bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multianalyte blood-based risk stratification of incidental pancreas lesions
Authors: Marcinak Clayton T. , Stephens Michelle D. , McDonald Bradon R. , Merali Nabeel , Dietmann Elise C. , McGregor Stephanie M. , Ronnekleiv-Kelly Sean M. , Weber Sharon M. , Nkadori Everlyne N. , Stadmeyer Peter G. , Benson Mark E. , Gopal Deepak V. , Zafar Syed Nabeel , Kelly Kaitlyn J. , Pirasteh Ali , Frampton Adam E. , Pfau Patrick R. , Sivakumar Shivan , Minter Rebecca M. , Murtaza Muhammed 
Published: December 2024

AbstractPurposeIncidental detection of pancreas lesions (IPLs) is common and creates an opportunity to intercept pancreatic ductal adenocarcinoma (PDAC). However, identifying patients at risk for progression who can benefit from surgical resection remains challenging. The current role of blood tests for risk stratification in patients with IPLs is limited.MethodsWe evaluated the performance of circulating glycoproteins (CA19-9, CEA and CA125), plasma DNA fragmentation analysis, and their combination, in 99 asymptomatic patients with IPLs, for detection of advanced pathology (high-grade dysplasia or invasive carcinoma). Plasma DNA fragmentation was analyzed using a machine learning model, adapted to detect PDAC in 242 patients with cancer and 300 healthy individuals.ResultsDuring 18.8 months of median follow-up by a multidisciplinary clinical team, 11 of 99 patients with IPLs were diagnosed with advanced pathology. We observed area under the receiver operating characteristic curves (AUROCs) of 0.78, 0.63, 0.54 and 0.74 using CA19-9, CEA, CA125 and plasma DNA fragmentation, respectively. Combined analysis of CA19-9, CA125 and plasma DNA fragmentation showed an AUROC of 0.93, with 91% sensitivity and 53% positive predictive value (PPV) at 90% specificity. In a subset of 25 patients with histologically confirmed diagnoses, AUROC improved to 0.96 and PPV improved to 91%. In one patient with an equivocal initial endoscopy, multi-analyte blood analysis predicted cancer 3 months before diagnosis of stage IA cancer.ConclusionOur results demonstrate a multianalyte blood test combining glycoprotein biomarkers with plasma DNA fragmentation could complement current clinical workflows for cancer detection in patients with IPLs.
Maternal influenza-like illness and neonatal health during the 1918 influenza pandemic in a Swiss city
Authors: Le Vu Mathilde , Matthes Katarina L , Schneider Eric , Moerlen Aline , Hösli Irene , Baud David , Staub Kaspar 
Published: December 2024

AbstractBackgroundExposure to the 1918 influenza pandemic may have been associated with preterm birth (<37 weeks). Other outcomes, such as infant size or weight, have rarely been explored.ObjectiveTo estimate whetherin uteroexposure to maternal influenza-like illness (ILI) during the 1918 pandemic was associated with pregnancy outcomes, and whether associations varied depending on ILI timing or on fetal sex.DesignCross-sectional study using historical birth records.SettingLausanne maternity hospital.Participants2,177 singletons born during the pandemic.MeasurementsThe impact of ILI on gestational age, stillbirth, and anthropometric measurements, adjusted on covariates in generalized linear models. Analyses were stratified by fetal sex.Results282 women developed ILI during pregnancy. ILI exposure was associated with lower anthropometric measurements: the odds ratio (OR) of low birth weight (<2,500g) was 2.06 [95%CI 1.33; 3.20]. In multivariable models, there was strong evidence that third trimester exposure was associated with adverse pregnancy outcomes, including with a higher preterm birth rate (OR 2.87 [95%CI 1.53; 5.39]). There was moderate evidence that first-trimester ILI exposure was associated with lower anthropometric measurements, in univariable models only. The magnitude of the declines in anthropometric parameters was higher among male fetuses, and they had a higher stillbirth risk. Only 41% of infants exposed to first-trimester ILI were males.Limitationour findings may not generalize to the entire population of Lausanne, as 34% of births were homebirths at the time.Conclusionmaternal ILI may have triggered premature birth. The low sex ratio at birth for first-trimester exposure may indicate selection against males through miscarriage, but males were still more vulnerable than females to third trimester exposure.Primary funding sourceSwiss National Science Foundation.
Safety, tolerability and clinical effects of BC007 (Rovunaptabin) on fatigue and quality of life in patients with post-COVID syndrome (reCOVer): a prospective, exploratory, randomised, placebo-controlled, double-blind, crossover phase IIa clinical trial
Authors: Hohberger Bettina , Ganslmayer Marion , Harrer Thomas , Kruse Friedrich , Maas Stefanie , Borst Tobias , Heimke-Brinck Ralph , Stog Andreas , Knauer Thomas , Rühl Eva , Zeisberg Victoria , Skornia Adam , Bartsch Alexander , Ströbel Armin , Wytopil Monika , Merkel Carolin , Hofmann Sophia , Schmidt Katja G. , Lakatos Petra , Schottenhamml Julia , Herrmann Martin , Mardin Christian , Rech Jürgen 
Published: December 2024

