bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring the genetic heterogeneity of Alzheimer’s disease: Evidence for genetic subtypes
Authors: Elman Jeremy A. , Schork Nicholas J. , Rangan Aaditya V. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: May 2023

ABSTRACTBackgroundAlzheimer’s disease (AD) exhibits considerable phenotypic heterogeneity, suggesting the potential existence of subtypes. AD is under substantial genetic influence, thus identifying systematic variation in genetic risk may provide insights into disease origins.ObjectiveWe investigated genetic heterogeneity in AD risk through a multi-step analysis.MethodsWe performed principal component analysis (PCA) on AD-associated variants in the UK Biobank (AD cases=2,739, controls=5,478) to assess structured genetic heterogeneity. Subsequently, a biclustering algorithm searched for distinct disease-specific genetic signatures among subsets of cases. Replication tests were conducted using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset (AD cases=500, controls=470). We categorized a separate set of ADNI individuals with mild cognitive impairment (MCI; n=399) into genetic subtypes and examined cognitive, amyloid, and tau trajectories.ResultsPCA revealed three distinct clusters (‘constellations’) driven primarily by different correlation patterns in a region of strong LD surrounding theMAPTlocus. Constellations contained a mixture of cases and controls, reflecting disease-relevant but not disease-specific structure. We found two disease-specific biclusters among AD cases. Pathway analysis linked bicluster-associated variants to neuron morphogenesis and outgrowth. Disease-relevant and disease-specific structure replicated in ADNI, and bicluster 2 exhibited increased CSF p-tau and cognitive decline over time.ConclusionsThis study unveils a hierarchical structure of AD genetic risk. Disease-relevant constellations may represent haplotype structure that does not increase risk directly but may alter the relative importance of other genetic risk factors. Biclusters may represent distinct AD genetic subtypes. This structure is replicable and relates to differential pathological accumulation and cognitive decline over time.
Human norovirus (HuNoV) GII RNA in wastewater solids at 145 United States wastewater treatment plants: Comparison to positivity rates of clinical specimens and modeled estimates of HuNoV GII shedders
Authors: Boehm Alexandria B. , Wolfe Marlene K. , White Bradley , Hughes Bridgette , Duong Dorothea , Banaei Niaz , Bidwell Amanda 
Published: May 2023

AbstractBackgroundHuman norovirus (HuNoV) is a leading cause of disease globally, yet actual incidence is unknown. HuNoV infections are not reportable in the United States, and surveillance is limited to tracking severe illnesses or outbreaks. Wastewater monitoring for HuNoV has been done previously and results indicate it is present in wastewater influent and concentrations are associated with HuNoV infections in the communities contributing to wastewater. However, work has mostly been limited to monthly samples of liquid wastewater at one or a few wastewater treatment plants (WWTPs).ObjectiveThe objectives of this study are to investigate whether HuNoV GII preferentially adsorbs to wastewater solids, investigate concentrations of HuNoV GII in wastewater solids in wastewater treatment plants across the county, and explore how those relate to clinical measures of disease occurrence. In addition, we aim to develop and apply a mass-balance model that predicts the fraction of individuals shedding HuNoV in their stool based on measured concentrations in wastewater solids.MethodsWe measured HuNoV GII RNA in matched wastewater solids and liquid influent in 7 samples from a WWTP. We also applied the HuNoV GII assay to measure viral RNA in over 6000 wastewater solids samples from 145 WWTPs from across the United States daily to three times per week for up to five months. Measurements were made using digital droplet RT-PCR.ResultsHuNoV GII RNA preferentially adsorbs to wastewater solids where it is present at 1000 times the concentration in influent. Concentrations of HuNoV GII RNA correlate positively with clinical HuNoV positivity rates. Model output of the fraction of individuals shedding HuNoV is variable and uncertain, but consistent with indirect estimates of symptomatic HuNoV infections in the United States.SignificanceThese findings support the utility of wastewater solids as a matrix for community infectious disease surveillance.Impact StatementIllness caused by HuNoV is not reportable in the United States so there is limited data on disease occurrence. Wastewater monitoring can provide information about the community spread of HuNoV. Data from wastewater can be available within 24 hours of sample receipt at a laboratory. Wastewater is agnostic to whether individuals seek medical care, are symptomatic, and the severity of illness. Knowledge gleaned from wastewater may be used by public health professionals to make recommendations on hand washing, surface disinfection, or other behaviors to reduce transmission of HuNoV, or medical doctors to inform clinical decision making.
The pleiotropic contribution of genes in dopaminergic and serotonergic pathways to addiction, aggression, and related behavioural traits
Authors: Antón-Galindo Ester , Cabana-Domínguez Judit , Torrico Bàrbara , Corominas Roser , Cormand Bru , Fernàndez-Castillo Noèlia 
Published: May 2023

