bluuebunny/crossref_metadata_2025_split huggingface dataset:
Auditory Localization Performance in Cochlear Implant Recipients With Single-Sided Deafness: The Challenges and Limitations of Current Outcome Metrics
Authors: Anidi Chioma , Abdulrazzak Obada , Jones Gerilyn , Epperson Madison V. , Ibrahim Nadine I. , Banakis Hartl Renee M. 
Published: July 2024

Hypothesis
Acoustic localization accuracy metrics currently employed in clinical literature both overestimate and underestimate performance benefit of cochlear implantation (CI) for single-sided deafness (SSD).

Background
Although localization in SSD with CI has been investigated, performance characterization has relied heavily on average error. Although attractively concise, this measure may misrepresent performance. Here, we characterize frequency-specific localization on a granular level in subjects with CI for SSD as a critical analysis of localization outcome metrics.

Methods
Eight CI recipients with SSD were recruited. Stimuli of broadband (BBN) and narrowband noise (NBN) at low (500 Hz), mid (1000 Hz), and high (4000 Hz) frequencies were presented in a semianechoic chamber. Localization accuracy was quantified in mean angular error (MAE) and linear regression slope.

Results
Use of a CI for SSD subjects improved localization performance by slope for all stimuli (p ≤ 0.0033) to a level that was equal to normal-hearing controls at 1 and 4 kHz (p ≥ 0.2281). MAE was also significantly improved for SSD subjects using CI for BBN stimuli (p ≪ 0.0001); however, no statistically significant improvement in MAE was seen for NBN (p ≥ 0.5773) with CI use. Descriptive analysis of individual subject performance highlights the reasons for contradictory results.

Conclusion
There is inherent challenge in characterizing localization benefit for individuals with CI for SSD. Our data demonstrate the limitations of utilization of average error as the sole metric for outcome benefit. We emphasize the importance of continued research investigating alternative outcome measures as we work toward a more refined understanding of the potential benefits and limitations of cochlear implantation for SSD.
Improving Evidence-based Management of Children and Adolescents with Elevated Blood Pressure during a Well-Child Encounter: A Quality Initiative
Authors: Ray Krista M. , Stille Christopher J. , Bunik Maya , Smith Hana , Lenssen Maureen , Fishbein Cassie 
Published: July 2024

INTRODUCTION:Pediatric hypertension requires accurate diagnosis and management to reduce the burden of cardiovascular disease across the lifespan. Despite national guidelines, hypertension (HTN) is one of the most frequently missed diagnoses within pediatric primary care. This quality improvement (QI) project aimed to improve the management of patients aged 3–18 years with elevated blood pressure (BP) by 25% during a well-child encounter.METHODS:Over one year, a single-center QI project was conducted at an academic general pediatrics center. Multidisciplinary interventions, including team education, workflow standardization, and clinical decision support tools, were implemented using Plan-Do-Study-Act cycles to improve adherence to evidence-based guidelines. Outcome measures were the percentage of youth with an elevated BP on screening who had documentation of provider actions. We used run charts to analyze the effect of interventions, and descriptive statistics for demographic data and process measures pre- and postintervention. Chi-square tests compared process measures pre- and postintervention and provider actions stratified by age.RESULTS:Key drivers of change were the percentage of documented confirmatory BPs, BP stage, and scheduled follow-up appointments. At baseline, 13% of children with elevated BP on screening had guideline-adherent provider actions documented. This increased to 40% postintervention; however, discrepancies in adherence stratified by age were observed. Youth 13 and older were significantly more likely to receive a provider action than younger children (P< 0.0001).CONCLUSION:BP management during a well-child encounter improved with multidisciplinary interventions that increased knowledge of evidence-based guidelines and standardized care.
Virtual brain twins for stimulation in epilepsy
Authors: Wang Huifang E. , Dollomaja Borana , Triebkorn Paul , Duma Gian Marco , Williamson Adam , Makhalova Julia , Lemarecha Jean-Didier , Bartolomei Fabrice , Jirsa Viktor 
Published: July 2024

