bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic architecture of brain age and its casual relations with brain and mental disorders
Authors: Leonardsen Esten H. , Vidal-Piñeiro Didac , Roe James M. , Frei Oleksandr , Shadrin Alexey A. , Iakunchykova Olena , de Lange Ann-Marie G. , Kaufmann Tobias , Taschler Bernd , Smith Stephen M. , Andreassen Ole A. , Wolfers Thomas , Westlye Lars T. , Wang Yunpeng 
Published: January 2023

AbstractThe difference between chronological age and the apparent age of the brain estimated from brain imaging data — the brain age gap (BAG) — is widely considered a general indicator of brain health. Converging evidence supports that BAG is sensitive to an array of genetic and non-genetic traits and diseases, yet few studies have examined the genetic architecture and its corresponding causal relationships with common brain disorders. Here, we estimate BAG using state-of-the-art neural networks trained on brain scans from 53,542 individuals (age range 3-95 years). A genome-wide association analysis across 28,104 individuals (40-84 years) from the UK Biobank revealed eight independent genomic regions significantly associated with BAG (p<5×10−8) implicating neurological, metabolic, and immunological pathways – among which seven are novel. No significant genetic correlations or causal relationships with BAG were found for Parkinson’s disease, major depressive disorder, or schizophrenia, but two-sample Mendelian randomization indicated a causal influence of AD (p=7.9×10−4) and bipolar disorder (p=1.35×10−2) on BAG. These results emphasize the polygenic architecture of brain age and provide insights into the causal relationship between selected neurological and neuropsychiatric disorders and BAG.
Effectiveness of an eHealth Intervention for Reducing Psychological Distress and Increasing COVID-19 Knowledge and Protective Behaviors among Ethnoracially Diverse Sexual and Gender Minority Adults: A Quasi-experimental Study (#SafeHandsSafeHearts)
Authors: Newman Peter A. , Chakrapani Venkatesan , Massaquoi Notisha , Williams Charmaine C. , Tharao Wangari , Tepjan Suchon , Roungprakhon Surachet , Forbes Joelleann , Sebastian Sarah , Akkakanjanasupar Pakorn , Aden Muna 
Published: January 2023

AbstractPurposeLesbian, gay, bisexual, transgender, queer, and other persons outside of heteronormative and cisgender identities (LGBTQ+) and ethnic/racial minority populations are at heightened vulnerability amid the Covid-19 pandemic. Systemic marginalization and resulting adverse social determinants of health contribute to health disparities among these populations that result in more severe consequences due to Covid-19 and the public health measures to control it. We developed and tested a tailored online intervention (#SafeHandsSafeHearts) to support ethnoracially diverse LGBTQ+ individuals in Toronto, Canada amid the pandemic.MethodsWe used a quasi-experimental pre-test post-test design to evaluate the effectiveness of a 3-session, peer-delivered eHealth intervention in reducing psychological distress and increasing Covid-19 knowledge and protective behaviors. Individuals ≥18-years-old, resident in Toronto, and self-identified as sexual or gender minority were recruited online. Depressive and anxiety symptoms, Covid-19 knowledge and protective behaviors were assessed at baseline, 2-weeks postintervention, and 2-months follow-up. We used generalized estimating equations and zero-truncated Poisson models to evaluate the effectiveness of the intervention on the four primary outcomes.ResultsFrom March to November 2021, 202 participants (median age, 27 years [Interquartile rage: 23-32]) were enrolled in #SafeHandsSafeHearts. Over half (54%, n=110) identified as cisgender lesbian or bisexual women or women who have sex with women, 26.2% (n=53) cisgender gay or bisexual men or men who have sex with men, and 19.3% (n=39) transgender or nonbinary individuals. The majority (75.7%, n=143) were Black and other people of color. The intervention led to statistically significant reductions in the prevalence of clinically significant depressive and anxiety symptoms, and increases in Covid-19 protective behaviors from baseline to postintervention.ConclusionWe demonstrated the effectiveness of a brief, peer-delivered eHealth intervention for ethnoracially diverse LGBTQ+ communities in reducing psychological distress and increasing protective behaviors amid the Covid-19 pandemic. Implementation through community-based health services with trained peer educators supports feasibility, acceptability, and the importance of engaging ethnoracially diverse LGBTQ+ communities in pandemic response preparedness. This trial is registered with ClinicalTrials.gov, numberNCT04870723.
Deep learning-based Segmentation of Multi-site Disease in Ovarian Cancer
Authors: Buddenkotte Thomas , Rundo Leonardo , Woitek Ramona , Sanchez Lorena Escudero , Beer Lucian , Crispin-Ortuzar Mireia , Etmann Christian , Mukherjee Subhadip , Bura Vlad , McCague Cathal , Sahin Hilal , Pintican Roxana , Zerunian Marta , Allajbeu Iris , Singh Naveena , Anju Sahdev , Havrilesky Laura , Cohn David E. , Bateman Nicholas W. , Conrads Thomas P. , Darcy Kathleen M. , Maxwell G. Larry , Freymann John B. , Öktem Ozan , Brenton James D. , Sala Evis , Schönlieb Carola-Bibiane 
Published: January 2023

