bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex differences in elite track and field performances and inferences about steroid doping
Authors: Collantes Diana B. , Senefeld Jonathon W. , Larson Kathryn F. , Coleman Doriane Lambelet , Joyner Michael J. , Kipp Shalaya
Published: May 2024

Females likely experience larger performance benefits from androgenic-anabolic steroids than males. We set out to determine if there were temporal differences in select athletics (track and field) records between females and males. Exploratory aims included: 1) evaluating the improvements in female and male world records over time, and 2) investigating the influence of doping programs on male and female world records before and after 1990 when sport’s governing bodies began to implement random out-of-competition and systematic in-competition drug testing. We collected the top 500 performances of all time for both sexes from an online database (worldathletics.org) in four running events (100m, 200m, 400m, and 800m) and two throwing events (discus throw and shot put). Data were stratified into quintiles based on world record ranking (1stto 100th, 101stto 200th, etc.). The temporal distribution of top 100 female performers was significantly earlier than top 100 male performers (year: 2000±1 vs 2005±1, respectively; p<0.001). Within event, the top performances occurred significantly earlier for females in the 800m (year: 1995±15 vs 2003±12; p<0.001) and shot put (year: 1992±14 vs 2003±17; p<0.001). Among females, world records rapidly improved through the 1980s, however following the 1990, the world records ceased to improve. Geographically, there was a greater representation of countries with state-sponsored doping programs, specifically among female performances. We postulate these sex differences in the temporal distribution of top performances are likely associated with enhanced effectiveness of exogenous androgens (steroid doping) among female athletes with lower endogenous androgen hormones compared to males.

Highlights

What is the central question of this study?

Despite a longstanding notion that top performance in athletics occurred earlier for females compared to males, likely due to the larger performance benefits of androgenic-anabolic steroids, no study has compared this temporal relation. Thus, we examined the temporal distribution of select athletics events between females and males.

What is the main finding and its importance?

The top-100 female performances occurred earlier than the top-100 male performances. The sex-related temporal differences were particularly notable for the shot put and 800m. Furthermore, there was a greater representation of countries with known state-sponsored doping programs, specifically among females. Our analyses suggest anabolic-androgenic steroids played a greater role in the world’s best female athletics performances.
Prevalence and associated factors of premarital sexual behavior among undergraduate youths of management colleges of Dhangadhi Sub-Metropolitan city, Kailali, Nepal
Authors: Bhatta Princy , Kunwar Min Bahadur , Joshi Arun Kumar , Bhatta Dharma Dev , Acharya Ankit
Published: May 2024

Background

Although sexuality remains a taboo in Nepali society, the prevalence of premarital sexual activities is increasing. Youth who begin early premarital sexual activity are more likely to be engaged in unsafe sex. This study aims to determine the prevalence and associated factors of premarital sex among college-going youths of Dhangadhi Sub-Metropolitan City, Kailali (DSMC).

Methodology

This descriptive cross-sectional study was conducted in management colleges with Bachelor of Business Studies (BBS) programs in DSMC. The sample size for the study was 374. The probability proportionate to size sampling technique was adopted for sample estimation for the selected colleges. The data was entered, cleaned, and analyzed in SPSS26. Bivariate analysis was done using Pearson’s chi-square test was used to determine differences between groups. A simple logistic regression model was conducted to assess the association between several characteristics of the respondents and the outcome variable- premarital sex, followed by multiple logistic regression to evaluate the combined impacts of various predictors on premarital sex.

Results

The prevalence of premarital sex among undergraduate college youths was 35.3%, of which 52.3% were males. Among those undergraduate youths, more than half (51.5%) had experienced their first intercourse before 18 years of age. At least 1 out of 10 respondents reported that their intercourse led to pregnancy. In model I, in simple logistic regression, predictors such as age, gender, relationship status, dating experience (p-value < 0.001), communication with parents (p-value = 0.002), family type (p-value = 0.020), and family income (p-value = 0.002) were significantly associated with premarital sex. Furthermore, not living with parents, parent’s education level, friends with sex partners, friends having dating experience, and awareness that friends have sex were also among the factors significantly associated with premarital sex. In the multiple logistic regression, in Model II, relationship status (aOR, 44.47; 95% CI: 7.88, 251.08), dating experience (aOR, 24.00; 95% CI: 5.36, 107.58), discussion about sexual health with parents (aOR, 8.16; 95% CI: 2.25, 29.62), and knowing friends who had premarital sex (aOR, 15.82; 95% CI: 2.92, 85.61) were significantly associated with premarital sex after controlling for potential confounding predictors.

