bluuebunny/crossref_metadata_2025_split huggingface dataset:
A gene-based model of fitness and its implications for genetic variation: linkage disequilibrium
Authors: Johri Parul , Charlesworth Brian 
Published: September 2024

AbstractA widely used model of the effects of mutations on fitness (the “sites” model) assumes that heterozygous recessive or partially recessive deleterious mutations at different sites in a gene complement each other, similarly to mutations in different genes. However, the general lack of complementation between major effect allelic mutations suggests an alternative possibility, which we term the “gene” model. This assumes that a pair of heterozygous deleterious mutations intransbehave effectively as homozygotes, so that the fitnesses oftransheterozygotes are lower than those ofcisheterozygotes. We examine the properties of the two different models, using both analytical and simulation methods. We show that the gene model predicts positive linkage disequilibrium (LD) between deleterious variants within the coding sequence, under conditions when the sites model predicts zero or slightly negative LD. We also show that focussing on rare variants when examining patterns of LD, especially with Lewontin’sD’ measure, is likely to produce misleading results with respect to inferences concerning the causes of the sign of LD. Synergistic epistasis between pairs of mutations was also modeled; it is less likely to produce negative LD under the gene model than the sites model. The theoretical results are discussed in relation to patterns of LD in natural populations of several species.
Altered Cytokine Profile in Clinically Suspected Seronegative Autoimmune Associated Epilepsy
Authors: Motovilov Katherine , Maguire Cole , Briggs Deborah , Melamed Esther 
Published: September 2024

AbstractBackground and ObjectivesAutoimmune-associated epilepsy (AAE), a condition which responds favorably to immune therapies but not traditional anti-seizure interventions, is emerging as a significant contributor to cases of drug-resistant epilepsy. Current standards for the diagnosis of AAE rely on screening for known neuronal autoantibodies in patient serum or cerebrospinal fluid. However, this diagnostic method fails to capture a subset of drug-resistant epilepsy patients with suspected AAE who respond to immunotherapy yet remain seronegative (snAAE) for known autoantibodies.MethodsTo identify potential biomarkers for snAAE, we evaluated the most comprehensive panel of assayed cytokines and autoantibodies to date, comparing patients with snAAE, anti-seizure medication (ASM) responsive epilepsy, and patients with other neuroinflammatory diseases.ResultsWe found a unique signature of 14 cytokines significantly elevated in snAAE patients including: GM-CSF, MCP-2/CCL8, MIP-1a/CCL3, IL-1RA, IL-6, IL-8, IL-9, IL-10, IL-15, IL-20, VEGF-A, TNF-b, LIF, and TSLP. Based on prior literature, we highlight IL-6, IL-8, IL-10, IL-13, VEGF-A, and TNF-b as potentially actionable cytokine biomarkers for snAAE, which could be of diagnostic utility in clinical evaluations of snAAE patients. Autoantibody-ome screening failed to identify autoantibodies targeting neuronal channel proteins in snAAE patients. Interestingly, ASM-responsive epilepsy patients displayed elevations in the proportion of autoantibodies targeting brain plasma membrane proteins, possibly pointing to the presence of immune hyperactivity/dysfunction despite well-controlled seizure activity and suggesting ASM-responsive patients may experience disease progression independent of seizure activity (PISA).DiscussionOverall, our findings suggest that simply expanding existing autoantibody screens may not sufficiently enhance diagnostic power for snAAE. Instead, we propose that cytokine analysis may serve as a promising diagnostic avenue for identifying immune dysregulation in AAE patients and enabling opportunities for trials of immunotherapies.
APOE4and Infectious Diseases Jointly Contribute to Brain Glucose Hypometabolism, a Biomarker of Alzheimer’s Pathology: New Findings from the ADNI
Authors: Lathika Rajendrakumar Aravind , Arbeev Konstantin G. , Bagley Olivia , Duan Matt , Yashin Anatoliy I. , Ukraintseva Svetlana ,   Alzheimer’s Disease Neuroimaging Initiative
Published: September 2024