AbstractPurposeTo determine if pelvic/ovarian and omental lesions of ovarian cancer can be reliably segmented on computed tomography (CT) using fully automated deep learning-based methods.Materials and MethodsA deep learning model for the two most common disease sites of high grade serous ovarian cancer lesions (pelvis/ovaries and omentum) was developed and compared against the well-established “no-new-Net” (nnU-Net) framework and unrevised trainee radiologist segmentations. A total of 451 pre-treatment and post neoadjuvant chemotherapy (NACT) CT scans collected from four different institutions were used for training (n=276), hyper-parameter tuning (n=104) and testing (n=71) of the methods. The performance was evaluated using the Dice similarity coefficient (DSC) and compared using a Wilcoxon test on paired resultsResultsOur model outperforms the nnU-Net framework by a significant margin for both disease (validation: p=1×10-4,1.5×10-6, test: p=0.004, 0.005) and it does not perform significantly different from a trainee radiologist for the pelvic/ovarian lesions (p=0.392). On an independent test set (n=71), the model achieves a performance of 72±19 mean DSC for the pelvic/ovarian and 64±24 for the omental lesions.ConclusionAutomated ovarian cancer segmentation on CT using deep neural networks is feasible and achieves performance close to a trainee-level radiologist for pelvic/ovarian lesions.SummaryDeep learning-based models were used to assess whether fully automated segmentation is feasible for the main two disease sites in high grade serous ovarian cancer.Key PointsFirst automated approach for pelvic/ovarian and omental ovarian cancer lesion segmentation on CT images.Automated segmentation of ovarian cancer lesions can be comparable with manual segmentation of trainee radiologists with three years of experience in oncological and gynecological imaging.Careful hyper-parameter tuning can provide models significantly outperforming strong state-of-the-art baselines.
Genomic landscape ofTP53-mutated myeloid malignancies
Authors: Abel Haley J. , Oetjen Karolyn A. , Miller Christopher A. , Ramakrishnan Sai M. , Day Ryan B. , Helton Nichole M. , Fronick Catrina C. , Fulton Robert S. , Heath Sharon E. , Tarnawsky Stefan P. , Srivatsan Sridhar Nonavinkere , Duncavage Eric J. , Schroeder Molly C. , Payton Jacqueline E. , Spencer David H. , Walter Matthew J. , Westervelt Peter , DiPersio John F. , Ley Timothy J. , Link Daniel C. 
Published: January 2023

AbstractTP53-mutated myeloid malignancies are most frequently associated with complex cytogenetics. The presence of complex and extensive structural variants complicates detailed genomic analysis by conventional clinical techniques. We performed whole genome sequencing of 42 AML/MDS cases with paired normal tissue to characterize the genomic landscape ofTP53-mutated myeloid malignancies. The vast majority of cases had multi-hit involvement at theTP53genetic locus (94%), as well as aneuploidy and chromothripsis. Chromosomal patterns of aneuploidy differed significantly fromTP53-mutated cancers arising in other tissues. Recurrent structural variants affected regions that includeETV6on chr12p,RUNX1on chr21, andNF1on chr17q. Most notably forETV6, transcript expression was low in cases ofTP53-mutated myeloid malignancies both with and without structural rearrangements involving chromosome 12p. Telomeric content is increased inTP53-mutated AML/MDS compared other AML subtypes, and telomeric content was detected adjacent to interstitial regions of chromosomes. The genomic landscape ofTP53-mutated myeloid malignancies reveals recurrent structural variants affecting key hematopoietic transcription factors and telomeric repeats that are generally not detected by panel sequencing or conventional cytogenetic analyses.Key PointsWGS comprehensively determinesTP53mutation status, resulting in the reclassification of 12% of cases from mono-allelic to multi-hitChromothripsis is more frequent than previously appreciated, with a preference for specific chromosomesETV6is deleted in 45% of cases, with evidence for epigenetic suppression in non-deleted casesNF1is mutated in 48% of cases, with multi-hit mutations in 17% of these casesTP53-mutated AML/MDS is associated with altered telomere content compared with other AMLs
Evaluating eating behaviour, energy homeostasis and obesity in childhood onset craniopharyngioma: A feasibility study
Authors: Hinton Elanor C. , Lithander Fiona E. , Elsworth Rebecca L. , Hawton Katherine , Narayan Kruthika , Szymkowiak Sophie , Bedford Holly L. , Naeem Nimra , Elson Ruth , Taylor-Miller Tashunka , Hamilton-Shield Julian P. , Crowne Elizabeth C. 
Published: January 2023