Conclusion

Sex education interventions within and beyond educational institutions are crucial to increase the level of awareness and protect the physical, mental, and social health of young unmarried partners in Nepal.
Effects of the COVID-19 pandemic on individuals with Chemical Intolerance
Authors: Palmer Raymond F. , Kattari David , Verduzco-Gutierrez Monica
Published: May 2024

Background

The Center for Disease Control has estimated that over 24 million have been infected with COVID-19 in the US with over 6,700,000 being hospitalized, and over 1,174,000 deaths. Several other industrialized countries show similar numbers (CSSE, 2021). Chemical Intolerance (CI) is characterized by multi-system symptoms initiated by a one-time high dose or persistent low-dose exposure to environmental toxins including chemicals, foods and drugs. With an estimated 20% prevalence in the US, the symptoms of CI include fatigue, headache, weakness, rash, mood changes, musculoskeletal pain, gastrointestinal issues, difficulties with memory, concentration, and respiratory problems which are similar to COVID-19 and its sequelae. The purpose of this study was to determine if the pandemic had differential effects on those individuals with CI.

Methods

A large U.S. population-based survey was launched involving 7,500 respondents asking if they ever had COVID-19, what the severity of it was, and if they have long COVID-19. Respondents were also assessed for CI using the Quick Environmental Exposure and Sensitivity Inventory (QEESI), a 50-item validated questionnaire designed to assess intolerances to inhaled chemicals, foods, and/or drugs. Respondents were classified as Low, Medium, or High CI.

Results

Those in the High Chemical Intolerance class reported a greater COVID-19 prevalence, symptom severity, and long COVID-19 then in the Medium and Low CI classes (P<.0001). These associations were independent of race, ethnicity, income, age, and gender. However, there was significantly increased odds of COVID-19 severity among females and those over 45 years old. Asian individuals were least likely to have severe symptoms compared to White individuals (OR = 0.60). Black/African American individuals reported a lower prevalence of COVID-19 than Non-Hispanic Whites (NHW), but African American individuals with high CI reported 2.2 greater odds of reporting COVID-19 prevalence. Further, African American individuals had significantly greater odds of increased symptom severity.

Discussion

Prior studies showed that higher risk for COVID-19-19 infection include the elderly, male sex, those with pre-existing comorbidities (e.g., challenged immunities) and those from minoritized racial/ethnic groups. The results of this study suggest that those with CI be included in a high risk group. Various risk subsets may exisit and future investigations could identify different risk subsets. Understanding these subgroups would be helpful in mounting targeted prevention efforts.
Tiny dLIF: A Dendritic Spiking Neural Network Enabling a Time-Domain Energy-Efficient Seizure Detection System
Authors: Herbozo Contreras Luis Fernando , Yu Leping , Huang Zhaojing , Zhang Ziyao , Nikpour Armin , Kavehei Omid
Published: May 2024

Epilepsy poses a significant global health challenge, driving the need for reliable diagnostic tools like scalp electroencephalogram (EEG), subscalp EEG, and intracranial EEG (iEEG) for accurate seizure detection, localization, and modulation for treating seizures. However, these techniques often rely on feature extraction techniques such as Short Time Fourier Transform (STFT) for efficiency in seizure detection. Drawing inspiration from brain architecture, we investigate biologically plausible algorithms, specifically emphasizing time-domain inputs with low computational overhead. Our novel approach features two hidden layer dendrites with Leaky Integrate-and-Fire (dLIF) spiking neurons, containing fewer than 300K parameters and occupying a mere 1.5 MB of memory. Our proposed network is tested and successfully generalized on four datasets from the USA and Europe, recorded with different front-end electronics. USA datasets are scalp EEG in adults and children, and European datasets are iEEG in adults. All datasets are from patients living with epilepsy. Our model exhibits robust performance across different datasets through rigorous training and validation. We achieved AUROC scores of 81.0% and 91.0% in two datasets. Additionally, we obtained AUPRC and F1 Score metrics of 91.9% and 88.9% for one dataset, respectively. We also conducted out-of-sample generalization by training on adult patient data, and testing on children’s data, achieving an AUROC of 75.1% for epilepsy detection. This highlights its effectiveness across continental datasets with diverse brain modalities, regardless of montage or age specificity. It underscores the importance of embracing system heterogeneity to enhance efficiency, thus eliminating the need for computationally expensive feature engineering techniques like Fast Fourier Transform (FFT) and STFT.
Associations of Long-term Sleep Duration Trajectories with Overall and Cause-Specific Mortality Among Middle-to-older Aged Black and White Adults
Authors: Full Kelsie M. , Shi Hui , Lipworth Loren , Dauer Lawrence T. , Mumma Michael T. , Xiao Qian
Published: May 2024