AbstractEstimating the epileptogenic zone network (EZN) is an important part of the diagnosis of drug-resistant focal epilepsy and plays a pivotal role in treatment and intervention. Virtual brain twins based on personalized whole brain modeling provides a formal method for personalized diagnosis by integrating patient-specific brain topography with structural connectivity from anatomical neuroimaging such as MRI and dynamic activity from functional recordings such as EEG and stereo-EEG (SEEG). Seizures demonstrate rich spatial and temporal features in functional recordings, which can be exploited to estimate the EZN. Stimulation-induced seizures can provide important and complementary information. In our modeling process, we consider invasive SEEG stimulation as the most practical current approach, and temporal interference (TI) stimulation as a potential future approach for non-invasive diagnosis and treatment. This paper offers a virtual brain twin framework for EZN diagnosis based on stimulation-induced seizures. This framework estimates the EZN and validated the results on synthetic data with ground-truth. It provides an important methodological and conceptual basis for a series of ongoing scientific studies and clinical usage, which are specified in this paper. This framework also provides the necessary step to go from invasive to non-invasive diagnosis and treatment of drug-resistant focal epilepsy.
Autoantibodies towards HFE and SYT5 in anti-neutrophil cytoplasm antibody-associated vasculitis relapse
Authors: Bayati Shaghayegh , Nazeer Jamsheela , Ng James , Hayes Michael , Little Mark A. , Nilsson Peter , Pin Elisa 
Published: July 2024

AbstractObjectiveIdentification of those at high and low risk of disease relapse is a major unmet need in the management of patients with ANCA-associated vasculitis (AAV). Precise stratification would allow tailoring of immunosuppressive medication. We profiled the autoantibody repertoire of AAV patients in remission to identify novel autoantibodies associated with relapse risk.MethodsPlasma samples collected from AAV patients in remission were screened for novel autoantibodies using in-house generated protein arrays including 42,000 protein fragments representing 18,000 unique human proteins. Patients were categorized based on the occurrence and frequency of relapses. We modelled the association between these antibodies and relapse occurrence using descriptive and high dimensional regression approaches.ResultsWe observed nine autoantibodies at higher frequency in samples from AAV patients experiencing multiple relapses compared to patients in long-term remission off therapy (LTROT). LASSO analysis identified six autoantibodies that exhibited an association with relapse occurrence after sample collection. Antibodies targeting HFE and SYT5 were identified as associated with relapse in both analyses.ConclusionThrough a broad protein array-based autoantibody screening, we identified two novel autoantibodies as candidate biomarkers of relapse in AAV.Key messages of this studyOur multi-step screening based on high-throughput and high-multiplexing protein arrays allowed to identify novel autoantibodies in AAV patients.Our study identified two new autoantibodies as candidate biomarkers for predicting AAV patients at risk of relapse.The risk of relapse may be better reflected by the presence of specific autoantibodies than by the overall autoantibody load in patients with AAV.
Disparate and shared transcriptomic signatures associated with cortical atrophy in genetic bvFTD
Authors: Shen Ting , Vogel Jacob W. , Van Deerlin Vivianna M , Suh EunRan , Dratch Laynie , Phillips Jeffrey S. , Massimo Lauren , Lee Edward B. , Irwin David J. , McMillan Corey T. 
Published: July 2024

AbstractCortical atrophy in behavioral variant frontotemporal degeneration (bvFTD) exhibits spatial heterogeneity across genetic subgroups, potentially driven by distinct biological mechanisms. Using an integrative imaging-transcriptomics approach, we identified disparate and shared transcriptomic signatures associated with cortical thickness inC9orf72,GRNorMAPT-related bvFTD. Genes associated with cortical thinning inGRN-bvFTD were implicated in neurotransmission, further supported by mapping synaptic density maps to cortical thickness maps. Previously identified genes linked to TDP-43 positive neurons were significantly overlapped with genes associated withC9orf72-bvFTD andGRN-bvFTD, but notMAPT-bvFTD providing specificity for our associations.C9orf72-bvFTD andGRN-bvFTD shared genes displaying consistent directionality of correlations with cortical thickness, whileMAPT-bvFTD displayed more pronounced differences in transcriptomic signatures with opposing directionality. Overall, we identified disparate and shared genes tied to regional vulnerability with increased biological interpretation including overlap with synaptic density maps and pathologically-specific gene expression, illuminating intricate molecular underpinnings contributing to heterogeneities in bvFTD.
The effect of highly effective modulator therapy on systemic inflammation in cystic fibrosis
Authors: Maher Rosemary E , Cytlak-Chaudhuri Urszula , Aleem Saad , Barry Peter J , Brice Daniel , Caamaño-Gutiérrez Eva , Driver Kimberley , Emmott Edward , Rothwell Alexander , Smith Emily , Travis Mark , Lee Dave , McNamara Paul S , Waller Ian , Smith Jaclyn A , Jones Andrew M , Lord Robert W 
Published: July 2024