AbstractBackgroundImpaired brain glucose metabolism is a preclinical feature of neurodegenerative diseases such as Alzheimer’s disease (AD). Infections may promote AD-related pathology. Therefore, we investigated the interplay between infections andAPOE4, a strong genetic risk factor for AD.MethodsWe analyzed data on 1,509 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database using multivariate linear regression models. The outcomes were rank- normalized hypometabolic convergence index (HCI), statistical regions of interest (SROI) for AD, and mild cognitive impairment (MCI). Marginal mean estimates for infections, stratified byAPOE4carrier status, were then computed.ResultsPrior infections were associated with greater HCI [β=0.15, 95% CI: 0.03, 0.27, p=0.01]. The combined effects of infections andAPOE4carriers on HCI levels were significantly greater than either variable alone. AmongAPOE4carriers, the estimated marginal mean was 0.62, rising to 0.77, with infections (p<0.001), indicating an interaction effect. Carriers with multiple infections showed greater hypometabolism (higher HCI), with an estimate of 0.44 (p=0.01) compared to 0.11 (p=0.08) for those with a single infection, revealing a dose-response relationship. The estimates for the association of infections with SROI AD and SROI MCI were β=-0.01 (p=0.02) and β=-0.01 (p=0.04), respectively.ConclusionOur findings suggest that infections andAPOE4jointly contribute to brain glucose hypometabolism and AD pathology, supporting a “multi-hit” mechanism in AD development.
The VIPR-1 trial (Visualizing Ischemia in the Pancreatic Remnant) - Assessing the role of intraoperative indocyanine green perfusion of the transected pancreas in predicting postoperative pancreatic leaks: protocol for a phase II clinical trial
Authors: Salgado-Garza Gustavo , Willy Annika , Rocha Flavio G. , Mayo Skye C. , Sheppard Brett C. , Worth Patrick J. 
Published: September 2024

AbstractSurgery of the pancreas has come a long way since its inception; however, postoperative morbidity is still high. Pancreatic leaks and fistulas are common complications in patients undergoing surgery to remove the pancreas. Fistulas delay subsequent oncological care after surgery and prolong the hospital stay. Hypoperfusion to the pancreas has been characterized as one factor leading to fistulas. Indocyanine green (ICG) injection allows the surgeon to evaluate blood perfusion to tissue in real-time. This protocol describes a trial that aims to assess the effectiveness of intraoperative ICG metrics of the cut edge of the pancreas to predict postoperative fistulas. A single group will participate in an observational, surgeon-blinded, phase II trial. ICG measurements of the cut edge of the pancreas will be recorded before reconstruction. International Study Group on Pancreatic Surgery criteria for pancreatic fistula will be used to define leaks and fistulas. The primary outcome will be the correlation between ICG measurements and the development or absence of fistula formation. Currently, limited objective intraoperative predictors exist for predicting postoperative fistulas. Having a reliable predictive tool could decrease the healthcare burden posed by fistulas. The findings of this trial will provide conclusions on the usefulness of ICG measurements in predicting postoperative pancreatic fistulas and leaks. This clinical trial is registered inClinicalTrials.govwith the IDNCT06084013. The current protocol version is v1.0.
Comparative Effectiveness of the mRNA-1273 and BNT162b2 COVID-19 Vaccines Among Adults With Underlying Medical Conditions: A Systematic Literature Review and Pairwise Meta-Analysis Using GRADE
Authors: Wang Xuan , Pahwa Ankit , Bausch-Jurken Mary T. , Chitkara Anushri , Sharma Pawana , Malmenäs Mia , Vats Sonam , Gordon Whitfield Michael , Zhi Hua Lai Kira , Dasari Priyadarsini , Gupta Ritu , Nassim Maria , Van de Velde Nicolas , Green Nathan , Beck Ekkehard 
Published: September 2024

