by fasting total cholesterol(TC) minus low-density lipoprotein cholesterol(LDL-C) and high-density lipoprotein cholesterol(HDL-C). Multivariable Cox regression analysis was used to identify the association between RC and all-cause mortality. Receiver operating characteristic(ROC) curve was used to compare the discrimination capacity of RC, TC, HDL-C and LDL-C to predict all-cause mortality.ResultsAmong the 662 oldest-old patients enrolled, 92.90% accepted statin therapy. The average age was 81.87 ± 2.14 years old. In the fully-adjusted Cox regression model, the Hazard ratio(HR) [95% confidence interval (CI)] of all-cause mortality was 1.17 (1.01, 1.36) for each standard deviation(SD) increase in RC. Compared to tertile 1, tertile 3 was associated with a 130% increased risk of all-cause mortality (HR:2.30;95%CI:1.45, 3.63). The increased risk of death from tertile 1 to tertile 3 was statistically significant (P for trend<0.001). The subgroup analysis confirmed the significant association between RC and all-cause mortality. ROC curve showed that RC had a better discrimination capacity at predicting all-cause mortality and improved the prognostic value of the Gensini score combined with left ventricular ejection fraction(LVEF).ConclusionRemnant cholesterol was associated with all-cause mortality in oldest-old patients with ACS in a long-term follow-up.Key learning pointsWhat is already known(1) Remnant cholesterol was a risk factor for atherosclerotic cardiovascular disease(ASCVD);(2) Emerging studies reported that RC was associated with all-cause mortality in general population, patients with disease status including ischemic heart disease(IHD), heart failure(HF) and metabolic dysfunction-associated fatty liver disease(MAFLD) or patients receiving special treatment such as peritoneal dialysis(PD) and kidney transplantation;(3) However, some studies found that there was no correlation between RC and all-cause mortality.What this study adds(1) We focused on oldest-old ACS patients who underwent angiography and found that RC was associated with all-cause mortality in this special population;(2) The correlation between RC and all-cause mortality was dose–response;(3) RC had a better discrimination capacity at predicting all-cause mortality and improved the prognostic value of the Gensini score combined with LVEF.
Pulse pressure modifies the association between diastolic blood pressure and decrease in kidney function: The Japan Specific Health Checkups (J-SHC) Study
Authors: Tamaki Hiroyuki , Eriguchi Masahiro , Yoshida Hisako , Uemura Takayuki , Tasaki Hikari , Furuyama Riri , Fukata Fumihiro , Nishimoto Masatoshi , Kosugi Takaaki , Matsui Masaru , Samejima Ken-ichi , Iseki Kunitoshi , Fujimoto Shouichi , Konta Tsuneo , Moriyama Toshiki , Yamagata Kunihiro , Narita Ichiei , Kasahara Masato , Shibagaki Yugo , Kondo Masahide , Asahi Koichi , Watanabe Tsuyoshi , Tsuruya Kazuhiko 
Published: September 2023

AbstractBackgroundUnlike systolic blood pressure (SBP), the prognostic value of diastolic blood pressure (DBP) in kidney function has not been established. We hypothesized that pulse pressure (PP), which is associated with arteriosclerosis, would affect the prognostic value of DBP.MethodsThis longitudinal study used data from the Japan Specific Health Checkups Study conducted between 2008 and 2014. The participants were stratified into 3 PP subgroups (low-PP ≤39, normal-PP 40–59, and high-PP ≥60 mmHg). The exposures of interest were SBP and DBP, and the association between SBP/DBP and kidney outcomes (30% decline in the estimated glomerular filtration rate from baseline) was examined in each PP subgroup using a Cox proportional hazards model.ResultsAmong 725,022 participants, 20,414 (2.8%) developed kidney outcomes during a median follow-up period of 34.6 months. Higher SBP was consistently associated with a higher incidence of kidney outcome in all PP subgroups. Although DBP had a positive linear association with the incidence of kidney outcome in low-and normal-PP subgroups, both lower (≤60 mmHg) and higher (≥101 mmHg) DBP were associated with a higher incidence of kidney outcome in high-PP subgroup with U-shaped curve. Hazard ratios (95% confidence intervals) of ≤60 mmHg (reference: 61-80 mmHg in normal-PP subgroup) and ≥101 mmHg were 1.26 (1.15–1.38) and 1.86 (1.62–2.14), respectively.ConclusionIn this large population-based cohort, DBP was differently associated with kidney outcome by PP levels; lower DBP was significantly associated with a higher incidence of kidney outcome in high-PP subgroup but not in low-and normal-PP subgroups.
Cardiac complications following cerebrovascular disease
Authors: Rohner Marco Heinrich , Gebhard Catherine , Luft Andreas , Hänsel Martin , Wegener Susanne 
Published: September 2023