ABSTRACTCo-occurrence of substance use disorders (SUD) and aggressive behaviour in the same individual has been frequently described. As dopamine (DA) and serotonin (5-HT) are key neurotransmitters for both phenotypes, we explored the genetic contribution of these pathways to SUD, aggressive behaviour and related behavioural traits. Here, we tested the association of 275 dopaminergic genes and 176 serotonergic genes with these phenotypes by performing gene-based, gene-set and transcriptome-wide association studies (TWAS) in 11 genome-wide association studies (GWAS) datasets on SUD (alcohol, cocaine, cannabis, opioids and a multivariate analysis of three drugs of abuse), aggressive behaviour (disruptive behaviour and antisocial behaviour) and related behaviours (irritability, neuroticism, risk taking and anxiety). At the gene-wide level, 68 DA and 27 5-HT genes were found to be associated with at least one GWAS on SUD or related behaviour. Among them, six genes had a pleiotropic effect, being associated with at least three phenotypes:ADH1C, ARNTL, CHRNA3, HPRT1, HTR1BandDRD2, the latter with five. Additionally, we found nominal associations between the DA gene sets and antisocial behaviour, opioid use disorder, SUD, irritability and neuroticism, and between the 5-HT-core gene set and neuroticism. Gene expression correlates in brain were also found for 19 genes, highlighting the association forCHRNA3andCELSR3with OUD, SUD and irritability andCELSR3also with neuroticism. Our study shows a pleiotropic contribution of dopaminergic and serotonergic genes to addiction, aggression and related behaviours, highlighting a special role for DA genes, which could explain, in part, the co-occurrence of these phenotypes.
Major UK non-commercial sponsors’ efforts to reduce research waste: a mixed methods study
Authors: Bruckner Till , Schuster Aminul , Chavarría Belén , Cruz Carolina , Lizárraga Karely , Borana Ronak , Bvute Tungamirai Ishe , Sánchez Daniel 
Published: May 2023

ABSTRACTThis study provides a snapshot of the scale of legacy research waste in the UK. It assesses the current publication status of 145 clinical trials sponsored by ten major UK non-commercial sponsors that were completed or terminated in 2017. Following outreach to sponsors and short-term follow-up, 116/145 trials (80%) had fully reported results, and 11/145 trials (8%) had reported results in the grey literature. Results for 18/145 trials (12%) that enrolled 637 people remained completely unpublished as of early March 2023. Sponsors indicated that they plan to make public the results of 14/18 unreported trials. Our study had an impact on accelerating the reporting of some results, and seems likely to lead to future reductions in research waste. We propose three changes to UK Health Research Authority policies that could improve clinical trial reporting.
Risk factors for acne scarring in Ecuador
Authors: Camacho Mikaela , Viteri María Isabel , Yepez Paola , Porter Jorge Estrella , Belhadi Drifa , Barnes Caroline , Guillemot Jonathan 
Published: May 2023

AbstractBackgroundAcne is a common disease that causes a large global disease burden. The Global Burden of Skin Disease reported that in 188 countries the burden from acne as measured by disability-adjusted life years (DALYs), years lived with disability and years of life lost is greatest in Western Europe, high-income North America and Southern Latin America. This paper aims to identify risk factors for acne scarring specific to the Ecuadorian population in order to adapt the 4-ASRAT tool accordingly.MethodsThis was an observational prospective study. Participants were recruited to complete a survey that was developed based on the potential risk factors for acne scarring and had facial photographs taken. To determine risk factors and their respective weighting, a logistic regression was performed.ResultsThe study included 404 participants. Results from univariate analyses indicated that male sex (OR=2.76 95%CI [1.72; 4.43]), severe or very severe acne scarring (OR=4.28 95%CI [1.24; 14.79]), acne duration over 1 year (OR=1.71 95%CI [1.12; 2.60]), oily skin (OR=2.02 95%CI [1.27; 3.22]) and the presence of acne on the neck (OR=2.26 95%CI [1.30; 3.92]), were all significantly associated with the presence of acne scarring. Male sex (2.56 95%CI [1.58;4.17]), oily skin (1.96 95%CI [1.20;3.20]) and severe or very severe acne (3.75 95%CI [1.05;13.37]) remained significant risk factors for acne scarring in the multivariate analysis.ConclusionBy identifying acne scarring risk factors and applying the tool in everyday dermatology visits, we can reduce the physical and psychological burden that acne scarring causes in the adolescent and adult population. Further research should be performed to reassess potential risk factors and complete the adaptation of the tool for the Ecuadorian population, with a larger and more representative study population.
COVID-19 Infection Is Associated with Poor Outcomes in Patients with Intracerebral Hemorrhage
Authors: Renedo Daniela , Leasure Audrey C. , Young Rebecca , Rivier Cyprien , Alhanti Brooke , Mac Grory Brian , Messe Steven R. , Reeves Matthew , Hassan Ameer E. , Schwamm Lee , De Havenon Adam , Matouk Charles C. , Sheth Kevin N. , Falcone Guido J. 
Published: May 2023

