bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intracranial Plaque Characteristics of Recurrent Ischemic Stroke After Intensive Medical Therapy for a 6-month Follow-up
Authors: Shi Zhang , Zhang Boyu , Zhao Ming , Zhang Shujie , Li Jing , Liu Qi , Zeng Mengsu , Lin Jiang , Lu Jianping , Wang He 
Published: December 2023

ABSTRACTBACKGROUNDIntensive medical management has been recommended to ischemic stroke of intracranial atherosclerosis (ICAS), but 9.4-15% probability of recurrent stroke remains an inevitable reality. The characteristics of high-risk intracranial plaque that contribute to stroke recurrence after intensive therapy is unclear.METHODSAll the patients for acute ischemic stroke due to ICAS underwent the 3D head&neck high-resolution vessel wall magnetic resonance imaging (hr-VW-MRI) at baseline and received intensive medical management within 90 days in this two-center and prospective study. The clinical risk factors and blood biomarkers were recorded. The morphological features, such as minimal lumen area (MLA), and histogram parameters including entropy were assessed based on MR images. The primary endpoint event after 6 months is recurrence of ischemic events (hyperintense signals on diffusion-weighted images or TIA in the ipsilateral vascular territory). Cox regression analysis was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for recurrent events.RESULTS222 patients (age, 59.5±12.1; males, 153) were included in the subsequent analysis. After an average of six months of follow-up (average days, 177.4±23.1), 38 patients have reached the primary endpoint. After adjusting the age, BMI and gender, the multivariate Cox regression demonstrated that three clinical factors including smoking (HR=4.321; 95%CI, 1.838-10.161;P=0.001), taking exercise (HR=0.409; 95%CI, 0.198-0.843;P=0.015) and blood pressure management (HR=0.180; 95%CI, 0.073-0.443;P=0.001), and two MR-related parameters (MLA [HR=0.771; 95%CI, 0.625-0.951;P=0.015] and entropy [HR=0.274; 95%CI, 0.130-0.576;P=0.001]) were significant predictors of recurrent ischemic stroke. The Kaplan– Meier curve depicted that the cumulative incidences of patients with all high-risk features were significantly higher than those without(P < 0.001).CONCLUSIONSThe plaque characteristics based on 3D head&neck hr-VW-MRI may provide complementary values over traditional clinical features in predicting ischemic recurrence for ICAS and help risk stratification of patients at risk of recurrent stroke.
Financial Cost Analysis Associated with a Locomotor Exercise Randomized Controlled Trial in Chronic Stroke
Authors: Hazen Emily M. , Bartsch Bria L. , Billinger Sandra A. 
Published: December 2023

AbstractBackgroundPost-stroke recovery trials pose distinct recruitment and retention challenges, and understanding the financial requirements of conducting randomized controlled trials is crucial to ensure sufficient resources for successful study execution. The purpose of this analysis was to quantify the costs at a single site with a large catchment area of the Moderate-Intensity Exercise Versus High-Intensity Interval Training to Recover Walking Post-Stroke, HIT Stroke Trial.MethodsTo determine cost, study expense reports were gathered and divided into four categories: oversight, recruitment, retention, and outcome assessments. Categories were then further divided into chronological order for initial contact and prescreening, consenting, initial screening, and baseline testing. The 12-week intervention was divided into 4-week blocks: intervention block 1, post 4-week outcome testing, intervention block 2, post 8-week outcome testing, intervention block 3, and post 12-week outcome testing.ResultsTotal direct cost for site execution was $539,768 with cost per participant approximated as $35,984. Oversight costs accounted for 65.8% of the budget at $355,661. To achieve goals related to inclusive participant recruitment ($21,923) and retention ($28,009), our site costs totaled $49,932. Direct study-related costs included screening assessments ($5,905), baseline assessments ($15,028), intervention ($76,952), and outcome assessments ($36,288).ConclusionClinical trials on walking rehabilitation and exercise, especially those involving multiple assessment visits, require intensive oversight. This cost analysis provides important and critical insight into the expenses required to successfully execute an exercise-based walking rehabilitation trial in the United States.
Mitochondrial morphology and function in mitochondrial disease
Authors: Faitg Julie , Davey Tracey , Laws Ross , Lawless Conor , Tuppen Helen , Fitton Eric , Turnbull Doug , Vincent Amy E. 
Published: December 2023

