bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ethnic differences in receipt of psychological interventions in Early Intervention in Psychosis services in England: a cross-sectional study
Authors: Schlief Merle , Rich Nathalie , Rains Luke Sheridan , Baldwin Helen , Rojas-Garcia Antonio , Nyikavaranda Patrick , Persaud Karen , Dare Ceri , French Paul , Lloyd-Evans Brynmor , Crawford Mike , Smith Jo , Kirkbride James B. , Johnson Sonia 
Published: March 2023

AbstractBackgroundThere is some evidence of inequitable psychosis care provision by ethnicity. We investigated variations in the receipt of CBTp and family intervention across ethnic groups in Early Intervention in Psychosis (EIP) teams throughout England, where national policy mandates offering these interventions to all.MethodsWe included data on 29,610 service users from the National Clinical Audit of Psychosis (NCAP), collected between 2018 and 2021. We conducted mixed effects logistic regression to examine odds ratios of receiving an intervention (CBTp, family intervention, or either intervention) across 17 ethnic groups while accounting for the effect of years and variance between teams and adjusting for individual- (age, gender, occupational status) and team-level covariates (care-coordinator caseload and mental health inequalities strategies).FindingsCompared with White British people, every minoritized ethnic group, except those of mixed Asian-White and mixed Black African-White ethnicities, had lower adjusted odds of receiving CBTp (aOR 0·39, 95%CI 0·32-0·47 to 0·80, 0·64-1·00). People of Black African (0·61, 0·53-0·69), Black Caribbean (0·67, 0·56-0·81), non-African/Caribbean Black (0·63, 0·51-0·79), non-British/Irish White (0·73, 0·64-0·84), and of “any other” (0·66, 0·54-0·81) ethnicity also experienced lower adjusted odds of receiving family intervention.InterpretationPervasive inequalities in receiving CBTp for first episode psychosis exist for almost all minoritized ethnic groups, and family intervention for many groups. Investigating how these inequalities arise should be a research priority, allowing co-produced development and testing of approaches to address them.FundingIndependent research commissioned and funded by the National Institute for Health Research Policy Research Programme.
A genomic perspective on the near-term impact of doxycycline post-exposure prophylaxis onNeisseria gonorrhoeaeantimicrobial resistance
Authors: Mortimer Tatum D. , Grad Yonatan H. 
Published: March 2023

AbstractPost-exposure prophylaxis with doxycycline (doxyPEP) is being introduced to prevent bacterial sexually transmitted infections (STIs). Pre-existing tetracycline resistance inNeisseria gonorrhoeaelimits doxyPEP effectiveness against gonorrhea, and selection for tetracycline resistant lineages may influence prevalence of resistance to other antimicrobials via selection for multi-drug resistant strains. Using genomic and antimicrobial susceptibility data from 5,644 clinical isolates ofN. gonorrhoeae, we assessed the near-term impact of doxyPEP onN. gonorrhoeaeantimicrobial resistance. We found that the impact on antimicrobial resistance is likely to be influenced by the strength of selection for plasmid-encoded and chromosomally-encoded tetracycline resistance, as isolates with high-level, plasmid-encoded resistance had lower minimum inhibitory concentrations to other antimicrobials compared to isolates with low-level tetracycline resistance. The impact of doxyPEP may differ across demographic groups and geographic regions within the United States due to variation in pre-existing tetracycline resistance.
Transcriptomic profiling of lymphocytic colitis highlights distinct diarrhoeal pathomechanisms
Authors: Bhardwaj Archana , Münch Andreas , Montague Julia , Koch Stefan , Rosenstiel Philip , Escudero-Hernández Celia 
Published: March 2023