Background

Both short and long sleep durations are adversely associated with numerous chronic conditions, including cardiovascular disease (CVD), diabetes, hypertension, and mortality. The American Academy of Sleep Medicine recommends adults in the United States sleep at least 7 hours and less than 9 hours per night to maintain optimal health. It remains unclear how sleep duration trajectories over time are associated with mortality.

Methods

This observational cohort study includes 46,928 Black and White adults (mean age: 53 ± 9 years) who enrolled in the Southern Community Cohort Study between 2002–2009 and completed a follow-up survey in 2008-2013. Participants were categorized into nine sleep duration trajectory categories based on the reported average sleep duration between study enrollment and at follow-up. Participant vital status and date and cause of death were ascertained via linkage to the National Death Index through 2022. Cox regression analysis was performed to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between sleep duration trajectory and all-cause and cause-specific mortality (CVD, cancer, and neurodegenerative disease) after adjustment for sociodemographic characteristics, health behaviors, and clinical factors.

Results

During a median 12.6 years of follow-up, we documented 13,579 deaths, including 4,135 from CVD, 3,067 from cancer, and 544 from neurodegenerative diseases. Compared to the optimal sleep duration trajectory (maintaining 7-9 hours), all sub-optimal trajectories were associated with significant 6 to 33% greater risk of all-cause mortality in fully adjusted models. Compared to the optimal sleep trajectory, three of the sub-optimal trajectories were associated with increased CVD mortality, with HRs ranging from 1.20 to 1.34. The short-long trajectory was associated with the greatest risk of all-cause mortality (HR:1.33; 95%CI: 1.21, 1.46) and the long-short trajectory was associated with the greatest CVD mortality risk (HR:1.34; 95%CI: 1.10, 1.65). The healthy-long trajectory was associated with the greatest risk of cancer mortality (HR: 1.19; 95%CI:1.00, 1.41). None of the sub-optimal trajectories was associated with neurodegenerative disease mortality.

Conclusions

Suboptimal sleep duration trajectories were associated with increased risk of all-cause mortality as well as CVD mortality. Findings highlight the importance of maintaining healthy sleep duration throughout midlife to reduce mortality risk.
Echocardiographic Characteristics and Non-Dipping Blood Pressure Profile: Is There an Association?
Authors: Villarreal Daniel , Ramos Federico , Gasca Daniel , Roa Camilo , Cardone Mariangela , Ayala Carolina , Alvarado Camilo
Published: May 2024

Background

The circadian rhythm of blood pressure is a fundamental aspect of cardiovascular physiology in healthy individuals. Beyond nocturnal hypertension, a blunted or impaired BP circadian variation is linked to heightened target organ damage and elevated cardiovascular disease risk. This includes alterations in cardiac structure and function, atherosclerotic cardiovascular disease, dementia and heart failure.

Methods

A retrospective cohort study involving 1600 participants enrolled between 2021 and 2023 identified 847 as dippers and 753 as non-dippers based on 24-hour ambulatory blood pressure monitoring. Echocardiographic evaluations were performed to assess cardiac structure and function.

Results

Non-dipping individuals displayed more signs of adverse cardiac remodeling, including a higher rate of eccentric hypertrophy (1.73 vs. 0.47%), increased left ventricular mass index in both men (75.82 vs. 70.10 g/m2) and women (65.44 vs. 63.92 g/m2), left ventricular internal diameter in diastole (4.38 vs. 4.23 cm), and left ventricular posterior wall thickness (0.82 vs. 0.81 cm). Additionally, non-dipping participants exhibited impaired ventricular relaxation, with higher E/e’ ratios medially (9.45 vs. 8.86) and laterally (7.61 vs. 7.23) and rates of type 1 diastolic dysfunction (9.31 vs. 4.49%). These differences persisted when analysing only participants with hypertension.

Conclusions

Our study highlights the substantial impact of non-dipping blood pressure patterns on cardiac structure and function. It suggests that non-dipping blood pressure patterns may serve as an independent predictor of adverse cardiac remodelling, irrespective of hypertension diagnosis. These results underscore the necessity of devising monitoring strategies and implementing targeted interventions to address the cardiovascular risks associated with non-dipping BP profile.