ABSTRACTBackgroundDespite significant clinical improvements, there is evidence of persisting airway inflammation in people with cystic fibrosis established on Elexacaftor/tezacaftor/ivacaftor (ETI) therapy. As CF is a multi-system disease, systemic immune profiles can reflect local inflammation within the lungs and other organs. Understanding systemic inflammation after ETI therapy may reveal important translational insights. This study aims to profile systemic inflammatory changes and relate these to the well-documented improvements observed with ETI therapy.MethodsWe conducted a single-centre longitudinal study with 57 CF subjects initiating ETI therapy. All participants were Phe508del homozygous or Phe508del/minimal function. Blood samples were collected pre-ETI and 3-12 months post-therapy initiation. Analyses included mass spectrometry-based proteomics, a multiplex immunoassay, and flow cytometry for peripheral immune cell counts and phenotype. Controls samples were provided by 29 age-matched healthy controls.ResultsSystemic inflammation reduced with ETI therapy; however, the immune profile remained distinct from healthy controls. ETI reduced neutrophil counts and was associated with a more mature, less inflammatory phenotype, as well as a shift toward an immune resolving state associated with increased CD206 expression. Cytokines known to influence neutrophil levels reduced with therapy. Despite ETI therapy, neutrophil and monocyte counts remained elevated compared to healthy controls. There was no obvious association between the ETI-related improvements in systemic inflammation and lung function.ConclusionsPatients with CF show evidence of persisting systemic inflammation despite ETI therapy, this may have long term potentially adverse effects on respiratory and other organ systems.
Haploinsufficiency ofITSN1is associated with Parkinson’s disease
Authors: Spargo Thomas P. , Sands Chloe F. , Juan Isabella R. , Mitchell Jonathan , Ravanmehr Vida , Butts Jessica C. , De-Paula Ruth B. , Kim Youngdoo , Hu Fengyuan , Wang Quanli , Vitsios Dimitrios , Garg Manik , Messa Mirko , del Angel Guillermo , Calame Daniel G. , Saade Hiba , Robak Laurie , Hollis Ben , Zoghbi Huda Y. , Shulman Joshua , Petrovski Slavé , Al-Ramahi Ismael , Tachmazidou Ioanna , Dhindsa Ryan S. 
Published: July 2024

AbstractBackgroundDespite its significant heritability, the genetic underpinnings of Parkinson disease (PD) remain incompletely understood, particularly the role of rare variants. Advances in population-scale sequencing now provide an unprecedented opportunity to uncover additional large-effect rare genetic risk factors and expand our understanding of disease mechanisms.MethodsWe leveraged whole-genome sequence data with linked electronic health records from 490,560 UK Biobank participants, identifying 3,809 PD cases and 247,101 controls without a neurological disorder. We performed both variant-and gene-level association analyses to identify novel genetic associations with PD. We analyzed two additional independent case-control cohorts for replication (totaling 3,739 cases and 58,156 controls). Additionally, we performed functional validation of a novel PD association in a human synuclein-expressingDrosophilamodel.FindingsIn the UK Biobank, we replicated associations in well-established loci includingGBA1andLRRK2.We also identified a novel association between protein-truncating variants (PTVs) inITSN1and an increased risk of PD, with an effect size exceeding those of established loci (Fisher’s Exact Test: p=6.1x10-7; Odds ratio [95% confidence interval] = 10.53 [5.20, 21.34]). We replicated theITSN1risk signal in a meta-analysis across all cohorts (Cochran-Mantel-Haenszel test p=5.7x10-9; Odds ratio [95% confidence interval] = 9.20 [4.66, 16.70]). InDrosophila, haploinsufficiency of theITSN1ortholog (Dap160) exacerbated α-synuclein-induced compound eye degeneration and motor deficits.InterpretationWe establishITSN1as a novel risk gene for PD, with PTVs substantially increasing disease risk.ITSN1encodes a scaffold protein involved in synaptic vesicle endocytosis, a critical pathway increasingly recognized in PD pathogenesis. Our findings highlight the power of large-scale sequencing coupled with preclinical functional modeling to identify rare variant associations and elucidate disease mechanisms.
Leisure-time physical activity, sedentary behavior, and biological aging: evidence from genetic correlation and Mendelian randomization analyses
Authors: Zhao Xunying , Wu Xueyao , He Lin , Xiao Jinyu , Xiang Rong , Sha Linna , Tang Mingshuang , Hao Yu , Qu Yang , Xiao Changfeng , Qin Chenjiarui , Hou Jiaojiao , Deng Qin , Zhu Jiangbo , Zheng Sirui , Zhou Jinyu , Yu Ting , Yang Bin , Song Xin , Han Tao , Liao Jiaqiang , Zhang Tao , Fan Mengyu , Li Jiayuan , Jiang Xia 
Published: July 2024

