bluuebunny/crossref_metadata_2025_split huggingface dataset:
COVID-19 vaccination-induced antibody responses and waning by age and comorbidity status in a large population-based prospective cohort study
Authors: Hoeve CE , Huiberts AJ , de Gier B , Andeweg SP , den Hartog G , de Melker HE , Hahne SJM , van de Wijgert JHHM , van den Hof S , Knol MJ 
Published: October 2023

BackgroundInformation on the magnitude and duration of antibody levels after COVID-19 vaccination in different groups may be useful for prioritizing of additional vaccinations.MethodsSerum samples were collected every six months in a prospective cohort study among adults in the Netherlands. Geometric mean concentrations (GMCs) of antibodies against the receptor binding domain of the SARS-CoV-2 spike protein were calculated after the primary series, first, and second booster vaccinations. Effects of age (18-59 vs 60-85 years) and medical risk conditions on GMC 2-6 weeks and 21-25 weeks after each vaccination, and on waning during 3-25 weeks after each vaccination, were estimated by linear regression.ResultsWe included 20,816, 16,820 and 5,879 samples collected after primary, first and second booster vaccination, respectively. GMCs at 2-6 and 21-25 weeks after primary series were lower in participants with older age or medical risk conditions. After the first booster, older age was associated with lower GMC at 2-6 weeks, higher GMC at 21-25 weeks, and slower waning. GMCs or waning after the first and second boosters (only 60-85) were not associated with medical risk conditions.ConclusionsSince antibody differences by age and medical risk groups have become small with increasing number of doses, other factors such as disease severity rather than antibody levels are useful for prioritization of additional vaccinations.
Frequency of Variants in Mendelian Alzheimer’s Disease Genes within the Alzheimer’s Disease Sequencing Project (ADSP)
Authors: Wang Dongyu , Scalici Alexandra , Wang Yanbing , Lin Honghuang , Pitsillides Achilleas , Heard-Costa Nancy , Cruchaga Carlos , Ziegemeier Ellen , Bis Joshua C. , Fornage Myriam , Boerwinkle Eric , De Jager Philip L , Wijsman Ellen , Dupuis Josée , Renton Alan E. , Seshadri Sudha , Goate Alison M. ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI),   The Alzheimer’s Disease Sequencing Project, DeStefano Anita L. , Peloso Gina M. 
Published: October 2023

ABSTRACTBackgroundPrior studies using the ADSP data examined variants within presenilin-2 (PSEN2), presenilin-1 (PSEN1), and amyloid precursor protein (APP) genes. However, previously-reported clinically-relevant variants and other predicted damaging missense (DM) variants have not been characterized in a newer release of the Alzheimer’s Disease Sequencing Project (ADSP).ObjectiveTo characterize previously-reported clinically-relevant variants and DM variants inPSEN2, PSEN1, APPwithin the participants from the ADSP.MethodsWe identified rare variants (MAF <1%) previously-reported inPSEN2,PSEN1,andAPPin the available ADSP sample of 14,641 individuals with whole genome sequencing and 16,849 individuals with whole exome sequencing available for research-use (Ntotal= 31,490). We additionally curated variants in these three genes from ClinVar, OMIM, and Alzforum and report carriers of variants in clinical databases as well as predicted DM variants in these genes.ResultsWe detected 31 previously-reported clinically-relevant variants with alternate alleles observed within the ADSP: 4 variants inPSEN2, 25 inPSEN1, and 2 inAPP. The overall variant carrier rate for the 31 clinically-relevant variants in the ADSP was 0.3%. We observed that 79.5% of the variant carriers were cases compared to 3.9% were controls. In those with AD, the mean age of onset of AD among carriers of these clinically-relevant variants was 19.6 ± 1.4 years earlier compared with noncarriers (p-value=7.8×10-57).ConclusionA small proportion of individuals in the ADSP are carriers of a previously-reported clinically-relevant variant allele for AD and these participants have significantly earlier age of AD onset compared to noncarriers.
Adverse Childhood Events, Mood and Anxiety Disorders, and Substance Dependence: Gene X Environment Effects and Moderated Mediation
Authors: Kranzler Henry R. , Davis Christal N. , Feinn Richard , Jinwala Zeal , Khan Yousef , Oikonomou Ariadni , Silva-Lopez Damaris , Burton Isabel , Dixon Morgan , Milone Jackson , Ramirez Sarah , Shifman Naomi , Levey Daniel , Gelernter Joel , Hartwell Emily E. , Kember Rachel L. 
Published: October 2023