AbstractMitochondria play a crucial role in maintaining cellular health. It is interesting that the shape of mitochondria can vary depending on the type of cell, mitochondrial function, and other cellular conditions. The morphology of this network is maintained by the balance between mitochondrial fusion and fission, necessary for the proper functioning of the mitochondrial energetics as well as the maintenance of mitochondria DNA (mtDNA) (Chan, 2006; Friedman and Nunnari, 2014; Glancy et al., 2015). If the balance between the two processes is slightly perturbed, dramatic changes in mitochondrial morphology can occur.However, there are limited studies that link functional assessment with mitochondrial morphology evaluation at high magnification, even fewer that do soin situand none in human muscle biopsies. Therefore, we have developed a method which combines functional assessment of mitochondria through Cytochrome c Oxidase (COX) histochemistry, with a 3D electron microscopy (EM) technique, serial block-face scanning electron microscopy (SBFSEM). Using this technique, we examine the relationship between 3D mitochondrial morphology and mitochondrial activity in human skeletal muscle.Here we apply COX-SBFSEM to muscle samples from patients with single, large-scale mtDNA deletions, a cause of mitochondrial disease. These deletions cause oxidative phosphorylation deficiency, which can be observed through changes in COX activity, and a typical mosaic pattern of enzyme deficiency with both COX normal and deficient fibres present in the same biopsy.Using COX-SBFSEM, we can distinguish three distinct mitochondrial populations within muscle fibres: COX normal (+), COX intermediate (±) and COX deficient (-) mitochondria. COX+ mitochondria were larger and more complex than the COX- mitochondria, However, in fibres that were generally COX-, there was no apparent difference between the three types of mitochondria and all mitochondria in fibres that are COX- overall are fragmented and spherical. One of the main advantages of combining 3D-EM with the COX reaction is the ability to look at how per-mitochondrion oxidative phosphorylation status is spatially distributed within muscle fibres. Here we show a robust spatial pattern in fibres that are generally COX+ and that the spatial pattern is less clear in fibres that are predominantly COX± and COX- .
Long-Term Immunogenicity Study of an Aluminum Phosphate-Adjuvanted Inactivated Enterovirus A71 Vaccine in Children: An Extension to a Phase 2 Study
Authors: Chiu Nan-Chang , Lin Chien-Yu , Chen Charles , Cheng Hao-Yuan , Hsieh Erh-Fang , Liu Luke Tzu-Chi , Chiu Cheng-Hsun , Huang Li-Min 
Published: December 2023

AbstractBackgroundEV-A71 causes hand, foot, and mouth disease with potentially fatal complications such as encephalitis and acue flaccid myelitis in infants and children. This study examined the long-term immunity conferred by EV71vac, an inactivated EV-A71 vaccine based on the B4 subgenotype adjuvanted with aluminum phosphate, in children from the age of > 2 months to < 6 years for up to 5 years after the first immunization.MethodsA total of 227 subjects from age of 2 months to 6 years who had previously received either EV71vac or placebo in the phase 2 clinical study were enrolled. Subjects were split into age groups: 2 years to < 6 years (Group 2b), 6 months to < 2 years (Group 2c), and 2 months to < 6 months (Group 2d). Serum samples were taken periodically for up to five years after the first dose for immunogenicity against EV-A71.ResultsAt year 5, the neutralizing antibody titers against B4 subgenotype remained high at 621.38 to 978.20, 841.40 to 1159.93, and 477.71 to 745.07 for Groups 2b, 2c, and 2d, respectively. Cross-neutralizing titers at year 5 were 99.14 to 444.30 and 341.94 to 998.20 against B5 and C4a subgenotypes, respectively. Nearly all subjects remained seroprotected at year five (95.8 to 100%). No long-term safety issues were reported.ConclusionThis study shows that using the current dosing regimen, EV71vac conferred persistent immunity against EV-A71 for at least five years after the first vaccination in children from the age of two months to six years.SummaryEV-A71 neutralizing antibody persisted at high level throughout five years post vaccination in children of two months to six years old.
Genetics, primary care records and lifestyle factors for short-term dynamic risk prediction of colorectal cancer: prospective study of asymptomatic and symptomatic UK Biobank participants
Authors: Ip Samantha , Harrison Hannah , Usher-Smith Juliet A. , Barclay Matthew , Tyrer Jonathan , Dennis Joe , Yang Xin , Lush Michael , Renzi Cristina , Pashayan Nora , Denaxas Spiros , Lyratzopoulos Georgios , Antoniou Antonis C. , Wood Angela 
Published: December 2023