ABSTRACTBackgroundPatients with ischemic stroke and concomitant coronavirus 2019 (COVID-19) infection have worse outcomes than those without this infection. However, research on the impact of COVID-19 infection on outcomes following hemorrhagic stroke remains limited. We aim to study whether concomitant COVID-19 infection leads to worse outcomes in spontaneous intracerebral hemorrhage (ICH).DesignWe conducted an observational study using data from Get With The Guidelines® Stroke, an ongoing, multi-center, nationwide quality assurance registry.MethodsWe implemented a two-stage design: first, we compared outcomes of ICH patients with and without COVID-19 infection admitted during the pandemic (from March 2020 to February 2021). Second, we compared the same outcomes between ICH patients admitted before (March 2019 to February 2020) and during (March 2020 and February 2021) the pandemic. Main outcomes were poor functional outcome (defined as a modified Rankin Scale of 4 to 6 [mRS] at discharge), mortality and discharge to skilled nursing facility (SNF) or hospice.ResultsThe first stage included 60,091 COVID-19-negative and 1,326 COVID-19-positive ICH patients. In multivariable analyses, ICH patients with versus without COVID-19 infection had 68% higher odds of poor outcome (OR 1.68, 95%CI 1.41-2.01), 51% higher odds of mortality (OR 1.51, CI 1.33-1.71) and 66% higher odds of being discharged to a SNF/hospice (OR 1.66, 95%CI 1.43-1.93). The second stage included 62,743 pre-pandemic and 64,681 intra-pandemic ICH cases. In multivariable analyses, ICH patients admitted during versus before the COVID-19 pandemic had a 10% higher odds of poor outcome (OR 1.10, 95%CI 1.07-1.14), 5% higher mortality (OR 1.05, 95%CI 1.02-1.08) and no significant difference in the risk of being discharged to SNF/hospice (OR 0.93, 95%CI 0.90-0.95).ConclusionsThe pathophysiology of the COVID-19 infection and changes in healthcare delivery during the pandemic played a role in worsening outcomes in this patient population. Further research is needed to identify these factors and understand their effect on the long-term outcome.
Interface-acting nucleotide controls polymerization dynamics at microtubule plus- and minus-ends
Authors: McCormick Lauren A , Cleary Joseph M , Hancock William O , Rice Luke M 
Published: May 2023

AbstractGTP-tubulin is preferentially incorporated at growing microtubule ends, but the biochemical mechanism by which the bound nucleotide regulates the strength of tubulin:tubulin interactions is debated. The ‘self-acting’ (cis) model posits that the nucleotide (GTP or GDP) bound to a particular tubulin dictates how strongly that tubulin interacts, whereas the ‘interface-acting’ (trans) model posits that the nucleotide at the interface of two tubulin dimers is the determinant. We identified a testable difference between these mechanisms using mixed nucleotide simulations of microtubule elongation: with self-acting nucleotide, plus- and minus-end growth rates decreased in the same proportion to the amount of GDP-tubulin, whereas with interface-acting nucleotide, plus-end growth rates decreased disproportionately. We then experimentally measured plus- and minus-end elongation rates in mixed nucleotides and observed a disproportionate effect of GDP-tubulin on plus-end growth rates. Simulations of microtubule growth were consistent with GDP-tubulin binding at and ‘poisoning’ plus-ends but not at minus-ends. Quantitative agreement between simulations and experiments required nucleotide exchange at terminal plus-end subunits to mitigate the poisoning effect of GDP-tubulin there. Our results indicate that the interfacial nucleotide determines tubulin:tubulin interaction strength, thereby settling a longstanding debate over the effect of nucleotide state on microtubule dynamics.
Computational insights into the conformational transition of STING: mechanistic, energetic considerations, and the influence of crucial mutations
Authors: Li Zhenlu , Yue Congran , Xie Shangqiang , Shi Sai , Ye Sheng 
Published: May 2023