AbstractBackgroundAs recent data suggest an involvement of GPCR-fAAb in PCS pathogenesis, neutralisation of such GPCR-fAAbs by BC007 could improve PCS symptoms. The aim of the reCOVer trial was to investigate safety, tolerability and clinical effects of BC007 on fatigue, its severity and quality of life in PCS patients.MethodsreCOVer is a prospective, exploratory, randomised, placebo-controlled, double-blind, crossover phase IIa clinical trial with 1350 mg BC007 at the University of Erlangen-Nürnberg, Germany. Eligible participants were 18-80 years with GPCR-fAAb, whose PCS symptoms persisted ≥3 months after PCR-confirmed COVID-19, with fatigue as the major symptom (Bell score ≤60) and at least three of eight defined PCS symptoms. Participants were randomly assigned (1:1) according to a crossover design to either receive BC007 (sequence A) or placebo (sequence B) at day 0 and day 48 with a follow-up of 28 days, respectively. A crossover design was chosen to increase patient adherence. Occurrence of treatment-emergent adverse events (TEAEs) in comparison between sequence A and B from d0 to d28 and d0 to d70 were the primary and co-primary endpoint, respectively.FindingsBetween 31.10.2023 and 12.06.2024, 30 PCS patients were randomised and analysed. The trial has been concluded. Summarising all AE rates, no statistically significant differences between sequence A und sequence B were observed within day 28 and day 70. One report of a serious adverse event, not related to treatment, was recorded. As a secondary endpoint, BC007 showed a significant improvement on self-reported fatigue and its severity, as well as quality of life.InterpretationAs BC007 was well tolerated and showed a significant improvement of fatigue and quality of life, it might offer a therapeutic option for an autoimmune subgroup of PCS patients.Trial registrationEudraCT, number 2022-001781-35.FundingGerman Federal Ministry of Education and Research, German Research Foundation.
Pragmatic modeling supports current dosing guidelines for carbamazepine and valproic acid for the treatment of epilepsy in children
Authors: van der Heijden Joyce E.M. , Gijsen Violette , van Uden Anne M. , de Hoop-Sommen Marika , Freriksen Jolien J.M. , Jacobs Elke , Greupink Rick , de Wildt Saskia N. 
Published: December 2024

AbstractBackgroundCarbamazepine (CBZ) and valproic acid (VPA) are long-standing treatments for epilepsy in children. Interestingly, they display unique drug disposition characteristics and maturation of drug metabolizing enzymes further complicates personalized dosing. Physiologically-based pharmacokinetic (PBPK) modeling includes these mechanisms and is hence a promising tool to optimize dosing. Our aim is to better support pediatric drug dosing of CBZ and VPA.MethodsAll CBZ and VPA dosing simulations were conducted with Simcyp, using available CBZ and VPA compound models linked with adult and pediatric population models. Current Dutch national dosing strategies were simulated to evaluate their appropriateness to achieve therapeutic levels. Where doses could be optimized, alternative dosing strategies were proposed based on simulations.ResultsTherapeutic levels of CBZ and VPA will be reached after 1 or 2 weeks of treatment with the current dosing strategies. Simulations suggest a CBZ starting dose of 7 mg/kg/day for neonates rather than 10 mg/kg/day. In contrast, children aged 12 to 18 years may receive a higher starting dose (e.g., 400 mg/day instead of 200 mg/day), to reach therapeutic levels more quickly. For VPA, when higher doses are needed (i.e., ≥30 mg/kg/day), measuring unbound VPA concentrations are advised to guide dosing.ConclusionWe demonstrate that PBPK modeling is a valuable tool to confirm and further optimize dosing recommendations in children. The use of PBPK modeling offers a practical, cost-effective, and swift method to provide valuable comprehensive evidence for guiding clinical practice and potentially informing pediatric drug labeling, thus eliminating the necessity for clinical studies.
Genetic predisposition to raised circulating levels of dietary antioxidants and the association with respiratory health in high-risk populations
Authors: Saied A , Horsfall L. J. 
Published: December 2024