Graphical abstract
Exploring Pharmacogenetic Factors Influencing Hydroxyurea Response in Tanzanian Sickle Cell Disease Patients: A Genomic Medicine Approach
Authors: Nkya Siana , Nzunda Collin , Saukiwa Emmanuel , Kaywanga Frida , Buchard Eliud , Solomon David , Christopher Heavenlight , Ngowi Doreen , Johansen Julieth , Urio Florence , Mgaya Josephine , Kindole Christina , Yonazi Mbonea , Karim Salman , Alimohamed Mohamed Zahir , Sangeda Raphael Z. , Chamba Clara , Dandara Collet , Novelli Enrico , Chimusa Emile R. , Makani Julie
Published: May 2024

Sickle cell disease (SCD) continues to pose a significant public health challenge, particularly in sub-Saharan Africa. Despite its discovery over a century ago, the progress in developing and accessing effective interventions has been notably restricted. Currently, hydroxyurea stands as the primary drug in widespread use, and has been associated with elevated levels of fetal hemoglobin (HbF) and enhanced clinical outcomes. Notably, a substantial proportion, up to 30%, of patients do not exhibit a positive response to hydroxyurea treatment. There is compelling evidence suggesting that genetic factors play a crucial role in influencing the effectiveness of hydroxyurea. In this study, we present findings on the investigation of genetic variants influencing hydroxyurea response in 13 genetic loci associated with HbF synthesis and hydroxyurea drug metabolism focusing onMYB,HBB,HBG1,HBG2,BCL11A,KLF10,HAO2,NOS1,ARG2,SAR1A,CYP2C9,CYP2E1. We report remarkable genetic associations withCYP2C9,CYP2E1, KLF10,BCL11A,ARG2,HBG1,SAR1A,MYB, andNOS1loci with hydroxyurea response. We also highlight associated pathway’s enrichment and gene-gene interactions analysis in the context of hydroxyurea treatment response.
Transarterial Embolization Using a Liquid Embolic Enhances Tumor Necrosis to Enable Improved Efficacy Compared with a Particle Embolic in a Translational Rat Model of Hepatocellular Carcinoma
Authors: Gurevich Alexey , Islam Ariful , Wakim Jonathan , Yarsky Eva , Kiefer Ryan , El-Ghazal Ryan , McClung George , Cormode David Peter , Nadolski Gregory Jon , Avritscher Rony , Hunt Stephen James , Gade Terence Peter Ferrante
Published: May 2024

Purpose

To compare the effectiveness of transarterial embolization (TAE) using a liquid embolic (LE) to TAE using particle embolics (PE) with respect to tumor ischemia and treatment response in a translational rat model.

Materials and Methods

HCC was induced in male Wistar rats using diethylnitrosamine. Rats were randomized into three treatment groups: sham transarterial embolization (TAE), TAE with LE, and TAE with PE. Tumor response to TAE was monitored via serial T2-weighted MRI scans and assessed using RECIST. Tumor necrosis and hypoxia were assessed through hematoxylin and eosin staining and pimonidazole immunohistochemistry, respectively. Statistical analyses were performed using chi-square tests, Kaplan-Meier estimates, and one-way ANOVAs, with significance set at p<0.05.

Results

Twenty-nine rats were randomized to TAE with LE (n=13), PE (n=13), or sham (n=3). TAE with LE demonstrated a significantly higher objective response rate (83%) compared to TAE with PE (28%; χ2 = 11.25, P=0.0008). Complete responses were observed in 50% of the LE-treated tumors versus 10% in the PE-treated group. LE treatment prolonged local progression-free survival (hazard ratio = 0.23; p=0.0085). Histological analysis, with an additional 14 rats randomized to TAE with LE (n=5), PE (n=6), or sham (n=3), showed greater necrosis and hypoxia in LE-treated tumors compared to PE. LE induced a significant reduction in viable tumor tissue (p<0.05) and increased necrotic and hypoxic tissue areas compared to PE (p<0.01).