AbstractBackgroundAccumulating evidence suggest that cardiac complications after stroke are an important yet understudied manifestation of brain-heart interactions. Our aim was to investigate and compare cardiac findings after different cerebrovascular events (acute ischemic stroke, transient ischemic attack, and hemorrhagic stroke).Methods7113 patients treated between December 2013 and December 2020 at the University Hospital Zurich for ischemic stroke, transient ischemic attack, and hemorrhagic stroke were screened. 721 patients without evidence of previous cardiac disease or presumed cardioembolic origin of their cerebrovascular disease and with at least one cardiac check-up were included. Clinical reports from the year following disease onset were screened for new cardiac findings, which were categorized as arrhythmia/electrocardiographic (ECG) changes, myocardial alterations, valvular abnormalities, coronary perfusion insufficiency, and hypotensive/hypertensive blood pressure abnormalities. Differences in proportions of findings between groups were analyzed using Pearson’s Chi-Square Test or Fisher’s exact Test.ResultsECG changes were observed in 81.7% of patients with ischemic stroke, 71.4% with transient ischemic attack, and 55.8% with hemorrhagic stroke (p<0.001). Myocardial alterations occurred often in all three groups (60.9% ischemic stroke, 59.2% transient ischemic attack, 44.2% hemorrhage, p=0.1). Hypotensive/hypertensive blood pressure abnormalities were most frequent (48.8%) in hemorrhagic stroke patients (p<0.001).ConclusionsCardiac complications are frequent in patients with cerebrovascular disease, even without prior cardiac problems or suspected cardiac etiology. While findings were different in the three event types, our data suggest that all patients with acute cerebrovascular events should receive thorough workup searching for cardiac complications.
Both brain network topology and striatal dopamine depletion mediate the effects of autonomic dysfunction on disease burden of Parkinson’s disease
Authors: Chen Zhichun , Li Guanglu , Zhou Liche , Zhang Lina , Liu Jun 
Published: September 2023

AbstractBackgroundAutonomic dysfunction is one of the most common non-motor symptoms in Parkinson’s disease (PD). Whether autonomic dysfunction contributes to disease progression and brain network abnormalities in PD remain largely unknown. The objective of this study is to evaluate how autonomic dysfunction affects clinical features and brain networks of PD patients.MethodsPD patients from Parkinson’s Progression Markers Initiative (PPMI) database were included if they received magnetic resonance imaging. According to the scores of Scale for Outcomes in Parkinson’s Disease-Autonomic (SCOPA-AUT), PD patients were classified into lower quartile group (SCOPA-AUT score rank: 0%~25%), interquartile group (SCOPA-AUT score rank: 26%~75%), and upper quartile group (SCOPA-AUT score rank: 76%~100%) based on their SCOPA-AUT score quartiles to examine how autonomic dysfunction shapes clinical manifestations and brain networks.ResultsPD patients in the upper quartile group showed more severe motor and non-motor symptoms, as well as more deficits in dopamine transporter binding compared to lower quartile group. Additionally, they also showed statistically different topological properties in structural and functional network compared to lower quartile group. Both structural and functional network metrics mediated the effects of autonomic dysfunction on clinical symptoms of PD patients. Reduced dopamine transporter binding also contributed to the effects of autonomic dysfunction on disease burden of PD patients.ConclusionsPD patients with more severe autonomic dysfunction exhibit worse disease and impairment of brain network topology. Both network topology and striatal dopamine depletion mediate the effects of autonomic dysfunction on clinical symptoms of PD patients.
Incorporating prior knowledge to seeds of adaptive sampling molecular dynamics simulations of ligand transport in enzymes with buried active sites
Authors: Sarkar Dheeraj Kumar , Surpeta Bartlomiej , Brezovsky Jan 
Published: September 2023