ABSTRACTBackground and AimsThe pathobiology of the non-destructive inflammatory bowel disease (IBD) lymphocytic colitis (LC) is poorly understood. Our aim was to define a LC-specific transcriptome to gain insight into LC pathology, identify genetic signatures uniquely linked to LC, and uncover potentially druggable disease pathways.MethodsWe performed whole mucosa bulk RNA-sequencing of LC and CC samples from patients with active disease, and healthy controls (n=4-10 per cohort). Differential gene expression was analyzed by gene-set enrichment and deconvolution analyses to identify pathologically relevant pathways and cells, respectively, altered in LC. Key findings were validated using reverse transcription quantitative PCR and/or immunohistochemistry. Finally, we compared our sequencing data to a previous cohort of ulcerative colitis and Crohn’s disease patients (n=4 per group) to distinguish non-destructive from classic IBD.ResultsThe LC-specific transcriptome was defined by a limited mucosal immune response against microbiota compared to CC and classic IBD samples. In contrast, we noted a distinct induction of regulatory non-coding RNA species in LC samples. Moreover, compared to CC, we observed decreased water channel and cell adhesion molecule gene expression, which was associated with reduced intestinal epithelial cell proliferation.ConclusionsWe conclude that LC is a pathomechanistically distinct disease that is characterized by a dampened immune response despite massive mucosal immune cell infiltration. Our results point to regulatory micro-RNAs as a potential disease-specific feature that may be amenable to therapeutic intervention.
The effect ofM. tuberculosislineage on clinical phenotype
Authors: Du Duc Hong , Geskus Ronald B , Zhao Yanlin , Codecasa Luigi Ruffo , Cirillo Daniela Maria , van Crevel Reinout , Pascapurnama Dyshelly Nurkartika , Chaidir Lidya , Niemann Stefan , Diel Roland , Omar Shaheed Vally , Grandjean Louis , Rokadiya Sakib , Ortitz Arturo Torres , Lân Nguyễn Hữu , Minh Hà Đặng Thị , Smith E. Grace , Robinson Esther , Dedicoat Martin , Hoang Nhat Le Thanh , Thwaites Guy E , Van Le Hong , Thuong Thuong Nguyen Thuy , Walker Timothy M 
Published: March 2023

AbstractEight lineages ofMycobacterium tuberculosis sensu strictoare described. Single-country or small observational data suggest differences in clinical phenotype between lineages. We present strain lineage and clinical phenotype data from 12,246 patients from 3 low-incidence and 5 high-incidence countries. We used multivariable logistic regression to explore the effect of lineage on site of disease and on cavities on chest radiography, given pulmonary TB; multivariable multinomial logistic regression to investigate types of extra-pulmonary TB, given lineage; and accelerated failure time and Cox proportional-hazards models to explore the effect of lineage on time to smear and culture-conversion. Mediation analyses quantified the direct effects of lineage on outcomes. Pulmonary disease was more likely among patients with lineage(L) 2, L3 or L4, than L1 (adjusted odds ratio (aOR) 1.79, (95% confidence interval 1.49-2.15), p<0.001; aOR=1.40(1.09-1.79), p=0.007; aOR=2.04(1.65-2.53), p<0.001, respectively). Among patients with pulmonary TB, those with L1 had greater risk of cavities on chest radiography versus those with L2 (aOR=0.69(0.57-0.83), p<0.001) and L4 strains (aOR=0.73(0.59-0.90), p=0.002). L1 strains were more likely to cause osteomyelitis among patients with extra-pulmonary TB, versus L2-4 (p=0.033, p=0.008 and p=0.049 respectively). Patients with L1 strains showed shorter time-to-sputum smear conversion than for L2. Causal mediation analysis showed the effect of lineage in each case was largely direct. The pattern of clinical phenotypes seen with L1 strains differed from modern lineages (L2-4). This has implications for clinical management and could influence clinical trial selection strategies.
Novel kinetoplastid-specific cAMP binding proteins identified by RNAi screening for cAMP resistance inT. brucei
Authors: Bachmaier Sabine , Gould Matthew K. , Polatoglou Eleni , Omelianczyk Radoslaw , Brennand Ana E. , Aloraini Maha A. , Munday Jane C. , Horn David , Boshart Michael , de Koning Harry P. 
Published: March 2023