AbstractBackgroundObservational studies of raised dietary antioxidants suggest a beneficial effect on health, but the results from interventional studies generally show no effect. There are no robust studies targeting people exposed to high levels of environmental oxidants where any effects of raised antioxidants are plausibly stronger.ObjectivesTo examine whether people genetically predisposed to raised dietary serum antioxidants have improved respiratory health.MethodsWe identified single-nucleotide polymorphisms (SNPs) associated with serum ascorbate (vitamin C), retinol (vitamin A), and β-carotene from external data sources. Outcome data on forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), were derived from individual-level data from over 285,000 UK Biobank participants. We used linear regression to explore relationships between the SNPs and lung function. To quantify any relationships, we instrumented the association using exposure beta coefficient from published literature and genome wide association studies (Mendelian randomization).ResultsWe found no consistent relationship between genetically raised serum antioxidant levels and respiratory health measures. There was no evidence of effect modification by exposures linked to oxidative stress including cigarette smoke, air pollution and poor diet.ConclusionsOur findings support interventional studies showing no causal relationship between dietary antioxidants and respiratory disease outcomes. Further, our results do not support interventions to increase serum levels of ascorbate, retinol, or β-carotene in people exposed to high levels of environmental oxidants (Wellcome Grant ID: 209207/Z/17/Z and 225195/Z/22/Z).
Cost-utility analysis of current COVID-19 vaccination program recommendations in Canada
Authors: Simmons Alison E. , Miranda Rafael N. , Li Michael W.Z. , Gebretekle Gebremedhin B. , Xi Min , Salvadori Marina I. , Warshawsky Bryna , Wong Eva , Ximenes Raphael , Andrew Melissa K. , Wilson Sarah , Tunis Matthew , Tuite Ashleigh R. 
Published: December 2024

ABSTRACTBackgroundAs COVID-19 becomes established as an endemic disease with widespread population immunity, there is uncertainty about the economic benefit of ongoing COVID-19 vaccination programs. We assessed the cost-effectiveness of a COVID-19 vaccination program similar to current Canadian recommendations, modelled as annual vaccination for people aged less than 65 years with chronic medical conditions and biannual vaccination for adults aged 65 years and older.MethodsUsing a static individual-based model of medically attended COVID-19 in a population of 1 million people, we estimated costs (in 2023 Canadian dollars), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). We used health system and societal perspectives and a 1.5% discount rate. Parameters were based on recent COVID-19 epidemiology, vaccine characteristics, and costs.ResultsBetween July 2024 and September 2025, a program similar to current Canadian recommendations was estimated to avert 3.1% (95% credible interval (CrI): 3.0 to 3.2%) of outpatient cases, 8.8% (95% CrI: 7.3 to 10.4%) of inpatient cases, 3.6% (95% CrI: 2.8 to 4.3%) of PCC cases, and 9.4% (95% CrI: 5.6 to 13.8%) of deaths compared to no vaccination. The number needed to vaccinate to prevent one hospitalization and one death was 1,121 (95% CrI: 941 to 1,357) and 8,656 (95% CrI: 5,848 to 14,915), respectively. For the health system perspective, the program would cost an additional $4.695 million but result in 221.17 QALYs gained, leading to an ICER of $21,227 per QALY compared to no vaccination. Vaccine price influenced cost-effectiveness, with higher prices reducing the likelihood the program met common cost-effectiveness thresholds.ConclusionsA program similar to current COVID-19 recommendations in Canada is likely effective and cost-effective compared to no vaccination. However, unlike some other research studies, alternate vaccination strategies that may offer better value for money were not evaluated.
Going Digital or Stayin’ Clinical?: Modelling Primary Health Care Consultation Types Using Register Data from Sweden
Authors: Ekman Björn 
Published: December 2024