ABSTRACTBackground:Adverse childhood events (ACEs) contribute to the development of mood and anxiety disorders and substance dependence. However, the extent to which these effects are direct or indirect and whether genetic risk moderates them is unclear.Methods:We examined associations among ACEs, mood/anxiety disorders, and substance dependence in 12,668 individuals (44.9% female, 42.5% African American/Black, 42.1% European American/White). We generated latent variables for each phenotype and modeled direct and indirect effects of ACEs on substance dependence, mediated by mood/anxiety disorders (forward or “self-medication” model) and of ACEs on mood/anxiety disorders, mediated by substance dependence (reverse or “substance-induced” model). In a sub-sample, we also generated polygenic scores for substance dependence and mood/anxiety disorder factors, which we tested as moderators in the mediation models.Results:Although there were significant indirect effects in both directions, mediation by mood/anxiety disorders (forward model) was greater than by substance dependence (reverse model). Greater genetic risk for substance dependence was associated with a weaker direct effect of ACEs on substance dependence in both the African- and European-ancestry groups (i.e., gene-environment interaction) and a weaker indirect effect in European-ancestry individuals (i.e., moderated mediation).Conclusion:We found greater evidence that substance dependence results from self-medication of mood/anxiety disorders than that mood/anxiety disorders are substance induced. Among individuals at higher genetic risk for substance dependence who are more likely to develop a dependence diagnosis, ACEs exert less of an effect in promoting that outcome. Following exposure to ACEs, multiple pathways lead to mood/anxiety disorders and substance dependence. Specification of these pathways could inform individually targeted prevention and treatment approaches.
Multiple Treatment Interruptions and Protecting HIV-Specific CD4 T-Cells Enables Durable CTL Response and Viral Control
Authors: Jain Anshika , Canepa Gaspar E. , Liou Mei-Ling , Fledderman Emily L. , Chapoval Andrei I. , Xiao Lingzhi , Mukherjee Ipsita , Galvin Jeffrey A. , Kumar Princy N. , Bordon José , Conant Marcus A. , Boyle Jefferey S. 
Published: October 2023

ABSTRACTBACKGROUNDThe cell and gene therapy product AGT103-T was evaluated (NCT04561258) for safety, immunogenicity, and persistence for up to 180 days post infusion. We sought to investigate the impact following analytical treatment interruptions (ATIs).METHODSSix patients suspended their antiretroviral therapy (ART) until their viral load reached 100,000 copies/mL in two successive visits, or their CD4 count fell below 300 cells/μL. We measured the magnitude of viral rebound, the persistence of AGT103-T transduced CD4+ T-cells and the impact on HIV-specific immune responses.RESULTSDuring the ATI, all patients experienced logarithmic viral rebound followed by a 2-5-fold increase in total CD8 counts, that coincided with a rise in HIV-specific CD8 T-cells. This was attributed to the increase in antigen availability and memory recall. Thus, to determine if the immune response generated during this “auto-vaccination” event can contribute to viral suppression upon subsequent exposures, a second ATI was initiated. During the second ATI, the Gag-specific CD8 T cells were either maintained or rose and the peak viremia was substantially decreased with viral set-points ranging from 7,000-25,000 copies/mL. Upon ART resumption, faster viral control was demonstrated without any serious adverse events (SAEs) or drug resistance.CONCLUSIONAGT103-T gene therapy and multiple ATIs were not associated with SAEs and allowed subjects to establish a low viral set-point with relatively stable CD4 T cell counts. Additionally, multiple ATIs are beneficial for the study design when induction of CD8 T cells is required to establish viral control.REGISTRATIONClinicalTrials.govNCT05540964FUNDINGAmerican Gene Technologies International Inc.
Prospective validation of a predictive non-invasive SNP-based biomarker signature in resectable pancreatic cancer: a study protocol
Authors: Seeger Nico , Gutknecht Stefan , Zschokke Irin , Fleischmann Isabella , Roth Nadja , Metzger Juerg , Weber Markus , Breitenstein Stefan , Grochola Lukasz Filip 
Published: October 2023