Conclusion

LE significantly enhanced the therapeutic efficacy of TAE in a rat model of HCC compared to conventional PE. The results highlight LE’s potential to improve ischemia and necrosis, thereby offering a promising option improving the efficacy of embolization for HCC treatment.
Vaccine-induced human monoclonal antibodies to PfRH5 show broadly neutralizing activity againstP. falciparumclinical isolates
Authors: Thiam Laty G. , McHugh Kirsty , Ba Aboubacar , Li Rebecca , Guo Yicheng , Pouye Mariama N. , Cisse Awa , Pipini Dimitra , Diallo Fatoumata , Sene Seynabou D. , Patel Saurabh D. , Thiam Alassane , Sadio Bacary D. , Mbengue Alassane , Vigan-Womas Inés , Sheng Zizhang , Shapiro Lawrence , Draper Simon J. , Bei Amy K.
Published: May 2024

Vaccines to thePlasmodium falciparumreticulocyte binding-like protein homologue 5 (PfRH5) target the blood-stage of the parasite life cycle. PfRH5 has the potential to trigger the production of strain-transcendent antibodies and has proven its efficacy both in pre-clinical and early clinical studies. Vaccine-induced monoclonal antibodies (mAbs) to PfRH5 showed promising outcomes against culturedP. falciparumlaboratory strains from distinct geographic areas. Here, we assessed the functional impact of vaccine-induced anti-PfRH5 mAbs on more genetically diverseP. falciparumclinical isolates. We used mAbs previously isolated from single B cells of UK adult PfRH5 vaccinees and used ex-vivo growth inhibition activity (GIA) assays to assess their efficacy againstP. falciparumclinical isolates. Next-generation sequencing (NGS) was used to assess the breadth of genetic diversity inP. falciparumclinical isolates and to infer the genotype/phenotype relationship involved in antibody susceptibility. We showed a dose-dependent inhibition of clinical isolates with three main GIA groups: high, medium and low. Except for one isolate, our data show no significant differences in the mAb GIA profile betweenP. falciparumclinical isolates and the 3D7 reference strain, which harbors the vaccine allele. We also observed an additive relationship for mAb combinations, whereby the combination of GIA-low and GIA-medium antibodies resulted in increased GIA, having important implications for the contribution of specific clones within polyclonal IgG responses. While our NGS analysis showed the occurrence of novel mutations in thepfrh5gene, these mutations were predicted to have little or no functional impact on the antigen structure or recognition by known mAbs. Our present findings complement earlier reports on the strain transcendent potential of anti-PfRH5 mAbs and constitute, to our knowledge, the first report on the susceptibility ofP. falciparumclinical isolates from natural infections to vaccine-induced human mAbs to PfRH5.
A practical strategy for data assimilation of cerebral intra-aneurysmal flows using a variational method with boundary control of velocity
Authors: Ichimura Tsubasa , Yamada Shigeki , Watanabe Yoshiyuki , Kawano Hiroto , Ii Satoshi
Published: May 2024

Background and objective

Evaluation of hemodynamics is crucial to predict growth and rupture of cerebral aneurysms. Variational data assimilation (DA) is a powerful tool to characterize patient-specific intra-aneurysmal flows. The DA method inversely estimates a boundary condition in fluid equations using personalized flow data; however, its high computational cost in optimization problems makes its use impractical.

Methods

This study proposes a practical strategy for the DA to evaluate patient-specific intra-aneurysmal flows. To estimate personalized flows, a variational DA method was combined with computational fluid dynamics (CFD) analysis and observed intra-aneurysmal velocity data, and an inverse problem was solved to estimate the spatiotemporal velocity profile at a boundary of the aneurysm neck. To circumvent an ill-posed inverse problem, model order reduction based on a Fourier series expansion was used to describe temporal changes in state variables.

Results

In numerical validation using synthetic data from a direct CFD analysis, the present DA method achieved excellent agreement with the ground truth, with a velocity mismatch of approximately 18%. In flow estimations for three patient-specific datasets, the velocity mismatch for the present DA method was markedly lower than that for the direct CFD analysis and would mitigate unphysical velocity distributions in flow data from phase contract magnetic resonance imaging.

Conclusions

By focusing only on the intra-aneurysmal region, the present DA approach provides an attractive way to evaluate personalized flows in aneurysms with greater reliability than conventional CFD and better efficiency than existing DA approaches.
Child Mortality in England after the Pandemic. Increasing Mortality and Inequalities
Authors: Odd David , Stoianova Sylvia , Williams Tom , Fleming Peter , Luyt Karen
Published: May 2024

Background

During the COVID-19 pandemic children and young people (CYP) mortality in England reduced to the lowest on record, but it is unclear if the mechanisms which facilitated a reduction in mortality had a longer lasting impact, and what impact the pandemic, and its social restrictions, have had on deaths with longer latencies (e.g. malignancies). The aim of this analysis was to quantify the relative risk of childhood deaths, in England, before, during, and after the COVID pandemic and its social changes.