AbstractCyclic AMP signalling in trypanosomes differs from most eukaryotes due to absence of known cAMP effectors and cAMP independence of PKA. We have previously identified four genes from a genome-wide RNAi screen for resistance to the cAMP phosphodiesterase (PDE) inhibitor NPD-001. The genes were named cAMP Response Protein (CARP) 1 through 4. Here, we report an additional six CARP candidate genes from the original sample, after deep sequencing of the RNA interference target pool retrieved after NPD-001 selection (RIT-seq). The resistance phenotypes were confirmed by targeted RNAi knockdown and highest level of resistance to NPD-001, approximately 17-fold, was seen for knockdown of CARP7 (Tb927.7.4510). CARP1 and CARP11 contain predicted cyclic AMP binding domains and bind cAMP as evidenced by capture and competition on immobilised cAMP. CARP orthologues are strongly enriched in kinetoplastid species, and CARP3 and CARP11 are unique toTrypanosoma. Localization data and/or domain architecture of all CARPs predict association with theT. bruceiflagellum. This suggests a crucial role of cAMP in flagellar function, in line with the cell division phenotype caused by high cAMP and the known role of the flagellum for cytokinesis. The CARP collection is a resource for discovery of unusual cAMP pathways and flagellar biology.ImportanceTrypanosomes are major pathogens of humans and livestock. In addition they have been invaluable as a model system to investigate new biological systems, and not just of protozoa. Equally, they are known to have a lot of unique biology and biochemistry. One example of this is signal transduction by cyclic nucleotides. Some elements, including phosphodiesterases and the catalytic domains of its dozens of adenylate cyclase isoforms, are highly conserved, while the absence of G-proteins, a cAMP-responsive protein kinase A and other known effector types suggests a unique cAMP-dependent pathway, which as yet is mostly uncharacterised. Here, we identify a set of tenTrypanosoma bruceiproteins, all localised to its flagellum, that appear to be involved in the production of cAMP, or in mediating its cellular effects. These cAMP Response Proteins (CARPs) were mostly unique to trypanosomes, suggesting a completely novel pathway. Two of the CARPs were shown to bind cAMP and were found to possess structurally conserved cyclic nucleotide binding domains.
Changes in morbimortality patterns due to heart failure in patients of the Unified Health System and their economic impacts: a challenge for Public Health management
Authors: Lins Matheus Manoel Diogo , Borges Vivian Fernandes Alves 
Published: March 2023

AbstractA descriptive ecological study was conducted to form a profile of morbimortality due to cardiac care in the Brazilian population based on patients registered in the Department of Informatics of the Unified Health System (DATASUS). The results of the article show that, during the studied period, 2,984,424 patients were hospitalized due to cardiac care, predominantly represented by males, with the age group predominating in elderly individuals between 70 and 79 years old, of white ethnicity, and with a character of emergency care. The average hospitalization cost was estimated at R$ 1,371.67, generating an annual cost to the Brazilian economy of R$ 341,137,000.SummaryBackgroundHeart failure (HF) is a complex syndrome considered the common endpoint of various cardiovascular diseases, and due to its high prevalence, it is necessary to understand its morbidity and mortality profile.ObjectiveTo describe the morbidity and mortality profile of HF among patients registered in the Department of Informatics of the Unified Health System (DATASUS) and its impact on public health between 2008 and 2020.Materials and MethodsA descriptive epidemiological study was conducted using data obtained from the TABNET application developed by DATASUS. Patients of both sexes, without age restrictions, who were hospitalized with a confirmed diagnosis of HF in Brazil, from January 2008 to December 2020 were included. Data were stratified by sex, age group, self-reported ethnicity/race, type of healthcare plan, and nature of care.ResultsDuring the study period, 2,984,424 patients were hospitalized due to HF in the SUS. The majority were male: 1,533,469 (51.38%); elderly with the predominant age group between 70 and 79 years: 788,367 (26.41%); of white ethnicity: 1,102,860 (36.95%); private healthcare plan: 1,196,559 (46.10%), and with emergency care character: 2,827,354 (94.73%). The average hospitalization cost was estimated at R$ 1,371.67, generating an annual cost to the Brazilian economy of R$ 341,137,000.ConclusionsHeart failure is an important public health problem, causing not only high morbidity in affected individuals but also a significant financial burden on the Unified Health System (SUS).
Pre-pandemic inequalities in the burden of disease: a Scottish Burden of Disease study
Authors: Grant Ian , Chalmers Neil , Fletcher Eilidh , Lakha Fatim , McCartney Gerry , Stockton Diane , Wyper Grant 
Published: March 2023

AbstractBackgroundHealth inequalities in Scotland are well documented, including the contribution of different causes to inequalities in mortality. Our aim was to estimate inequalities within a burden of disease framework, accounting for both premature mortality and the effects of morbidity, to understand the contribution of specific diseases to health inequalities prior to the COVID-19 pandemic.MethodsDisability Adjusted Life Years (DALYs) for 70 individual causes of disease and injury were sourced from the Scottish Burden of Disease Study. Area-level deprivation was measured using the Scottish Index of Multiple Deprivation. Inequalities were measured by the range, Relative Index of Inequality, Slope Index of Inequality, and attributable DALYs were estimated by using the least deprived decile as a reference.ResultsThe overall disease burden was double that in the most deprived areas (50,305 vs 20,955 DALYS per 100, 000), largely driven by inequalities in premature mortality. The rate in the most deprived decile was around 48% higher than the mean population rate (RII = 0.96), with 35% of DALYs attributed to differences in area-based deprivation. Many leading causes of disease burden in 2019 – heart disease, drug use disorders, lung cancer and COPD – were also the leading drivers of absolute and relative inequalities in the disease burden.ConclusionOur study evidences the extent of the stark levels of absolute and relative inequality prior to the COVID-19 pandemic. Given pre-pandemic stalling of mortality trend improvements and widening health inequalities, and the exacerbation of these caused by COVID-19, urgent policy attention is required to address this.
Alpha globin gene copy number and incident ischemic stroke risk among Black Americans
Authors: Ruhl A. Parker , Jeffries Neal , Yang Yu , Brooks Steven D. , Naik Rakhi P. , Pecker Lydia H. , Mott Bryan T. , Winkler Cheryl A. , Armstrong Nicole D. , Zakai Neil A. , Gutierrez Orlando M. , Judd Suzanne E. , Howard Virginia J. , Howard George , Irvin Marguerite R. , Cushman Mary , Ackerman Hans C. 
Published: March 2023