ABSTRACTObjectivesTo quantify the contributions of polygenic scores, primary care records (presenting symptoms, medical history and common blood tests) and lifestyle factors, for short-term risk prediction of colorectal cancer (CRC) in both all and symptomatic individuals.DesignProspective cohort study.SettingUK Biobank with follow-up until 2018.ParticipantsAll participants with linked primary care records (n=160,507), and a subcohort of participants with a recent (last two years) presentation of a symptom associated with CRC (n=42,782).Main outcome measuresOutcome was the first recorded CRC diagnosis within two years. Dynamic risk models with time-varying predictors were derived in a super-landmark framework. Contributions to model discrimination were quantified using novel inclusion-order-agnostic Shapley values of Harrel’s C-index using cross-validation.ResultsC-indices [95% CIs] were 0.73 [0.72-0.73] and 0.69 [0.68-0.70] for the models derived in all and symptomatic participants respectively. The Shapley contributions to model discrimination [95% CIs] differed between the two groups of participants for different predictors: 33% [25%-42%] (34% [9%-75%] in the symptomatic participants) for core predictors (e.g., age, sex, smoking), 16% [8%-26%] (8% [-21%-35%]) for polygenic scores, 32% [19%-43%] (41% [16%-73%]) for primary care blood tests, 11% [4%-17%] (9% [-25%-37%]) for primary care medical history, 6% [0%-11%] (–5% [-32%-13.4%]) for additional lifestyle factors and 3% [-2%-7%] (13% [-19%-41%]) for symptoms.ConclusionsPolygenic scores contribute substantially to short-term risk prediction for CRC in both general and symptomatic populations; however, the contribution of information in primary care records (including presenting symptoms, medical history and common blood tests) is greater. There is, however, only a small contribution by the additional lifestyle risk factors which are not routinely collected in primary care.
Epidemiology of alcohol use and alcohol use disorder among female sex workers in Mbeya City, Tanzania
Authors: Augustine Andrew Kapaya , Maganga Lucas , Francis Joel Msafiri 
Published: December 2023

AbstractBackgroundAlcohol misuse is a global concern, contributing to 5.3% of total deaths and 132.6 million disability-adjusted life years worldwide. In Sub-Saharan African countries, the prevalence of Alcohol Use Disorder (AUD) has risen, especially among female sex workers, due to increased availability and advertising. However, there are limited studies on alcohol use and AUD among female sex workers in Tanzania.Study ObjectiveThis study aimed to determine the prevalence, patterns, and factors associated with alcohol use and AUD among sex workers in Mbeya city, Tanzania.MethodsIn this cross-sectional study, 212 female sex workers in Mbeya city, Tanzania, seeking enrolment in the National Institute for Medical Research Mbeya Medical Research Centre’s registration cohort from July to November 2022. Structured interviews covered socio-demographics, alcohol screening (AUDIT-C and Timeline Follow Back Calendar), and sexual behaviours data. Data were analysed using Stata version 17. Descriptive analysis assessed alcohol consumption and AUD prevalence. Factors associated with alcohol use and AUD at bivariate analysis were identified using Chi-square/Fisher’s exact tests. All variables with p-value ≤ 0.20 multivariable logistic regression models were done to identify factors associated with alcohol use and AUD.ResultsAmong 212 participants, 86.6% reported alcohol use in the past 12 months, 85% in the past 30 days, and 98.5% met AUD criteria. Factors linked to recent alcohol consumption included primary education or higher, income above the median, and more than 10 sexual partners. Education level, marital status, income, and having dependents were significantly associated with heavy drinking episodes.Discussion and conclusionThe prevalence of AUD, alcohol use, and heavy episodic drinking were high among female sex workers in Mbeya city. Socio-demographic factors and risky sexual behaviours were associated with alcohol use and heavy episodic drinking highlighting the need for targeted interventions to combat alcohol abuse among female sex workers within the HIV program.
An estimation of global genetic prevalence of PLA2G6-associated neurodegeneration
Authors: Kurtovic-Kozaric Amina , Singer-Berk Moriel , Wood Jordan , Evangelista Emily , Panwala Leena , Hope Amanda , Heinrich Stefanie M. , Baxter Samantha , Kiel Mark J. 
Published: December 2023