Methods and Findings

Mortality for each analysis year was calculated per 1,000,000 person years. Poisson regression was used to test for an overall trend across the time period, and tested if trends differed between April 2019 to March 2021 (Period 1)) and April 2021 to March 2023 (Period 2). This was then repeated for each category of death and demographic group. The underlying population profile was obtained from 2021 ONS Census data. 12,828 deaths were included in the analysis. 59.4% of deaths occurred under 1 year of age. Mortality rate (per 1,000,000 CYP per year) dropped from 272.2 (264.8-283.8) in 2019-20, to 242.2 (233.4-251.2) in 2020-21, increasing to 296.1 (286.3-306.1) in 2022-23. Overall, death rate reduced in Period 1 (RR 0.96 (0.92-0.99)) and then increased in Period 2 (RR 1.12 (1.08-1.16)). Asian (p<0.001), Black (p-0.012), and Other (p=0.003) ethnic groups, and those in more deprived areas (p<0.001), had evidence of an initial reduction mortality, and then a subsequent increase. Death rates for children from White (p=0.601) or Mixed (p=0.823) ethnic backgrounds, or those in the least deprived areas, did not change over the study period.

Conclusions

Different temporal profiles were seen across cause of death categories, with reassuring trends in deaths from Suicide and Intrapartum deaths (after pandemic peaks). However, for all other causes of death, rates are either static, or increasing. Overall child mortality in England is now higher than before the pandemic. In addition, any reductions in health inequalities seen moving into, and during, the pandemic have now disappeared.
Disparities in self-reported Mental Health, Physical Health, and Substance Use Across Sexual Orientations in Canada
Authors: Bellows Zachary , Kim Chungah , Bai Yihong , Cao Peiya , Chum Antony
Published: May 2024

Background

While prior studies have shown LGB individuals have elevated risk of poor mental health, poor physical health, and substance use, existing study designs may be improved by using representative samples, wider ranges of health outcomes, heterosexual comparison groups, and disaggregated data. The goal of this study is to provide estimates of multiple health disparities across sexual orientations in Canada based on these principles.

Methods

Using data from 2009-2014 Canadian Community Health Surveys, a sample of 19,980,000 weighted individuals was created. Outcomes included mental health, physical health, binge drinking, illicit drug use, and cannabis use. The study used logistic regression models adjusted by covariates, stratified by sex, to estimate health disparities across sexual orientations.

Results

Among LGB individuals, there was evidence for elevated risk of poor mental health (i.e. gay men, bisexual men, bisexual women), poor physical health (i.e. bisexual men, bisexual women), binge drinking (i.e. lesbians, bisexual women), illicit drug use (i.e. lesbians, bisexual women), and cannabis use (i.e. lesbians, bisexual women) relative to their heterosexual counterparts. Those identifying as ‘don’t know’ or ‘refuse’ showed reduced odds of substance use. Bisexual women exhibited highest disparities in health outcomes, e.g. OR=3.3, 95% 2.58 to 4.22 for poor mental health. Trends over time showed worsening mental health among bisexual women (relative to changes in heterosexual women), and decreasing substance use in gay and bisexual men, and lesbians.

Conclusion

This study highlights health disparities across sexual orientations in Canada, especially bisexual women, calling for targeted interventions (e.g. increased training of service providers in working with bisexual women and community outreach against biphobia). Future research should aim to explore these disparities longitudinally while also including the use of administrative-linked health data to reduce potential bias in self-reported data.
A Prospective Observational Study to Assess the Impact of Pharmacogenetics on Outcomes in Vascular Surgery (PROSPER)
Authors: Burke Kerry A , Mirza Selman , Wright Stuart J , Greaves Nicholas S , Newman William G , McDermott John H
Published: May 2024

Introduction

Patients with chronic limb threatening ischaemia (CLTI) are often prescribed clopidogrel in order to reduce their risk of major adverse limb and cardiovascular events. Clopidogrel is metabolised by the CYP2C19 enzyme, and genetics variations inCYP2C19are common. These variants can influence an individual’s ability to metabolise clopidogrel to its active metabolite. This work aims to establish the relationship between patient genotype and outcomes after revascularisation in patients with CLTI who are prescribed clopidogrel. It will consider whether pharmacogenetics can be used to ensure patients are prescribed effective medications to optimise their outcomes.