AbstractIntroductionCraniopharyngiomas are rare brain tumours (incidence 1.1-1.7 cases/million/year). Although benign, craniopharyngioma causes major endocrine and visual morbidities including hypothalamic obesity, yet mechanisms leading to obesity are poorly understood. This study investigated the feasibility and acceptability of eating behaviour measures in patients with craniopharyngioma, to inform the design of future trials.MethodsPatients with childhood-onset craniopharyngioma and controls matched for sex, pubertal stage and age were recruited. After an overnight fast, participants received the following measures: body composition, resting metabolic rate, oral-glucose-tolerance-test including MRI (patients only), appetite ratings, eating behaviour and quality of life questionnaires, ad libitum lunch, and an acceptability questionnaire. Data are reported as median ± IQR, with effect size measure (Cliff’s delta) and Kendall’s Tau for correlations, due to the small sample size.ResultsEleven patients (median age=14yrs; 5F/6M) and matched controls (median age=12yrs; 5F/6M) were recruited. All patients had received surgery and 9/11 also received radiotherapy. Hypothalamic damage post-surgery was graded (Paris grading): grade 2 n=6; grade 1 n=1; grade 0 n=2. The included measures were deemed highly tolerable by participants and their parent/carers. Preliminary data suggests a difference in hyperphagia between patients and controls (d=0.5), and a relationship between hyperphagia with body mass index (BMISDS) in patients (τ=0.46).DiscussionThese findings demonstrate that eating behaviour research is feasible and acceptable to craniopharyngioma patients and there is an association between BMISDS and hyperphagia in patients. Thus, food approach and avoidance behaviours may be useful targets for interventions to manage obesity in this patient group.
ADHD and Autism Spectrum Disorder (ASD) in Childhood: establishing the feasibility and validity of a nation-wide e-cohort
Authors: Langley Kate , Pozo-Banos Marcos Del , Daalsgard Søren , Paranjothy Shantini , Riglin Lucy , John Ann , Thapar Anita 
Published: January 2023

AbstractObjectivesWe investigated the feasibility and validity of establishing a nationwide e-cohort of individuals with a diagnosis of ADHD and/or ASD for future longitudinal research.DesignIndividuals with a childhood diagnosis of ADHD/ASD as recorded on routinely available healthcare datasets were compared with matched controls and a sample of directly assessed individuals with ADHD.SettingThis study utilised data from the Welsh Secure Anonymised Information Linkage (SAIL) Databank in Wales, UK. Routinely collected data from primary care, Emergency Department and hospital admissions were linked at person level.ParticipantsAll individuals in Wales, UK born between 01/01/1991 and 31/12/2000. Individuals with a recorded diagnosis of ADHD and/or ASD by age 18 years were identified using ICD-10 and NHS Read codes and matched to three controls each and 154 individuals with ADHD recruited from an established research study.Outcome measuresRecorded service use for anxiety and depression, alcohol and drug use and self-harm including Emergency Department use in young adulthood (age 16 years to 25).Results7726 individuals had a recorded diagnosis of ADHD (80% male) and 5001 of ASD (79% male); % and 0.9% of the population respectively. Cox’s regression analyses showed ADHD was associated with increased risks of anxiety/depression (HR:2.36, 95% CI:2.20,2.53), self-harm (HR: 5.70, 95% CI:5.07,6.40), alcohol (HR:3.95, 95%CI:3.42,4.56), drug use (HR:5.88, 95%CI:5.08,6.80) and Emergency department service use (HR:1.36, 95%CI:1.31,1.41). Those with ASD were at increased risk of anxiety/depression (HR:2.11, 95%CI: 1.91,2.34), self-harm (HR:2.93, 95%CI: 2.45,3.50) and drug use (HR:2.21, 95%CI: 1.66,2.95) but not alcohol use. The ADHD e-cohort were similar to the directly assessed cohort.ConclusionsOur identification strategy demonstrated the feasibility of establishing a large e-cohort of those with ADHD/ASD with expected patterns of poorer early adult outcomes, demonstrating a valid method of identifying large samples for future longitudinal studies without selective attrition.Article summaryStrengths and limitations of this studyThis study used population wide administrative data from a well-established and comprehensive databankData from both primary and secondary care was combinedThe study utilised a directly assessed sample of those with ADHD to help validate the establishment of the administratively identified sampleNot all individuals had passed through the whole follow up period at the end of the studyStudies utilising administrative data is dependent upon that data having been collected an recorded.
THE ROLE OF KNOWLEDGE AND ATTITUDE ON HIV AND AIDS PREVENTION PRACTICES AMONG SECONDARY SCHOOL STUDENTS: A CROSS-SECTIONAL STUDY OF GWASSI SOUTH SUB-COUNTY, HOMA BAY COUNTY, KENYA
Authors: Akello Kennedy Odhiambo , Ogendi Japheths , Asweto Collins Otieno 
Published: January 2023