AbstractPhysical inactivity and sedentary behavior are associated with higher risks of age-related morbidity and mortality. However, whether they causally contribute to accelerating biological aging has not been fully elucidated. Utilizing the largest available genome-wide association study (GWAS) summary data, we implemented a comprehensive analytical framework to investigate the causal relationships between moderate-to-vigorous leisure-time physical activity (MVPA), leisure screen time (LST), and four epigenetic age acceleration (EAA) measures: HannumAgeAccel, intrinsic HorvathAgeAccel, PhenoAgeAccel, and GrimAgeAccel. Shared genetic backgrounds across these traits were quantified through genetic correlation analysis. Overall and independent causal effects were assessed through univariable and multivariable Mendelian randomization (MR). A recently developed tissue-partitioned MR approach was further adopted to explore potential tissue-specific pathway that contributes to the observed causal relationships. Among the four EAA measures investigated, consistent results were identified for PhenoAgeAccel and GrimAgeAccel. These two measures were negatively genetically correlated with MVPA (rg=−0.18∼−0.29) and positively genetically correlated with LST (rg=0.22∼0.37). Univariable MR yielded a robust effect of genetically predicted LST on GrimAgeAccel (βIVW=0.69,P=1.10×10−7), while MVPA (βIVW=−1.02,P=1.50×10−2) and LST (βIVW=0.37,P=1.90×10−2) showed marginal causal effects on PhenoAgeAccel. Multivariable MR suggested an independent causal role of LST in GrimAgeAccel after accounting for effects of MVPA and other important confounders. Tissue-partitioned MR suggested skeletal muscle tissue associated variants be predominantly responsible for driving the effect of LST on GrimAgeAccel. Findings support sedentary lifestyles as a modifiable causal risk factor in accelerating epigenetic aging, emphasizing the need for preventive strategies to reduce sedentary screen time for healthy aging.
Characterisation of Microbial Community Dynamics and Antibiotic Resistance Gene Dissemination in Malaysian Wastewater during the COVID-19 Pandemic
Authors: Shahid Umama , Li Hooi Suet , Yong Lim Shu , Mohd Aris Alijah , Chin Khor Bee , Ayub Qasim , Siew Tan Hock 
Published: July 2024

AbstractWastewater is a well-known hotspot for pathogens and spread of antibiotic resistance across species. Surveillance of wastewater microbial community can help draw clearer representation of actively culturing taxonomic groups and resistance-inducing mobile genetic elements before and after treatment. Studies have suggested that COVID-19 pandemic may also have caused increased dissemination of antibiotic-resistance genes (ARGs) and antibiotic-resistant bacteria in wastewater. Although immensely significant, no research has yet been performed on Malaysian wastewater microbial community and ARGs or their correlation with COVID-19 infections. This study utilised 16S metagenomics approach to characterise microbial community in Malaysian wastewater during high and low-case phases of pandemic. Among 20 most prevalent genera around Kuala Lumpur, Malaysia, those belonging to Bacteriodales, Bacillales, Actinomycetales and opportunistic pathogens-Arcobacters, Flavobacteria, and Campylobacterales, Neisseriales, were enriched during high-case periods of the COVID-19 pandemic. Copy number profiling of ARGs in water samples showed prevalence of elements conferring resistance to antibiotics like sulphonamides, cephalosporins, and colistin. High prevalence ofintI1and other ion-based transporters in samples highlight an extensive risk of horizontal gene transfer to previously susceptible species. Our study emphasises the importance of wastewater surveillance in understanding microbial community dynamics and ARG dissemination, particularly during public health crises like the COVID-19 pandemic.
Longitudinal Dynamics and Pluripotentiality of Polysymptomatic Clustering in Adolescent Mental Health
Authors: Kennedy Michelle F. , Schwenn Paul , Boyes Amanda , Mills Lia , Prince Taliah , Parker Marcella , Hermens Daniel F. 
Published: July 2024