Methods and analysis

This is a prospective observational cross-sectional study of patients undergoing lower limb surgical, endovascular or hybrid revascularisation for CLTI. Patients taking clopidogrel post-procedure, as well as those prescribed a non-clopidogrel based medication regimen, will be recruited prior to or shortly after revascularisation. Patients will undergoCYP2C19genotyping and will be followed-up using online records.

Ethics and dissemination

Manchester University Research Ethics Committee approval as obtained was part of the Implementing Pharmacogenetics to Improve Prescribing (IPTIP) trial process (IRAS 305751). The results of the study will be published in a peer-review journal and presented at international conferences.

Registration

This work is a sub-protocol for the IPTIP study which is registered asISRCTN14050335.
Host blood protein biomarkers to screen for Tuberculosis disease: a systematic review and meta-analysis
Authors: Gaeddert Mary , Glaser Kerstin , Chendi Bih H. , Sultanli Ayten , Koeppel Lisa , MacLean Emily L. , Broger Tobias , Denkinger Claudia M.
Published: May 2024

Introduction

Non-sputum tests are needed to improve TB diagnosis and close the diagnostic gap. The World Health Organization target product profile (TPP) for point-of-care (POC) screening tests requires minimum sensitivity 90% and specificity 70%. Our objective was to identify host blood protein biomarkers meeting TPP criteria.

Methods

A systematic review was conducted and reported following PRISMA guidelines. Data extraction and quality assessment with QUADAS-2 were completed for included studies. Heterogeneity was assessed. For biomarkers reporting sensitivity and specificity in at least four studies, a random-effects meta-analysis was performed for biomarkers with similar cut-offs.

Results

We screened 4,651 citations and included 65 studies that enrolled 16,010 participants and evaluated 156 host proteins. Most (47/65) studies enrolled adult pulmonary TB (PTB), with 15 studies in adult extra-pulmonary TB and 5 in children. Small early-stage discovery studies with case-control design were common (24/65) and had high risk of bias. For adult PTB, CRP, IP-10, NCAM-1, and SAA met TPP criteria in high-quality studies. There was a high degree of heterogeneity in biomarker cut-offs and study design. CRP at 10mg/L cut-off was meta-analyzed from 10 studies; pooled sensitivity 86% (95% CI: 80-95) and pooled specificity 67% (95% CI: 54-79). In people living with HIV (6 studies) CRP pooled sensitivity was 93% (95% CI: 90-95) and pooled specificity 59% (95% CI: 40-78).

Discussion

We identified promising biomarkers that performed well in high-quality studies. Data overall are limited and highly heterogenous. Further standardized validation across subgroups in prospective studies is needed before translating into POC assays.
Macromolecular condensation is unlikely to buffer intracellular osmolality
Authors: Kay Alan R. , Aminzare Zahra
Published: May 2024

Watsonet al. (2023, Macromolecular condensation buffers intracellular water potential, Nature 623: 842-852) have proposed that the reversible formation and disassembly of molecular condensates could act as the primary buffer of cytoplasmic osmolality in the face of changes in extracellular osmolality. In this communication, we show using well-established membrane biophysics, that the water permeability of plasma membranes is likely to overwhelm any cytoplasmic water buffers.
BMP signaling promotes heart regeneration via alleviation of replication stress
Authors: Vasudevarao Mohan Dalvoy , Pena Denise Posadas , Ihle Michaela , Bongiovanni Chiara , Maity Pallab , Redaelli Simone , Happ Kathrin , Geissler Dominik , Mohammadi Hossein Falah , Rall-Scharpf Melanie , Wu Chi-Chung , Beisaw Arica , Scharffetter-Kochanek Karin , D’Uva Gabriele , Wiesmüller Lisa , Weidinger Gilbert
Published: May 2024