ABSTRACTIntroductionPeople with African ancestry have greater stroke risk and greater heritability of stroke risk than people of other ancestries. Given the importance of nitric oxide (NO) in stroke, and recent evidence that alpha globin restricts nitric oxide release from vascular endothelial cells, we hypothesized that alpha globin gene (HBA)deletion would be associated with reduced risk of incident ischemic stroke.MethodsWe evaluated 8,947 participants self-reporting African ancestry in the national, prospective Reasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. Incident ischemic stroke was defined as non-hemorrhagic stroke with focal neurological deficit lasting ≥ 24 hours confirmed by the medical record or focal or non-focal neurological deficit with positive imaging confirmed with medical records. Genomic DNA was analyzed using droplet digital PCR to determineHBAcopy number. Multivariable Cox proportional hazards regression was used to estimate the hazard ratio (HR) ofHBAcopy number on time to first ischemic stroke.ResultsFour-hundred seventy-nine (5.3%) participants had an incident ischemic stroke over a median (IQR) of 11.0 (5.7, 14.0) years’ follow-up.HBAcopy number ranged from 2 to 6: 368 (4%) -α/-α, 2,480 (28%) -α/αα, 6,014 (67%) αα/αα, 83 (1%) ααα/αα and 2 (<1%) ααα/ααα. The adjusted HR of ischemic stroke withHBAcopy number was 1.04; 95%CI 0.89, 1.21; p = 0.66.ConclusionsAlthough a reduction inHBAcopy number is expected to increase endothelial nitric oxide signaling in the human vascular endothelium,HBAcopy number was not associated with incident ischemic stroke in this large cohort of Black Americans.
Impact of COVID-19 and effects of booster vaccination with BNT162b2 on six-month long COVID symptoms, quality of life, work productivity and activity impairment during Omicron
Authors: Di Fusco Manuela , Sun Xiaowu , Moran Mary M. , Coetzer Henriette , Zamparo Joann M. , Alvarez Mary B. , Puzniak Laura , Tabak Ying P. , Cappelleri Joseph C. 
Published: March 2023

AbstractBackgroundLongitudinal estimates of long COVID burden during Omicron remain limited. This study characterized long-term impacts of COVID-19 and booster vaccination on symptoms, Health-Related Quality of Life (HRQoL), and Work Productivity Activity Impairment (WPAI).MethodsOutpatients with ≥1 self-reported symptom and positive SARS-CoV-2 test at CVS Health United States test sites were recruited between 01/31-04/30/2022. Symptoms, EQ-5D and WPAI were collected via online surveys until 6 months following infection. Both observed and model-based estimates were analyzed. Effect sizes based on Cohen’s d quantified the magnitude of outcome changes over time, within and between vaccination groups. Mixed models for repeated measures were conducted for multivariable analyses, adjusting for covariates. Logistic regression assessed odds ratio (OR) of long COVID between vaccination groups.ResultsAt long COVID start (Week 4), 328 participants included 87 (27%) Boosted with BNT162b2, 86 (26%) with a BNT162b2 primary series (Primed), and 155 (47%) Unvaccinated. Mean age was 42.0 years, 73.8% were female, 26.5% had ≥1 comorbidity, 36.9% prior infection, and 39.6% reported ≥3 symptoms (mean: 3.1 symptoms). At Month 6, among 260 participants, Boosted reported a mean of 1.1 symptoms versus 3.4 and 2.8 in Unvaccinated and Primed, respectively (p<0.001). Boosted had reduced risks of ≥3 symptoms versus Unvaccinated (observed: OR 0.22, 95% CI, 0.10-0.47, p<0.001; model-based: OR: 0.36, 95% CI, 0.15-0.87, p=0.019) and Primed (observed: OR 0.29, 95% CI, 0.13-0.67, p=0.003; model-based: OR 0.59, 95% CI, 0.21-1.65, p=0.459). Results were consistent using ≥2 symptoms. Regarding HRQoL, among those with long COVID, Boosted had higher EQ-5D Utility Index (UI) than Unvaccinated (observed: 0.922 versus 0.731, p=0.014; model-based: 0.910 versus 0.758, p-value=0.038) and Primed (0.922 versus 0.648, p=0.014; model-based: 0.910 versus 0.708, p-value=0.008). Observed and model-based estimates for EQ-VAS and UI among Boosted were comparable with pre-COVID since Month 3. Subjects vaccinated generally reported better WPAI scores.ConclusionsLong COVID negatively impacted HRQoL and WPAI. The BNT162b2 booster could have a beneficial effect in reducing the risk and burden of long COVID. Boosted participants reported fewer and less durable symptoms, which contributed to improve HRQoL and maintain WPAI levels. Limitations included self-reported data and small sample size for WPAI.
The Extra-Islet Pancreas Supports Autoimmunity in Human Type 1 Diabetes
Authors: Barlow G.L. , Schürch C.M , Bhate S.S. , Phillips D. , Young A. , Dong S. , Martinez HA. , Kaber G. , Nagy N. , Ramachandran S. , Meng J. , Korpos E. , Bluestone J.A. , Nolan G.P. , Bollyky P.L. 
Published: March 2023