ABSTRACTBackgroundHoma Bay County HIV prevalence is the highest and 4.5 times the national prevalence. Young people aged 15-24 years account for 22% of this prevalence in the County. Majority of these young people are high school students, yet their knowledge, attitudes, practices and risk perception towards HIV prevention have not been unascertained. This could be one of the obstacles to HIV prevention in the county.ObjectiveThe study aimed at assessing HIV-related Knowledge, Attitudes and Practices (KAPs) of high school students in Homa Bay County.MethodologySurvey was conducted among 260 systematically sampled students from 11 randomly selected schools in Gwassi South ward, Suba South sub-County, Homa Bay County. A head teacher or health master from each of the 11 schools was purposively sampled and took part in key informants’ interview about available strategies for HIV prevention. Data was analyzed using SPSS version 18.0. Proportion was used to determine knowledge, attitude, and risk perception among the students. Logistic regression was used determine association between knowledge, attitude towards HIV & AIDS and sexual practices.ResultsMajority (64%) of students had moderate to high knowledge on HIV & AIDS and exhibited positive attitude towards HIV & AIDS (61.1%). However, 15% to 25% of students reported to have engaged in a risky sexual practice. Higher to moderate knowledge had increased likelihood of positive attitude towards HIV and AIDS. Similarly, those with higher to moderate knowledge demonstrated lower risk sex practices. Moreover, students with negative attitude towards HIV & AIDS were 4 times more likely to have high risk sex practices. There were HIV & AIDS intervention strategies in secondary schools within Gwassi South Ward.ConclusionKnowledge and attitude of the students play a big role in their HIV risk perception as well as sex practices. Understanding knowledge, attitude, practice and intervention strategies of HIV and AIDS is significant in policy formulation by Ministries of Education, and leads to improved health-related practice by the Ministry of Health and researchers focusing on HIV and AIDS in high burden area.
Is platelet activation a link between metabolic syndrome and cognitive impairment in patients with schizophrenia?
Authors: Okusaga Olaoluwa O. , Vijayan K. Vinod , Rumbaut Rolando E. 
Published: January 2023