AbstractSTING (stimulator of interferon genes) is a crucial protein in the innate immune system’s response to viral and bacterial infections. In this study, we investigated the mechanistic and energetic mechanism of the conformational transition process of STING activated by cGAMP binding. We found that the STING connector region undergoes an energetically unfavorable transition during this process, which is compensated by the favorable interaction between cGAMP and the STING ligand binding domain. We utilized enhanced sampling methods to study STING’s rotation and finds that several disease-causing mutations, such as N154S and V155L, can result in a smoother transition process, while V147L exhibits unfavorable conformational transition energy. These findings indicate that V147L may not be a gain-of-function mutation, as previously thought, and are further supported by an evolutionary analysis of the STING connector region. Overall, our study provides detailed insights into the mechanism of STING’s rotation and has implications for the development of treatments for STING-related diseases.
Spatio-temporal patterns of ovarian development andVgRgene silencing reduced fecundity of parthenogeneticArtemia
Authors: Duan Hu , Shao Xuanxuan , Liu Wei , Xiang Jianhai , Pan Namin , Wang Xuehui , Du Guoru , Li Ying , Zhou Jiaping , Sui Liying 
Published: May 2023

ABSTRACTHalophilic zooplankton brine shrimpArtemiahas been used as an experimental animal in multidisciplinary research. However, the reproductive patterns and regulation mechanisms ofArtemiaremain a mystery. In this study, the ovarian development process of parthenogeneticArtemia(P.Artemia) was distinguished into five stages, and oogenesis or egg formation process was identified with six phases. The mode of oogenesis was assumed polytrophic. Moreover, we traced the dynamic translocation of germline stem cells (GSCs) by EdU labeling, elucidated several key cytological events in oogenesis through HE staining and florescent image. Notably, distinguished from the ovary structure of insects and crustaceans, P.Artemiagermarium originated from ovariole buds and located in the base of the ovarioles. RNA-seq based on five stages of ovarian development revealed that 2657 up-regulated genes related to reproduction were obtained by pair-to-pair comparison of RNA-seq. Furthermore,Gbb, Dpp, piwi, vasa, nanos, VgAandVgRassociated with GSCs recognition and reproductive development genes were screened and also verified by qPCR. Silencing of theVgRgene in P.Artemia(PA-VgR) at stage L of ovarian development led to a low level of gene expression (<10%) within five days, which resulted variations of oogenesis-related gene expression and significantly inhibited vitellogenesis, impeded oocyte maturation, and eventually decreased the offspring number. In conclusion, we illustrated the patterns of ovarian development, outlined the key spatio-temporal features of oogenesis and established a platform for gene function research using P.Artemiaas an experimental animal. These results lay the foundation for studying the reproductive biology of invertebrates, may also provide a novel insight in the reproductive regulation mechanism of aquatic animals in extreme environments.SUMMARY STATEMENTArtemia is a novel experimental platform and potential “model” crustacean for studying specific process and mechanism of reproduction.
DRUM-PD/HD: The Impact of a Pilot Group Drum-Based Music Therapy Intervention on Quality of Life and Motor Symptoms in Parkinson Disease and Huntington Disease
Authors: Wainwright Lavinia , Kang Kyurim , Dayanim Gabriel , Bedell Chris , Devlin Kerry , Lanham Diane , Suarez-Cedeno Gerson , Baker Jason Armstrong , Bastepe-Gray Serap , Bang Jee , Pantelyat Alexander 
Published: May 2023