ABSTRACTIntroductionThis systematic literature review and pairwise meta-analysis evaluated the comparative effectiveness of mRNA-1273 versus BNT162b in patients with at least one underlying medical condition at high risk for severe COVID-19.MethodsMEDLINE, Embase, and Cochrane databases were searched for relevant articles from January 1, 2019 to February 9, 2024. Studies reporting effectiveness data from at least two doses of mRNA-1273 and BNT162b2 vaccination in adults with medical conditions at high risk of developing severe COVID-19 according to the US Centers for Disease Control and Prevention were included. Outcomes of interest were SARS-CoV-2 infection (overall, symptomatic, and severe), hospitalization due to COVID-19, and death due to COVID-19. Risk ratios (RRs) were calculated with random effects models. Subgroup analyses by specific medical conditions, number of vaccinations, age, and SARS-CoV-2 variant were conducted. Heterogeneity between studies was estimated with chi-square testing. The certainty of evidence was assessed using the Grading of Recommendations, Assessments, Development, and Evaluations framework.ResultsSixty-five observational studies capturing the original/ancestral-containing primary series to Omicron-containing bivalent original-BA4-5 vaccinations were included in the meta-analysis. mRNA-1273 was associated with significantly lower risk of SARS-CoV-2 infection (RR, 0.85 [95% CI, 0.79–0.92];I2=92.5%), symptomatic SARS-CoV-2 infection (RR, 0.75 [95% CI, 0.65–0.86];I2=62.3%), severe SARS-CoV-2 infection (RR, 0.83 [95% CI, 0.78–0.89];I2=38.0%), hospitalization due to COVID-19 (RR, 0.88 [95% CI, 0.82–0.94];I2=38.7%), and death due to COVID-19 (RR, 0.84 [95% CI, 0.76–0.93];I2=1.3%) than BNT162b2. Findings were generally consistent across subgroups. Evidence certainty was low or very low because sufficiently powered randomized controlled trials are impractical in this heterogeneous population.ConclusionMeta-analysis of 65 observational studies showed that vaccination with mRNA-1273 was associated with a significantly lower risk of SARS-CoV-2 infection and COVID-19-related hospitalization and death than BNT162b2 in patients with medical conditions at high risk of severe COVID-19.
The Breast Cancer Genetic Testing Experience: Probing the Potential Utility of an Online Decision Aid in Risk Perception and Decision Making
Authors: Vaynrub Anna , Salazar Brian , Feng Yilin Eileen , West Harry , Michel Alissa , Umakanth Subiksha , Crew Katherine D. , Kukafka Rita 
Published: September 2024

ABSTRACTBackgroundDespite the role of pathogenic variants (PVs) in cancer predisposition genes conferring significantly increased risk of breast cancer (BC), uptake of genetic testing (GT) remains low, especially among ethnic minorities. Our prior study identified that a patient decision aid,RealRisks,improved patient-reported outcomes relative to standard educational materials. This study examined patients’ GT experience and its influence on subsequent actions. We also sought to identify areas for improvement inRealRisksthat would expand its focus from improved GT decision-making to understanding results.MethodsWomen enrolled in the parent randomized controlled trial were recruited and interviewed. Demographic data was collected from surveys in the parent study. Interviews were conducted, transcribed, and coded to identify recurring themes. Descriptive statistics were generated to compare the interviewed subgroup to the original study cohort of 187 women.ResultsOf the 22 women interviewed, 11 (50%) had positive GT results, 2 (9.1%) with aBRCA1/2PV, and 9 (40.9%) with variants of uncertain significance (VUS). Median age was 40.5 years and 15 (71.4%) identified as non-Hispanic. Twenty (90.9%) reported a family history of BC, and 2 (9.1%) reported a family history ofBRCA1/2PV. The emerging themes included a preference for structured communication of GT results and the need for more actionable knowledge to mitigate BC risk, especially among patients with VUS or negative results. Few patients reported lifestyle changes following the return of their results, although they did understand that their behaviors can impact their BC risk.ConclusionsPatients preferred a structured explanation of their GT results to facilitate a more personal testing experience. While most did not change lifestyle behaviors in response to their GT results, there was a consistent call for further guidance following the initial discussion of GT results. Empowering patients, especially those with negative or VUS results, with the knowledge and context to internalize the implications of their results and form accurate risk perception represents a powerful opportunity to mediate subsequent risk management strategies. Informed by this study, future work will expandRealRisksto foster an accurate perception of GT results and include decision support to navigate concrete next steps.
A plasma proteomic signature for atherosclerotic cardiovascular disease risk prediction in the UK Biobank cohort
Authors: Gupte Trisha P. , Azizi Zahra , Kho Pik Fang , Zhou Jiayan , Chen Ming-Li , Panyard Daniel J. , Guarischi-Sousa Rodrigo , Hilliard Austin T. , Sharma Disha , Watson Kathleen , Abbasi Fahim , Tsao Philip S. , Clarke Shoa L. , Assimes Themistocles L. 
Published: September 2024