AbstractBackgroundPrimary health care clinics use several different types of consultations, including on-site visits and remote contacts to see patients. However, it is not clear what factors determine the choice of consultation type taking into consideration the full spectrum of options.ObjectivesThis study uses national register data from Sweden on all primary care consultations in the years 2019 to 2022 (N = 15,3 – 19,5 million) to model four types of consultations: office visits, digital contacts (text messages or video), home visits, and telephone/letter contacts.MethodsThe modelling of consultation type takes the cross-sectional, panel, and multilevel structure of the data into consideration fitting multinomial logistic models while controlling for patient, clinic, and context factors.ResultsIn the current context, the choice of consultation type is determined by both patient (age, socioeconomic status, diagnosis) and clinic (public or private) factors, as well as context factors (reimbursement mechanism). From a policy perspective, only weak evidence is found to suggest that paying clinics for digital contacts increases those types of consultations.ConclusionsThe findings may inform the development and implementation of policies and regulations to improve the delivery of primary health care in similar contexts.
Genetic downregulation of interleukin-6 signaling and arteriolosclerotic cerebral small vessel disease: a drug target Mendelian randomization analysis
Authors: Tchuisseu-Kwangoua Larissa Ange , Omarov Murad , Shatunov Alexey , Markus Hugh S. , Kamtchum-Tatuene Joseph , Georgakis Marios K. 
Published: December 2024

ABSTRACTBackgroundArteriolosclerotic cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia, yet no disease-modifying therapies exist. Anti-inflammatory strategies targeting IL- 6 signaling have shown efficacy in preventing atherosclerotic cardiovascular disease, but their potential in arteriolosclerotic cSVD remains unexplored. We investigated whether genetically downregulated IL-6 signaling is associated with clinical, imaging, and pathological manifestations of arteriolosclerotic cSVD.MethodsWe applied two-sample Mendelian randomization (MR) using (i) 26 genetic variants nearIL6Rassociated with circulating C-reactive protein (CRP) levels and (ii) rs2228145, a well- characterizedIL6Rmissense variant, as proxies of IL-6 signaling downregulation. Outcomes included clinical (small-vessel stroke, MRI-defined lacunar stroke, non-lobar intracerebral hemorrhage [ICH], vascular dementia), imaging (white matter hyperintensity volume, extensive basal ganglia perivascular space, non-lobar/mixed cerebral microbleeds), and pathological (arteriolosclerosis burden in autopsy) traits of cSVD, as well as atherosclerosis traits (ultrasound- defined carotid plaque, large artery stroke) as positive controls. We used inverse-variance weighting and the Wald ratio estimator for primary analyses. MR-Egger regression, weighted median, and weighted mode estimators were used as sensitivity analyses.ResultsGenetically downregulated IL-6 signaling (30%-decrement in CRP via 26IL6Rvariants) was not associated with small-vessel stroke (OR: 1.02, 95%CI: 0.95–1.10), MRI-confirmed lacunar stroke (OR: 0.95, [0.81–1.11]), non-lobar ICH (OR: 1.04, [0.72–1.50]), or vascular dementia (OR: 1.09, [0.95–1.25]). Similarly, we found no significant association with cSVD imaging biomarkers or pathology-defined arteriolosclerosis. As expected, genetically downregulated IL-6 signaling was associated with lower odds of large artery stroke (OR: 0.79, [0.74-0.84]) and carotid plaque (OR: 0.88, [0.83–0.94]). Results were consistent across sensitivity analyses and when using the rs2228145 missense variant to proxy IL-6 signaling downregulation.ConclusionGenetically proxied IL-6 signaling downregulation is not associated with clinical, imaging or pathological manifestations of arteriolosclerotic cSVD. Therefore, genetic data suggest that targeting IL-6 signaling is unlikely to prevent cSVD manifestations.
EpiInvert, an R application to restore, analyze, compare and forecast epidemiological time series
Authors: Morel Jean-David , Morel Jean-Michel , Alvarez Luis 
Published: December 2024

AbstractThe Covid-19 pandemic produced regional time series of incidence, hospital, ICU admission and death. TheEpiInvertpackage estimates the incidence trend and the daily reproduction numberRtof any infectious disease, compares related time series such as incidence and death, and provides incidence forecasts.EpiInvertis an R package with the following features: (1)EpiInvertinputs raw daily incidence time series and the pandemic time serial interval. It outputs a weekly seasonality, an incidence trend and its reproduction number. (2)EpiIndicatorsinputs two related epidemiological time series such as daily incidence and death count. It outputs a daily ratio and delay between both time series. (3)EpiInvertForecastinputs an incidence trend obtained byEpiInvertand a database of past observed time series. Using the most similar past series, it forecasts the incidence in the next four weeks.EpiInvertis in the CRAN repositoryhttps://cran.r-project.org/web/packages/EpiInvert/index.html.
Probing nanomechanics by direct indentation using Nanoendoscopy-AFM reveals the nuclear elasticity transition in cancer cells
Authors: Ichikawa Takehiko , Kono Yohei , Kudo Makiko , Shimi Takeshi , Miyashita Naoyuki , Maesaka Tomohiro , Ishibashi Kojiro , Yoshida Takeshi , Sivashanmugan Kundan , Hanayama Rikinari , Hirata Eishu , Miyata Kazuki , Kimura Hiroshi , Fukuma Takeshi 
Published: December 2024