AbstractBackgroundA growing body of work suggests that inherited genetic variants can be utilized as non-invasive biomarkers to predict cancer-specific patient outcomes and guide therapy after resection of pancreatic ductal adenocarcinoma (PDAC). Specifically, two recent retrospective analyses led to the identification and retrospective validation of three single nucleotide polymorphisms (SNPs) in the CD44 and CHI3L2 genes (SNPrs187115, SNPrs353630, SNPrs684559) genes that can serve as predictive biomarkers to help select patients who are likely to benefit from pancreatic resection. Those SNPs have been shown to associate with an over 2-fold increased risk for tumour-related death in three independent PDAC study cohorts from Europe and the U.S (Hazard ratio (HR) up-to 0.38; p-value up-to 1x10−8).MethodsIn order to translate these retrospective findings into clinical practice, we aim to utilise a cohort of PDAC patients who undergo pancreatic resection in three hospitals in Switzerland to prospectively validate the association of the identified SNPs in the CD44 and CHI3L2 genes with PDAC survival after resection in a controlled clinical setting. All patients with a histopathological diagnosis of PDAC who undergo pancreatic resection and fulfil the inclusion criteria will be included consecutively. The SNP genotypes will be determined using standard genotyping techniques from patient blood samples. For each genotyped locus, log-rank and Cox multivariate regression tests will be performed, accounting for the relevant covariates AJCC-stage and resection-status. Clinical follow-up data will be collected for at least 3 years. Sample size calculation resulted in a number of 150 patients (80% power to detect allelic differences in survival; effect size>2.0 between genotypes; two-sided α-level of 0.05; drop-out rate of 10%; potential additional error margin of 10%).DiscussionThis is the first prospective study of the CD44 and CHI3L2 gene SNP-based biomarker signature in PDAC. A prospective validation of these biomarkers would enable its utilization as a non-invasive, predictive signature of survival after pancreatic resection that is readily available at the time of PDAC diagnosis. The results of this study may lead to improved patient outcomes in resectable PDAC.Trial registrationNot listed in a registry, because no results of a health care intervention are reported.
Associations of Skeletal Muscle Mass, Muscle Fat Infiltration, Mitochondrial Energetics, and Cardiorespiratory Fitness with Liver Fat Among Older Adults
Authors: Igudesman Daria , Mucinski Justine , Harrison Stephanie , Cawthon Peggy M. , Linge Jennifer , Goodpaster Bret H. , Cummings Steven R. , Hepple Russell T. , Jurczak Michael J. , Kritchevsky Stephen B. , Marcinek David , Coen Paul M. , Corbin Karen D. 
Published: October 2023

AbstractBackgroundMuscle mass loss may be associated with liver fat accumulation, yet scientific consensus is lacking and evidence in older adults is scant. It is unclear which muscle characteristics might contribute to this association in older adults.MethodsWe associated comprehensive muscle-related phenotypes including muscle mass normalized to body weight (D3-creatine dilution), muscle fat infiltration (MRI), carbohydrate-supported muscle mitochondrial maximal oxidative phosphorylation (respirometry), and cardiorespiratory fitness (VO2peak) with liver fat among older adults. Linear regression models adjusted for age, gender, technician (respirometry only), daily minutes of moderate to vigorous physical activity, and prediabetes/diabetes status tested main effects and interactions of each independent variable with waist circumference (high: women—≥88 cm, men—≥102 cm) and gender.ResultsAmong older adults aged 75 (IQR 73, 79 years; 59.8% women), muscle mass and liver fat were not associated overall but were positively associated among participants with a high waist circumference (β: 25.2; 95%CI 11.7, 40.4;p=.0002; N=362). Muscle fat infiltration and liver fat were positively associated (β: 15.2; 95%CI 6.8, 24.3;p=.0003; N=378). Carbohydrate-supported maximum oxidative phosphorylation and VO2peak (adjusted β: −12.9; 95%CI −20.3, −4.8;p=0.003; N=361) were inversely associated with liver fat; adjustment attenuated the estimate for maximum oxidative phosphorylation although the point estimate remained negative (β: −4.0; 95%CI −11.6, 4.2;p=0.32; N=321).ConclusionsSkeletal muscle-related characteristics are metabolically relevant factors linked to liver fat in older adults. Future research should confirm our results to determine whether trials targeting mechanisms common to liver and muscle fat accumulation are warranted.
Synergistic impact of three complement polymorphisms in the donor, not the recipient, on long-term kidney allograft survival
Authors: Poppelaars Felix , Gaya da Costa Mariana , Faria Bernardo , Eskandari Siawosh K. , Petr Vojtech , Holers V. Michael , Daha Mohamed R. , Berger Stefan P. , Damman Jeffrey , Seelen Marc A. , Thurman Joshua M. 
Published: October 2023