AbstractBackgroundWhile risk stratification for atherosclerotic cardiovascular disease (ASCVD) is essential for primary prevention, current clinical risk algorithms demonstrate variability and leave room for further improvement. The plasma proteome holds promise as a future diagnostic and prognostic tool that can accurately reflect complex human traits and disease processes. We assessed the ability of plasma proteins to predict ASCVD.MethodClinical, genetic, and high-throughput plasma proteomic data were analyzed for association with ASCVD in a cohort of 41,650 UK Biobank participants. Selected features for analysis included clinical variables such as a UK-based cardiovascular clinical risk score (QRISK3) and lipid levels, 36 polygenic risk scores (PRSs), and Olink protein expression data of 2,920 proteins. We used least absolute shrinkage and selection operator (LASSO) regression to select features and compared area under the curve (AUC) statistics between data types. Randomized LASSO regression with a stability selection algorithm identified a smaller set of more robustly associated proteins. The benefit of plasma proteins over standard clinical variables, the QRISK3 score, and PRSs was evaluated through the derivation of Δ AUC values. We also assessed the incremental gain in model performance using proteomic datasets with varying numbers of proteins. To identify potential causal proteins for ASCVD, we conducted a two-sample Mendelian randomization (MR) analysis.ResultThe mean age of our cohort was 56.0 years, 60.3% were female, and 9.8% developed incident ASCVD over a median follow-up of 6.9 years. A protein-only LASSO model selected 294 proteins and returned an AUC of 0.723 (95% CI 0.708-0.737). A clinical variable and PRS-only LASSO model selected 4 clinical variables and 20 PRSs and achieved an AUC of 0.726 (95% CI 0.712-0.741). The addition of the full proteomic dataset to clinical variables and PRSs resulted in a Δ AUC of 0.010 (95% CI 0.003-0.018). Fifteen proteins selected by a stability selection algorithm offered improvement in ASCVD prediction over the QRISK3 risk score [Δ AUC: 0.013 (95% CI 0.005-0.021)]. Filtered and clustered versions of the full proteomic dataset (consisting of 600-1,500 proteins) performed comparably to the full dataset for ASCVD prediction. Using MR, we identified 11 proteins as potentially causal for ASCVD.ConclusionA plasma proteomic signature performs well for incident ASCVD prediction but only modestly improves prediction over clinical and genetic factors. Further studies are warranted to better elucidate the clinical utility of this signature in predicting the risk of ASCVD over the standard practice of using the QRISK3 score.
Circulating Biomarkers as Predictors of Improvement in Physical Function in Hospitalized Older Adults with Geriatric Syndromes: Findings from the REHAB-HF Trial
Authors: Damluji Abdulla A. , Bruce Scott A. , Reeves Gordon , Pastva Amy M. , Bertoni Alain G. , Mentz Robert J. , Whellan David J. , Kitzman Dalane W. , deFilippi Christopher R. 
Published: September 2024

ABSTRACTIntroductionCirculating biomarkers play an important role in patients with heart failure (HF) for risk stratification and mechanistic insights. We aimed to examine if a diverse set of biomarkers in the REHAB-HF trial would predict improvement in physical function following a 12-week tailored physical therapy rehabilitation intervention compared to attention control.MethodsThe study population consisted of participants ≥60 years of age who were hospitalized with acute HF and randomized to a subsequent multidomain outpatient physical rehabilitation intervention vs. attention control with outcomes of 12-week functional change including the Short Physical Performance Battery (SPPB) and six-minute walk distance (6MWD). Blood was collected prior to randomization and at 12-weeks for cardiac, renal, and inflammatory biomarkers. Linear trends across progressively higher biomarker values versus improvement in functional outcomes based on treatment assignment were evaluated. Classification and regression trees (CART) were created to estimate optimal biomarker levels associated with differential improvement in the two functional outcomes.ResultsA total of 242 of 349 participants (69%) had baseline biomarkers measured. In an adjusted regression model, higher baseline cardiac troponin (cTn) I and T were associated with greater gains in SPPB and 6MWD respectively with the rehabilitation intervention (P=0.04 and 0.03 for interaction) versus attention control. In the CART analysis of the physical rehabilitation and attention control participants, those with baseline C-reactive protein (CRP) ≥9.9 mg/L and hs-cTnT ≥36 ng/L receiving the rehabilitation intervention had a 129 m (95% CI 78-180m) greater 12-week 6MWD increase vs attention control. In contrast, for participants with CRP<9.9 mg/L there was no significant incremental 6MWD difference (30m, 95% CI -0.5m, 60.2m). For SPPB, a CRP ≥9.9 mg/L and creatinine ≥1.4 mg/dL optimally identified a differential improvement with the rehabilitation intervention versus attention control. The biomarkers (except for creatinine) decreased by 12 weeks post hospitalization but with no differences based on treatment assignment.ConclusionHigher baseline levels of biomarkers of inflammation, cardiac injury, and renal dysfunction identified older adults after a HF hospitalization with the greatest differential improvement in physical function with a rehabilitation intervention. Biomarkers may help clinicians predict the benefits of this treatment.(Funded by the National Institutes of Health and others; REHAB-HFClinicalTrials.govnumber,NCT02196038).
is metallic perception a taste, an aroma or a flavor ?
Authors: Buiret Guillaume , Thierry Thomas-Danguin , Gilles Feron 
Published: September 2024