AbstractDuring cancer invasion and metastasis, the mechanical properties of the nucleus change significantly, with reduced elasticity enhancing nuclear deformability to aid cell migration through tight spaces. Traditional methods of measuring nuclear elasticity, such as using bead-attached cantilevers on cells or isolated nuclei, are limited because they also measure the elasticity of surrounding structures, including cell membranes and cytoskeletons. In this study, we used a Nanoendoscopy-atomic force microscope (AFM) with a nanoneedle probe to directly measure nuclear elasticity in living cells. Our findings show that nuclear elasticity increases with serum depletion but decreases when serum-starved cells are treated with TGF-β, which induces epithelial-mesenchymal transition (EMT). In addition, trimethylation levels of histone H4 at lysine 20 but not the expression levels of nuclear lamins positively correlate with these nuclear elasticities. We propose that changes in nuclear elasticity during cancer progression are associated with alterations in chromatin structure.
Characterization of DNA methylation in PBMCs and donor-matched iPSCs shows methylation is reset during stem cell reprogramming
Authors: Reed Xylena , Weller Cory A. , Saez-Atienzar Sara , Beilina Alexandra , Solaiman Sultana , Portley Makayla , Kaileh Mary , Roy Roshni , Ding Jinhui , Moore A. Zenobia , Whitaker D. Thad , Traynor Bryan J. , Gibbs J. Raphael , Scholz Sonja W. , Cookson Mark R. 
Published: December 2024

SummaryDNA methylation is an important epigenetic mechanism that helps define and maintain cellular functions. It is influenced by many factors, including environmental exposures, genotype, cell type, sex, and aging. Since age is the primary risk factor for developing neurodegenerative diseases, it is important to determine if aging-related DNA methylation is retained when cells are reprogrammed to an induced Pluripotent Stem Cell (iPSC) state. Here, we selected peripheral blood mononuclear cells (PBMCs; n = 99) from a cohort of diverse and healthy individuals enrolled in the Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing (GESTALT) study to convert to iPSCs. After reprogramming we evaluated the resulting iPSCs for DNA methylation signatures to determine if they reflect the confounding factors of age and environmental factors. We used genome-wide DNA methylation arrays in both cell types to show that the epigenetic clock is largely reset to an early methylation age after conversion of PBMCs to iPSCs. We further examined the epigenetic age of each cell type using an Epigenome-wide Association Study (EWAS). Finally, we identified a set of methylation Quantitative Trait Loci (methQTL) in each cell type. Our results show that age-related DNA methylation is largely reset in iPSCs, and each cell type has a unique set of methylation sites that are genetically influenced.Graphical AbstractHighlightsGeneration of a population-level set of iPSC lines from healthy individuals across the lifespanAging-related features were reset based on epigenetic markers of cytosine methylation and telomere lengthBy comparing methQTLs in iPSC vs. their donor PBMCs, we find that detection of methQTLs reflect biological functions of different cell types
Molecular mechanism of co-transcriptional H3K36 methylation by SETD2
Authors: Walshe James L. , Ochmann Moritz , Neef Ute , Dybkov Olexandr , Dienemann Christian , Oberthür Christiane , Zheenbekova Aiturgan , Urlaub Henning , Cramer Patrick 
Published: December 2024

SUMMARYTri-methylation of histone H3 at residue lysine-36 (H3K36me3) is a hallmark of actively and recently transcribed genes and contributes to cellular memory and identity. The deposition of H3K36me3 occurs co-transcriptionally when the methyltransferase SETD2 associates with RNA polymerase II (Pol II). Here we present three cryo-EM structures of SETD2 bound to Pol II elongation complexes at different states of nucleosome passage. Together with functional probing, our results suggest a 3-step mechanism of transcription-coupled H3K36me3 deposition. First, binding to the elongation factor SPT6 tethers the catalytic SET domain in proximity to the upstream DNA. Second, Pol II nucleosome passage leads to the transfer of a hexasome from downstream to upstream, poised for methylation. Finally, continued transcription leads to upstream nucleosome reassembly, partial dissociation of the histone chaperone FACT and sequential methylation of both H3 tails, completing H3K36me3 deposition of an upstream nucleosome after Pol II passage.