AbstractBackgroundGenetic analysis in transplantation offers potential for personalized medicine. Given the crucial role of the complement system in renal allograft injury, we investigated in kidney transplant pairs the impact of complement polymorphisms on long-term outcomes.MethodsIn this observational cohort study, we analyzed polymorphisms in C3 (C3R102G), factor B (CFBR32Q), and factor H (CFHV62I) genes of 1,271 donor-recipient kidney transplant pairs and assessed their association with 15-year death-censored allograft survival.ResultsIndividually, only the presence of theCFB32Qvariant in the donor and the combined presence in donor-recipient pairs were associated with better graft survival (P=0.027 andP=0.045, respectively). In the combined analysis, theC3R102G,CFBR32Q, andCFHV62Ivariants in the donor independently associated with the risk of graft loss (HR 1.32; 95%-CI, 1.08– 1.58;P=0.005). Thus, donor kidneys carrying the genetic variants that promote the highest complement activity exhibited the worst graft survival, whereas those with the genetic variants causing the lowest complement activity showed the best graft survival (15-year death-censored allograft survival: 48.8% vs 87.8%,P=0.001).ConclusionOur study demonstrates that the combination of complement polymorphisms in the donor strongly associates with long-term allograft survival following kidney transplantation. These findings hold significance for therapeutic strategies involving complement inhibition in kidney transplantation.
Prediction of response to transcranial magnetic stimulation treatment for depression using electroencephalography and statistical learning methods, including an out-of-sample validation
Authors: Bailey Neil W , Fulcher Ben D. , Arns Martijn , Fitzgerald Paul B , Fitzgibbon Bernadette , van Dijk Hanneke 
Published: October 2023

AbstractBackgroundRepetitive transcranial magnetic stimulation (rTMS) has shown efficacy for treating depression, but not for all patients. Accurate treatment response prediction could lower treatment burden. Research suggests machine learning trained with electroencephalographic (EEG) data may predict response, but only a limited range of measures have been tested.ObjectivesWe used >7000 time-series features to comprehensively test whether rTMS treatment response could be predicted in a discovery dataset and an independent dataset.MethodsBaseline EEG from 188 patients with depression treated with rTMS (125 responders) were decomposed into the top five principal components (PCs). Thehctsatoolbox was used to extract 7304 time-series features from each participant and PC. A classification algorithm was trained to predict responders from the feature matrix separately for each PC. The classifier was applied to an independent dataset (N= 58) to test generalizability on an unseen sample.ResultsWithin the discovery dataset, the third PC (which showed a posterior-maximum and prominent alpha power) showed above-chance classification accuracy (68%,pFDR= 0.005, normalised positive predictive value = 114%). Other PCs did not outperform chance. The model generalized to the independent dataset with above-chance balanced accuracy (60%,p= 0.046, normalised positive predictive value = 114%). Analysis of feature-clusters suggested responders showed more high frequency power relative to total power, and a more negative skew in the distribution of their time-series values.ConclusionThe dynamical properties of PC3 predicted treatment response with moderate accuracy, which generalized to an independent dataset. Results suggest treatment stratification from pre-treatment EEG may be possible, potentially enabling better outcomes than ‘one-size-fits-all’ treatment approaches.
Upadacitinib and Cardiovascular Adverse Events in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis
Authors: Omidi Fatemeh , Delkash Parisa , Sarmastzadeh Tala , Nasiri Mohammad Javad 
Published: October 2023