AbstractGiven that most proteins have buried active sites, protein tunnels or channels play a crucial role in mitigating the transport of small molecules to the buried cavity for enzymatic catalysis. Tunnels can critically modulate the biological process of protein-ligand recognition. Various molecular dynamics methods have been developed for exploring and exploiting the protein-ligand conformational space to extract high-resolution details of the binding processes, one of the most recent represented by energetically unbiased high-throughput adaptive sampling simulations. The current study systematically contrasts the role of integrating prior knowledge while generating useful initial protein-ligand configurations, called seeds, for these simulations. Using a non-trivial system of haloalkane dehalogenase mutant with multiple transport tunnels leading to a deeply buried active site, these simulations were employed to derive kinetic models describing the process of association and dissociation of the substrate molecule. The more knowledge-based seed generation enabled high-throughput simulations that could more consistently capture the entire transport process, effectively explore the complex network of transport tunnels, and predict equilibrium dissociation constants,koff/kon, on the same order of magnitude as experimental measurements. Overall, the infusion of more knowledge into the initial seeds of adaptive sampling simulations could render analyses of transport mechanisms in enzymes more consistent even for very complex biomolecular systems, thereby promoting the rational design of enzymes with buried active sites and drug development efforts.
Quantitative monitoring of neuronal regeneration by functional assay and wireless neural recording
Authors: Liang Min-Zong , Yang Jenq-Wei , Chen Hsin , Cheng Mei-Yuan , Chen Linyi 
Published: September 2023

AbstractBrain injury is heterozygous in nature and no single scheme is ideal for diagnosis and prognosis. Assessing proteins in cerebrospinal fluid is limited or not applicable after surgery whereas plasma biomarkers can only report occurrence of injury. The lack of regeneration markers renders the difficulty during drug discovery. This study aims to establish a potential reporter that correlates the regeneration progress of injured brain neurons. According to our recent publication, treatment of mitochondrial uncoupler carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) could rescue motor function deficit of mice after traumatic brain injury. We thus measured the local field potential (LFP) at sites proximal to the injury region. The recorded neuronal activity reported stimulation of right forelimb of mice. Our experimental results indicate that the recovery of evoked LFP correlates with FCCP treatment and could potentially be used as a regeneration biomarker. These promising findings suggest future application of a wireless, non-invasive recording system as a potential companion diagnosis device during drug development.
A model for collagen secretion by intercompartmental continuities
Authors: Bunel Louis , Pincet Lancelot , Malhotra Vivek , Raote Ishier , Pincet Frédéric 
Published: September 2023

ABSTRACTNewly synthesized secretory proteins are exported from endoplasmic reticulum (ER) at specialized subcompartments called exit sites (ERES). Cargoes like procollagen are too large for export by the standard COPII-coated vesicle of 60 nm average diameter. We have previously suggested that procollagen is transported from the ER to the next secretory organelle, the ERGIC, in TANGO1-dependent inter-organelle tunnels. Here, we show that intrinsically disordered domains of TANGO1 in the ER lumen generate an entropic contraction that pulls procollagen towards the ERES. Molecular gradients of pH and HSP47 between the ER and ERGIC generate a force in the range of tens of femtoNewtons (fN), which is sufficient to propel procollagen from the ER at a speed of ∼1 nm.s-1. This calculated speed and the quantities of collagen secreted are similar to its observed physiological secretion rate in fibroblasts, consistent with the proposal that ER export is the rate limiting step for procollagen secretion. Our theoretical model explains how cells can utilize molecular gradients to export procollagens at a rate commensurate with physiological needs.Significance StatementProcollagen cannot be exported from the endoplasmic reticulum (ER) by standard COPII-coated vesicle of 60 nm average diameter. We have previously suggested that collagen is transported from the ER to the next secretory organelle, the ERGIC, in TANGO1-dependent inter-organelle tunnels. ER and ERGIC differ in molecular composition including their pH and protein composition. We propose a mechanical/entropic ratchet model whereby molecular gradients of pH and the collagen chaperone HSP47, provide the energy to propel procollagen from the ER at a speed that matches the physiological rate of collagen secretion.