AbstractBackgroundAdolescence represents a sensitive developmental period characterised by an increased incidence of emerging mental health symptoms and formal diagnostic onset. These conditions can remain a significant burden throughout life. The Longitudinal Adolescent Brain Study (LABS) commenced in 2018 to track the onset and trajectory of mental health symptoms among general population participants. This research aims to identify polysymptomatic clusters of emerging mental health symptoms in adolescents and examine how these clusters vary by age and change over time, providing insights into the pluripotentiality of disorder development.MethodsLABS participants aged 12-17 years (n=166) completed the Mini International Neuropsychiatric Interview (MINI Kid) approximately every 4 months, with up to 15 timepoints. Due to this high dimensional dataset, the data was first processed using a dimensionality reduction step (uniform manifold approximation and projection; UMAP). Following this, the data was clustered using Bayesian model averaging of k-means, gaussian mixture model and hierarchical clustering to identify distinct symptom clusters. Symptom clusters were described in terms of the original neuropsychiatric interview responses using separate XGBoost classifier models. Symptom cluster dynamics were analysed using Markov chain transition probability matrices and longitudinal analysis. To explore the relationship between symptom clusters and psychological distress and wellbeing, correlational analyses were conducted using scores from the Kessler Psychological Distress Scale (K10) and the COMPAS-W Wellbeing Scale.OutcomesSix symptom-based clusters (states) were identified: attention, anxiety, depression, manic episode - heritability, anhedonia, and well. Depression and anxiety clusters had the greatest pluripotentiality. Analysis of psychological distress and wellbeing demonstrated an inverse relationship between the states: those with greater psychological distress had more symptoms, conversely those with greater wellbeing had fewer symptoms.InterpretationsMapping polysymptomatic clusters of mental health symptoms and their pluripotential and transitory trajectories in adolescents enables more effective targeting of preventive interventions. This approach moves beyond categorical classifications to mitigate the progression of early symptoms into enduring psychiatric disorders.
Effects of Singing on Vascular Health in Older Adults with Coronary Artery Disease: A Randomized Trial
Authors: Bagherimohamadipour Mehri , Hammad Muhammad , Visotcky Alexis , Sparapani Rodney , Kulinski Jacquelyn 
Published: July 2024

ABSTRACTBackgroundThe impact of singing on cardiovascular health has not been extensively studied. The aim of this study is to investigate the effect of singing on cardiovascular biomarkers in an aging population with coronary artery disease.MethodsParticipants had three study visits separated by 2-7 days, according to a randomized, single-blind, cross-over, controlled design: (1) a 30-minute period of coached singing from an in-person music therapist, (2) a 30-minute period of singing along to an instructional video and (3) a 30-minute rest (control). Primary outcomes included macrovascular endothelial function assessed by brachial artery flow-mediated dilation and microvascular function assessed by peripheral arterial tonometry (Framingham reactive hyperemia index; fRHI). Heart rate variability was a secondary outcome.ResultsSixty-five subjects (mean age 67.7± 0.8, 40% women) completed the study. Compared to control, there was an increase in fRHI for the singing video intervention (estimate 0.54, SE 0.25, p=0.005) but not for the coaching intervention (estimate 0.11, SE 0.18, p=0.570). There was no change in macrovascular function with either intervention. The low frequency/high frequency (LF/HF) ratio increased by 2.80 (SE 1.03, p=0.008), and the LnHF power decreased by −0.90 ms2(SE 0.29, p=0.003) with the video (during to pre-change). When assessing post- to pre- change, the coaching intervention showed a significant change of −0.62 ms2(SE 0.29, p=0.036) in LnHF power.ConclusionsSinging along to an instructional video for 30 minutes improved microvascular, but not macrovascular, endothelial function, in older patients with CAD. HRV changes with singing are similar to that of exercise.