AbstractRhythm-based therapeutic interventions have widely been used in patients with neurologic disorders to address motor and quality of life outcomes. Although group drumming has been explored in several pilot studies of patients with Parkinson disease (PD) and Huntington disease (HD), caregiver burden and their quality-of-life outcomes have received less attention. Therefore, we aimed to evaluate the impact of group drumming on quality of life and motor symptoms in PD and HD patients as well as their caregivers. A total of 17 participants (PD = 6, caregivers of PD = 6, HD = 3, caregivers of HD = 2) attended the 60-minute drum-based group music therapy intervention twice a week for 12 weeks. Participants were assigned to two drumming intervention groups based on their diagnosis:1) patients diagnosed with PD and their study partners, 2) patients diagnosed with HD and their study partners. In group drumming sessions, both patients and caregiver participants utilized a variety of percussion instruments based on their personal preferences or physical abilities to facilitate movement skills and group cohesion. They were asked to complete questionnaires about quality of life and motor functioning at baseline, 6 weeks, 12 weeks, and 18 weeks (6 weeks post-intervention completion). Caregivers burden scores were also collected at these time points. Furthermore, all participants completed simple exit interview questionnaires in their follow-up visit. The PD participants and their caregivers showed an opposite trend in social role satisfaction. From baseline to 6 weeks, there were significant differences in social role satisfaction between PD participants and PD caregivers where PD participants reported a decrease in social satisfaction (Mean= -2.30,Standard Deviation= 1.64) while PD caregivers experienced an increase (M= 3.80,SD= 3.08),p= .02. In contrast, a different pattern was shown from 12 weeks to 18 weeks, where PD participants showed an increase in social satisfaction (M= 2.53,SD= 1.29), while PD caregivers demonstrated a decrease in social satisfaction (M= -2.10,SD= 3.35),p=.03. Drumming in a group setting may serve as an effective tool to enhance movement and promote social cohesion through rhythmic auditory-motor entrainment, thereby supporting quality of life in PD; further studies in HD are indicated as well.
THE IMPACT OF THE COVID-19 PANDEMIC ON NON-COVID-19 COMMUNITY-ACQUIRED PNEUMONIA, A RETROSPECTIVE COHORT STUDY
Authors: Lee Terry , Walley Keith R. , Boyd John H. , Cawcutt Kelly A. , Kalil Andre C. , Russell James A. 
Published: May 2023

ABSTRACTBACKGROUNDThe COVID-19 pandemic could impact frequency and mortality of non-COVID-19 community-acquired pneumonia (CAP). Changes in frequency, patient mix, treatment, and organ dysfunction could cascade together to increase mortality of CAP during compared to pre-COVID-19.METHODSHospitalized CAP patients at St. Paul’s Hospital, Vancouver, Canada pre- (fiscal years 2018/2019 and 2019/2020) and during COVID-19 pandemic (2020/2021 and 2021/2022) were evaluated.RESULTSIn 5219 CAP patients, there was no significant difference pre-versus during pandemic in mean age, gender and Charlson co-morbidity score. However, hospital mortality increased significantly from pre-versus during COVID-19 (7.5% versus 12.1% respectively, [95% CI for difference: 3.0-6.3%], p<0.001), a 61% relative increase, coincident with increases in ICU admission (18.3% versus 25.5% respectively, [95% CI for difference: 5.0-9.5%] p<0.001, 39% relative increase) and ventilation (12.7% versus 17.5%, respectively, [95% CI for difference: 2.8-6.7%] p<0.001, 38% relative increase). Results remained the same after regression adjustment for confounders. CAP hospital admissions decreased 27% from pre- (n=1349 and 1433, 2018/2019 and 2019/2020 respectively) versus the first COVID-19 pandemic year (n=1047 in 2020/2021) then rose to pre-pandemic number (n=1390 in 2021/2022). During pre-pandemic years, CAP admissions peaked in winter; during COVID-19, the CAP admissions peaked every six months.CONCLUSIONS AND RELEVANCEThe COVID-19 pandemic was associated with increases in hospital mortality, ICU admission and invasive mechanical ventilation rates of non-COVID-19 CAP and a transient, one year frequency decrease. There was no winter seasonality of CAP during the COVID-19 pandemic era. Future pandemic planning for CAP hospital care is needed.What is already known on this topicThe COVID-19 pandemic could impact frequency and mortality of non-COVID-19 community-acquired pneumonia (CAP). No prior study has examined this hypothesis.What this study addsThe COVID-19 pandemic was associated with increases in hospital mortality, ICU admission and invasive mechanical ventilation rates of non-COVID-19 CAP and a transient, one year frequency decrease. There was no winter seasonality of CAP during the COVID-19 pandemic era.How this study might affect research, practice or policyFuture pandemic planning for CAP hospital care is needed.