ABSTRACTAimMetallic taste is known to vanish with nasal occlusion, suggesting it should be termed metallic “aroma” rather than metallic “taste.” However, it also appears after neurological injuries, such as a chorda tympani section, which suppresses taste perception mediated by the facial nerve.MethodsIn 120 healthy volunteers, the perception of an iron sulfate solution was assessed at different lingual locations—corresponding to the facial and glossopharyngeal nerves—and with either open (n=60) or closed (n=60) noses to evaluate if it is a taste or an aroma.ResultsNasal occlusion significantly reduced the perception of iron sulfate. It prevented perception in 31.7% of participants, though it did not completely eliminate it in the remaining 68.3%. Additionally, in open-nosed subjects, the intensity of iron sulfate perception was significantly greater when applied to the base of the tongue (glossopharyngeal nerve) than to the tip (facial nerve). These differences did not persist with nasal occlusion.ConclusionNasal occlusion diminished but did not abolish the perception of iron sulfate. With an open nose, a differential taste perception was significant, but not with a closed nose. Therefore, metallic perception involves both retro-olfactory and gustatory components, suggesting it is a metallic flavor.
Bacterial growth temperature as a horizontally acquired polygenic trait
Authors: Farrell Anne A. , Nesbø Camilla L. , Zhaxybayeva Olga 
Published: September 2024

AbstractEvolutionary events leading to organismal preference for a specific growth temperature, as well as genes whose products are needed for a proper function at that temperature, are poorly understood. Using 64 bacteria from phylumThermotogotaas a model system, we examined how optimal growth temperature changed throughoutThermotogotahistory. We inferred thatThermotogota’s last common ancestor was a thermophile and that someThermotogotaevolved the mesophilic and hyperthermophilic lifestyles secondarily. By modeling gain and loss of genes throughoutThermotogotahistory and by reconstructing their phylogenies, we demonstrated that adaptations to lower and higher growth temperature require both the acquisition of necessary genes and loss of unnecessary genes. Via a pangenome-wide association study, we correlated presence/absence of 68 gene families with specific optimal growth temperature intervals. While some of these genes are poorly characterized, most are involved in metabolism of amino acids, nucleotides, carbohydrates, and lipids, as well as in signal transduction and regulation of transcription. Most of the 68 genes have a history of horizontal gene transfer to/from other bacteria and archaea, suggesting that parallel acquisitions of genes likely promote independent adaptations of differentThermotogotaspecies to specific growth temperatures.SignificanceWhile the currently known range of life-permitting temperatures spans from −15°C to +122°C, most living organisms, including microbes, can grow only in a narrow temperature interval around their optimal growth temperature. The genetic and genomic determinants of such preference remain poorly understood. Using genomes fromThermotogota, a group of bacteria that collectively can grow between 20° and 90°C, we detected 68 genes, presence of which strongly correlates with growth at specific optimal growth temperature. Our findings dramatically expand a list of genes that are likely important for both lowering and increasing preferred growth temperature of a microorganism. We also demonstrated that these genes were usually horizontally acquired from other bacteria and archaea that likely share environment withThermotogota, highlighting the importance of gene exchange in microbial adaptation.