AbstractBackgroundThe safety of Upadacitinib, a Janus kinase inhibitor, in the context of rheumatoid arthritis management has raised concerns regarding potential cardiovascular adverse events, but the evidence remains inconclusive.MethodsOur study involved a systematic search for articles conducted up to October 1, 2023, encompassing databases such as PubMed/Medline, Embase, and Cochrane CENTRAL. We employed meta-analysis to calculate pooled odds ratios (OR) and their 95% confidence intervals (CI). We assessed potential publication bias through the application of Begg’s and Egger’s tests.ResultsSix studies involving 4202 patients were included. The analysis of the 15 mg dosage revealed a pooled OR of 1.20 (95% CI: 0.3-4.3), indicating a small increase in cardiovascular adverse event likelihood without statistical significance. The 30 mg dosage analysis yielded a combined OR of 2.37 (95% CI: 0.6-9.1), suggesting a potential risk increase but lacking statistical significance. Begg’s and Egger’s tests indicated no publication bias.ConclusionWhile there is a suggestion of elevated cardiovascular risk, especially with the 30 mg dosage, the absence of statistical significance and wide confidence intervals underscore the need for cautious interpretation. Individualized treatment decisions, vigilant monitoring, and further research are essential to optimize patient care and deepen our understanding of Upadacitinib’s safety profile.
A stagewise response to mitochondrial dysfunction in mitochondrial DNA maintenance disorders
Authors: Vincent Amy E. , Chen Chun , Gomes Tiago Bernadino , Leo Valeria Di , Laalo Tuomas , Pabis Kamil , Capaldi Rodrick , Mauresch Mike , McDonald David , Filby Andrew , Fuller Andrew , Urban Diana Lehmann , Zeirz Stephan , Deschauer Marcus , Turnbull Doug , Reeve Amy K , Lawless Conor 
Published: October 2023

AbstractMitochondrial DNA deletions clonally expand in skeletal muscle of patients with mtDNA maintenance disorders, impairing mitochondrial oxidative phosphorylation dysfunction. Previously we have shown that these mtDNA deletions originally arise and accumulate in the perinuclear mitochondria causing localised mitochondrial dysfunction before spreading through the muscle fibre. We believe that mito-nuclear signalling is a key contributor in this process.To further understand the role of mito-nuclear signalling, we use imaging mass cytometry to characterise the levels of mitochondrial respiratory complexes I-IV and ATP synthase alongside a mitochondrial mass marker, in a cohort of patients with mtDNA maintenance dosirders. We then expanded this panel to include protein markers of key signalling pathways to investigate the cellular response in fibres with different combinations of oxidative phosphorylation dysfunction and in ragged red fibres.We find CI and CIV deficiency to be most common, with a smaller proportion of cells that are also CIII and/or CV deficient. Interestingly, we also note that in cells deficient for one or more complexes, any complexes which are not deficient are commonly upregulated beyond the increase of mitochondrial mass typically observed in ragged red fibres. We further find that oxidative phosphorylation deficient fibres exhibit an increase in abundance of proteins involved in the proteostasis e.g. HSP60 and LONP1, and mitochondrial protein synthesis e.g. PHB1. Our analysis suggests that the cellular response to mitochondrial dysfunction changes depending on the combination of deficient oxidative phosphorylation complexes in each cell.
Rebalancing the motor circuit restores movement in aCaenorhabditis elegansmodel for TDP-43-toxicity
Authors: Koopman Mandy , Güngördü Lale , Janssen Leen , Seinstra Renée I. , Richmond Janet E. , Okerlund Nathan , Wardenaar René , Islam Priota , Brown Andre E.X. , Jorgensen Erik M. , Nollen Ellen A.A. 
Published: October 2023

AbstractAmyotrophic lateral sclerosis (ALS) and frontotemporal dementia are caused by the abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm of neurons. How TDP-43 accumulation leads to disease symptoms is not well-characterized. Here, we use aC. elegansmodel for TDP-43-induced toxicity to identify the biological mechanisms that lead to disease-related phenotypes. By applying deep behavioral phenotyping, we established a phenotypic fingerprint of TDP-43 worms. This fingerprint was compared to that of 294C. elegansmutants, in which genes were mutated that are important for nervous system and muscle functioning. By using a computational clustering approach, we found that the release of acetylcholine and GABA was the primary defect in TDP-43 worms. We then functionally dissected the neuromuscular circuit to show that GABA transmission was more severely diminished compared to acetylcholine. Whereas the loss of GABA transmission was caused by a profound loss of GABA synapses, acetylcholine neurons appeared to be functionally silenced. Enhancing functional output of repressed acetylcholine neurons at the level of G-protein coupled receptors or through optogenetic stimulation restored neurotransmission, but inefficiently rescued locomotion. Surprisingly, rebalancing the excitatory and inhibitory input by simultaneous stimulation of GABA and acetylcholine input into muscles not only synergized the effects of boosting individual neurotransmitter systems, but instantaneously improved movement. Our results suggest that interventions accounting for the altered connectome may be more efficient in restoring motor function than those solely focusing on diseased neuron populations.