AbstractIn autoimmune Type 1 diabetes (T1D), immune cells infiltrate and destroy the islets of Langerhans — islands of endocrine tissue dispersed throughout the pancreas. However, the contribution of cellular programs outside islets to insulitis is unclear. Here, using CO-Detection by indEXing (CODEX) tissue imaging and cadaveric pancreas samples, we simultaneously examine islet and extra-islet inflammation in human T1D. We identify four sub-states of inflamed islets characterized by the activation profiles of CD8+T cells enriched in islets relative to the surrounding tissue. We further find that the extra-islet space of lobules with extensive islet-infiltration differs from the extra-islet space of less infiltrated areas within the same tissue section. Finally, we identify lymphoid structures away from islets enriched in CD45RA+T cells — a population also enriched in one of the inflamed islet sub-states. Together, these data help define the coordination between islets and the extra-islet pancreas in the pathogenesis of human T1D.
Acute pharmacodynamic responses to exenatide: Drug-induced increases in insulin secretion and glucose effectiveness
Authors: Taylor Simeon I. , Montasser May E. , Yuen Ashley H. , Fan Hubert , Yazdi Zhinoosossadat Shahidzadeh , Whitlatch Hilary B. , Mitchell Braxton D. , Shuldiner Alan R. , Muniyappa Ranganath , Streeten Elizabeth A. , Beitelshees Amber L. 
Published: March 2023

ABSTRACTBackgroundGLP1R agonists provide multiple benefits to patients with type 2 diabetes – including improved glycemic control, weight loss, and decreased risk of major adverse cardiovascular events. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses.MethodsExenatide (5 µg, sc) or saline (0.2 mL, sc) was administered to 62 healthy volunteers. Frequently sampled intravenous glucose tolerance tests were conducted to assess the impact of exenatide on insulin secretion and insulin action. This pilot study was designed as a crossover study in which participants received exenatide and saline in random order.ResultsExenatide increased first phase insulin secretion 1.9-fold (p=1.9×10-9) and accelerated the rate of glucose disappearance 2.4-fold (p=2×10-10). Minimal model analysis demonstrated that exenatide increased glucose effectiveness (Sg) by 32% (p=0.0008) but did not significantly affect insulin sensitivity (Si). The exenatide-induced increase in insulin secretion made the largest contribution to inter-individual variation in exenatide-induced acceleration of glucose disappearance while inter-individual variation in the drug effect on Sgcontributed to a lesser extent (β=0.58 or 0.27, respectively).ConclusionsThis pilot study provides validation for the value of an FSIGT (including minimal model analysis) to provide primary data for our ongoing pharmacogenomic study of pharmacodynamic effects of semaglutide (NCT05071898). Three endpoints provide quantitative assessments of GLP1R agonists’ effects on glucose metabolism: first phase insulin secretion, glucose disappearance rates, and glucose effectiveness.RegistrationNCT02462421 (clinicaltrials.gov)FundingAmerican Diabetes Association (1-16-ICTS-112); National Institute of Diabetes and Digestive and Kidney Disease (R01DK130238, T32DK098107, P30DK072488)