AbstractIntroductionSchizophrenia is a severe psychiatric condition associated with cognitive impairment and premature dementia. Furthermore, metabolic syndrome (MetS)—combined central obesity, diabetes, dyslipidemia and hypertension—is highly prevalent in patients with schizophrenia and is believed to contribute to cognitive impairment and premature dementia in patients with schizophrenia. However, the mechanisms by which MetS contributes to cognitive impairment in patients with schizophrenia is unclear. Based on the association of MetS with platelet activation and the ability of activated platelets to impact blood-brain-barrier function, we tested the hypothesis that platelet activation is associated with both MetS and cognitive impairment in two independent pilot samples of patients with schizophrenia.MethodsIn the first pilot sample (sample A) we recruited 13 veterans with either schizophrenia or schizoaffective disorder with MetS (MetS+, n=6), and without MetS (MetS-, n=7). We administered the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) on all 13 veterans and assessed platelet activation using flow cytometry. In the second pilot sample (sample B), we identified 10 non-veteran MetS+ patients with schizophrenia and 10 age-, and sex-matched MetS-patients with schizophrenia from previously collected data on 106 patients enrolled in a non-MetS study. Participants in sample B had data on the NIH Toolbox cognitive battery (NIH Toolbox) and plasma soluble P-selectin (sP-selectin), a marker of platelet activation. We compared flow cytometry platelet activation in MetS+ and MetS- using the Mann Whitney test and the median test to compare sP-selectin and cognitive measures. We also measured the correlation between platelet activation and cognition using Spearman’s rho correlation.ResultsPlatelet activation was significantly higher in MetS+ than MetS- (mean rank 8.60 vs. 3.83, p=0.017). Median score for the picture vocabulary test (language ability) was significantly lower in MetS+ relative to MetS- (82.35 vs. 104, p=0.015). In addition, platelet activation correlated negatively (rho = −0.74, p= 0.009) with the Wechsler Memory Scale: Spatial Span (nonverbal working memory) and plasma sP-selectin correlated negatively (rho = −0.55, p= 0.029) with the List Sorting Working Memory Test.ConclusionOur preliminary findings suggest that platelet activation is involved in the association of MetS with cognitive impairment in patients with schizophrenia. Future studies are needed to elucidate the role of platelets in MetS-related cognitive impairment in patients with schizophrenia.
MANF stimulates autophagy and restores mitochondrial homeostasis to treat toxic proteinopathy
Authors: Kim Yeawon , Li Chuang , Gu Chenjian , Tycksen Eric , Puri Anuradhika , Pietka Terri A. , Sivapackiam Jothilingam , Fang Yili , Kidd Kendrah , Park Sun-Ji , Johnson Bryce G. , Kmoch Stanislav , Duffield Jeremy S. , Bleyer Anthony J. , Jackrel Meredith E. , Urano Fumihiko , Sharma Vijay , Lindahl Maria , Chen Ying Maggie 
Published: January 2023

AbstractMisfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), one of the leading hereditary kidney diseases, and Alzheimer’s disease etc. There are no targeted therapies. ADTKD is also a genetic form of renal fibrosis and chronic kidney disease, which affects 500 million people worldwide. For the first time, in our newly generated mouse model recapitulating human ADTKD-UMODcarrying a leadingUMODdeletion mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are severely impaired, leading to cGAS- STING activation and tubular injury. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a novel endoplasmic reticulum stress-regulated secreted protein. We provide the first study that inducible tubular overexpression of MANF after the onset of disease stimulates autophagy/mitophagy and clearance of the misfolded UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, resulting in protection of kidney function. Conversely, genetic ablation of endogenous MANF upregulated in the mutant mouse and human tubular cells worsens autophagy suppression and kidney fibrosis. Together, we discover MANF as a novel biotherapeutic protein and elucidate previously unknown mechanisms of MANF in regulating organelle homeostasis to treat ADTKD, which may have broad therapeutic application to treat various proteinopathies.
Exosome based multivalent vaccine: achieving potent immunization, broadened reactivity, and strong T cell responses with nanograms of proteins
Authors: Cacciottolo Mafalda , Nice Justin B , Li Yujia , LeClaire Michael J. , Twaddle Ryan , Mora Ciana , Adachi Stephanie Y. , Chin Esther R. , Young Meredith , Angeles Jenna , Elliott Kristi , Sun Minghao 
Published: January 2023

ABSTRACTCurrent approved vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have focused solely on the spike protein to provide immunity. The first vaccines were developed rapidly using spike mRNA delivered by lipid nanoparticles but required ultra-low storage and have had limited immunity against variations in spike. Subsequently, protein-based vaccines were developed which offer broader immunity but require significant time for development and use of an adjuvant to boost immune response. Here, exosomes were used to deliver a bi-valent protein-based vaccine, in which two independent viral proteins were used. Exosomes were engineered to express either SARS-CoV-2 Delta spike (Stealth X-Spike, STX-S) or the more conserved nucleocapsid (Stealth X-Nucleocapsid, STX-N) protein on the surface. When administered as single product (STX-S or STX-N) or in combination (STX-S+N), both STX-S and STX-N induced a strong immunization with the production of a potent humoral and cellular immune response. Interestingly, these results were obtained with administration of only nanograms of protein and without adjuvant. In two independent animal models (mouse and rabbit), administration of nanograms of the STX-S+N vaccine resulted in increased antibody production, potent neutralizing antibodies with cross-reactivity to other variants of spike and strong T-cell responses. Importantly, no competition in immune response was observed, allowing for delivery of nucleocapsid with spike to offer improved SARS-CoV-2 immunity. These data show that the StealthXTMexosome platform has an enormous potential to revolutionize vaccinology by combining the advantages of mRNA and recombinant protein vaccines into a superior, rapidly generated, low dose vaccine resulting in potent, broader immunity.