AbstractBackgroundPLA2G6-associated neurodegeneration (PLAN) comprises three diseases with overlapping features: infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (atypical NAD), and PLA2G6-related dystonia-parkinsonism. INAD is an early onset disease characterized by progressive loss of vision, muscular control, and mental skills. The prevalence of PLA2G6-associated diseases has not been previously calculated.MethodsTo provide the most accurate prevalence estimate, we utilized two independent approaches: database-based approach which included collecting variants from ClinVar, Human Gene Mutation Database (HGMD) and high confidence predicted loss-of-function (pLoF) from gnomAD (Rare Genomes Project Genetic Prevalence Estimator; GeniE), and literature-based approach which gathered variants through Mastermind Genomic Search Engine (Genomenon, Inc). Genetic prevalence of PLAN was calculated based on allele frequencies from gnomAD, assuming Hardy–Weinberg equilibrium.ResultsIn the PLA2G6 gene, our analysis found 122 pathogenic, 82 VUS, and 15 variants with conflicting interpretations (pathogenic vs VUS) between two approaches. Allele frequency was available for 58 pathogenic, 42 VUS, and 15 conflicting variants in gnomAD database. If pathogenic and VUS variants are included, the overall genetic prevalence was estimated to be 1 in 220,322 pregnancies, with the highest genetic prevalence in African/African-American populations at 1 in 86,012 pregnancies. Similarly, the highest carrier frequencies observed were in African/African-American and Asian populations.ConclusionOur estimates highlight the significant underdiagnosis of PLA2G6-associated neurodegeneration and underscores the need for increased awareness and diagnostic efforts. Furthermore, our study revealed a higher carrier frequency of PLA2G6 variants in African and Asian populations, stressing the importance of expanded genetic sequencing in non-European populations to ensure accurate and comprehensive diagnosis. Future research should focus on confirming our findings and implementing expanded sequencing strategies to facilitate maximal and accurate diagnosis, particularly in non-European populations.
Immunogenicity and Safety of a 14-valent pneumococcal polysaccharide conjugate vaccine (PNEUBEVAX 14TM) administered to 6-8 weeks old healthy Indian Infants: A single blind, randomized, active-controlled, Phase-III study
Authors: Matur Ramesh V , Thuluva Subhash , Gunneri Subbareddy , Yerroju Vijay , Mogulla Rammohan reddy , Thammireddy Kamal , Paliwal Piyush , Mahantshetty Niranjana S , Ravi Mandyam Dhati , Prashanth S. , Verma Savita , Narayan Jai Prakash 
Published: December 2023

ABSTRACTBackgroundIntroduction of pneumococcal conjugate vaccines (PCV) reduced the cases of pneumococcal disease at global level. However, there is an increase in clinical and economic burden of PD from non-PCV serotypes, particularly in pediatric and elder population. In this study, immunogenicity and safety of the BE’s 14-valent PCV (PNEUBEVAX 14TM; BE-PCV-14) containing two additional epidemiologically important serotypes (22F and 33F) in comparison to PCV-13 was evaluated in infants.MethodsThis is a pivotal phase-3 single blind randomized active-controlled study conducted at 12 sites across India in 6-8 weeks old healthy infants in 6-10-14 weeks dosing schedule to assess immunogenic non-inferiority and safety of a candidate BE-PCV-14. In total, 1290 infants were equally randomized to receive either BE-PCV-14 or PCV-13. Solicited local reactions and systemic events, adverse events (AEs), serious AEs (SAEs) and medically attended AEs (MAAEs) were recorded. Immunogenicity was assessed by measuring anti-PnCPS IgG concentration and functional antibody titers by opsonophagocytic activity (OPA), one month after completing three dose schedule. Cross protection to serotype 6A offered by serotype 6B was also assessed in this study.FindingsThe safety profile of BE-PCV-14 was comparable to PCV-13 vaccine. Majority of reported AEs were mild in nature and no severe or serious AEs were reported. Primary immunogenicity objective was met for all 14 serotypes. For the twelve common serotypes non-inferiority to those 12 serotypes in PCV-13 was met. Additional serotypes in BE-PCV-14 (22F and 33F) also met NI criteria as defined by WHO TRS-977. A significant seroconversion, about 69% for serotype 6A was observed even though this antigen was not present in BE-PCV-14. This indicates that serotype 6B of BE-PCV-14 cross protects serotype 6A. BE-PCV-14 also elicited comparable serotype specific functional OPA immune responses to all the serotypes in PCV-13.InterpretationsBE-PCV-14 was found to be safe and induced robust and functional serotype specific immune responses to all 14 serotypes. All serotype-specific IgG responses were comparable to those in PCV-13. These findings suggest that BE-PCV-14 can be safely administered to infants and achieve protection against pneumococcal disease caused by serotypes covered in the vaccine.The study was prospectively registered with clinical trial registry of India-CTRI/2020/02/023129
Pitfalls in Time-to-Event Analysis of Registry Data: A Tutorial based on Simulated and Real Cases
Authors: Alligon Mickaël , Mahlaoui Nizar , Bouaziz Olivier 
Published: December 2023

ABSTRACTSurvival analysis (also referred to as time-to-event analysis) is the study of the time elapsed from a starting date to some event of interest. In practice, these analyses can be challenging and, if methodological errors are to be avoided, require the application of appropriate techniques. By using simulations and real-life data based on the French national registry of patients with primary immunodeficiencies (CEREDIH), we sought to highlight the basic elements that need to be handled correctly when performing the initial steps in a survival analysis. We focused on right censoring, left truncation, competing risks, and recurrent events. Our simulations show that ignoring these aspects induces a bias in the results; we then explain how to analyze the data correctly in these situations. Rare disease registries are extremely valuable in medical research. We discuss the application of appropriate methods for the analysis of time-to-event from the CEREDIH registry. The objective of this tutorial article is to provide clinicians and healthcare professionals with better knowledge of the issues facing them when analyzing time-to-event data.Key messages boxWhen comparing naïve approaches and the proper methodology, we show that:Not considering right censoring leads to underestimation of survivalNot considering left truncation leads to overestimation of survivalTreating competing risks as right-censoring leads to overestimation of survivalAppropriate recurrent event methods allow to study all events for each patient and not only account for the first event.
Hybrid immunity improves the immune response after fourth Covid-19 vaccine dose in individuals with medical conditions predisposing to severe Covid-19
Authors: Ekström Nina , Leino Tuija M. , Juutinen Aapo , Lehtonen Toni , Haveri Anu , Liedes Oona , Vara Saimi , Salo Heini , Palmu Arto A. , Nohynek Hanna , Martelius Timi , Melin Merit 
Published: December 2023

AbstractBackgroundData on Covid-19 booster vaccinations and subsequent infections on immune responses in the immunocompromised is limited. We studied antibody responses after the fourth dose and subsequent breakthrough infection to define patient groups benefiting most from boosters.MethodsIn Finland, fourth vaccine (booster) doses were first recommended for severely immunocompromised individuals, whom we invited to participate in 2022. We assessed spike protein specific IgG antibody levels and neutralizing antibodies (NAb) against the ancestral and Omicron BA.1 strains one month after the fourth dose from 488 adult participants and compared to the levels of 35 healthy controls after 3 doses. We used Bayesian generalized linear modelling to assess factors explaining antibody concentrations after the fourth dose. We assessed vaccine-induced and hybrid immunity six months after the last vaccine dose.ResultsChronic kidney disease (CKD) and immunosuppressive therapy (IT) were identified as factors explaining sub-optimal antibody responses. The proportion of participants with a normal antibody response and NAbs were significantly lower in CKD patients as compared to controls. By the 6-month sampling one third of the participants became infected, which enhanced antibody levels notably in most immunocompromised participants.ConclusionsImpaired antibody responses, especially NAbs against the Omicron lineage, predict limited protection in individuals with CKD, and highlight the need for alternative pharmaceutical preventive strategies. Vaccination strategies should take into account development of robust hybrid immunity responses also among the immunocompromised.