One hallmark of aging is a decline in tissue regeneration, which can be caused by DNA replication stress. Whether highly regenerative species like zebrafish are immune from such hindrances to replication is unknown. In contrast to most mammals, adult zebrafish achieve complete heart regeneration via cell cycle entry and proliferation of mature cardiomyocytes. We found that cycling cardiomyocytes experience replication stress, which is induced by the demands of regeneration, but does not occur during physiological heart growth. Since zebrafish cardiomyocyte regeneration is remarkably efficient, heart regeneration appears to depend on elevated capabilities to overcome replication stress. Indeed, pharmacological inhibition of ATM and ATR kinases revealed that DNA damage response signaling is essential for heart regeneration. Using inducible overexpression of ligands and inhibitors of the Bone Morphogenetic Protein (BMP)-Smad pathway, combined with analysis of genetic mutants, we found that BMP signaling alleviates cardiomyocyte replication stress. In the absence of BMP signaling, cardiomyocytes become arrested in the S-phase of the cell cycle, which prevents progression to mitosis and results in heart regeneration failure. Interestingly, BMP signaling can also rescue neonatal mouse cardiomyocytes and human fibroblasts from hydroxyurea-induced replication stress. DNA fiber spreading assays in human cancer cells and human hematopoietic stem and progenitor cells (HSPCs) indicate that BMP signaling acts directly on replication dynamics by accelerating DNA replication fork progression and by facilitating their re-start after replication stress-induced stalling. Our results identify the ability to overcome replication stress as key factor for the elevated heart regeneration capacity in zebrafish. Notably, the conserved capability of BMP signaling to promote stress-free DNA replication might unlock new avenues towards anti-aging and pro-regenerative applications in humans.
Mild hyperthermia-induced thermogenesis in the endoplasmic reticulum defines stress response mechanisms
Authors: Dukic Barbara , Ruppert Zsófia , Tóth Melinda E. , Hunya Ákos , Czibula Ágnes , Bíró Péter , Tiszlavicz Ádám , Péter Mária , Balogh Gábor , Erdélyi Miklós , Timinszky Gyula , Vígh László , Gombos Imre , Török Zsolt
Published: May 2024

Previous studies reported that a mild, non-protein denaturing, fever-like temperature increase induced the unfolded protein response (UPR) in mammalian cells. Our dSTORM super-resolution microscopy experiments revealed that the master regulator of the UPR, the IRE1 (inositol-requiring enzyme 1) protein is clustered as a result of UPR activation in a human osteosarcoma cell line (U2OS) upon mild heat stress. Using ER thermo yellow, a temperature-sensitive fluorescent probe targeted to the endoplasmic reticulum (ER), we detected significant intracellular thermogenesis in mouse embryonic fibroblast (MEF) cells. Temperatures reached at least 8°C higher than the external environment (40°C), resulting in exceptionally high ER temperatures similar to those previously described for mitochondria. Mild heat-induced thermogenesis in the ER of MEF cells was likely due to the uncoupling of the Ca2+/ATPase (SERCA) pump. The high ER temperatures initiated a pronounced cytosolic heat shock response in MEF cells, which was significantly lower in U2OS cells in which both the ER thermogenesis and SERCA pump uncoupling were absent. Our results suggest that, depending on intrinsic cellular properties, mild hyperthemia-induced intracellular thermogenesis defines the cellular response mechanism, and determines the outcome of hyperthermic stress.
Ccrk-Mak/Ick kinase signaling axis is a ciliary transport regulator essential for retinal photoreceptor maintenance
Authors: Chaya Taro , Maeda Yamato , Tsutsumi Ryotaro , Ando Makoto , Ma Yujie , Kajimura Naoko , Tanaka Teruyuki , Furukawa Takahisa
Published: May 2024

Primary cilia are microtubule-based sensory organelles whose dysfunction leads to ciliopathies in humans. The formation, function, and maintenance of primary cilia depend crucially on intraflagellar transport (IFT); however, the regulatory mechanisms of IFT and their physiological roles are poorly understood. In the current study, we screened and identified that the ciliopathy kinase Mak is a ciliary tip-localized IFT regulator that cooperatively acts with the ciliopathy kinase Ick, an IFT regulator. Simultaneous disruption ofMakandIckresulted in loss of photoreceptor ciliary axonemes and severe degeneration in the mouse retina. Mak overexpression restored ciliary defects caused byIckdeficiency in cultured cells. Gene delivery ofIckand pharmacological inhibition of FGF receptors, negative regulators of Ick, ameliorated retinal degeneration inMak−/−mice. In addition, we identified that Ccrk kinase is an upstream activator of Mak and Ick in retinal photoreceptor cells. Furthermore, overexpression of Mak, Ick, and Ccrk and pharmacological inhibition of FGF receptors suppressed ciliopathy-related phenotypes caused by cytoplasmic dynein inhibition in cultured cells. Collectively, our results show that the Ccrk-Mak/Ick axis is an essential IFT regulator crucial for retinal photoreceptor maintenance. This study sheds light on pathological mechanisms underlying retinitis pigmentosa caused by mutations in the humanMAKgene and presents activation of Ick as a potential therapeutic approach for this retinal degenerative disease.
Modular Design and Scaffold-Synthesis of Multi-Functional Fluorophores for Targeted Cellular Imaging and Pyroptosis
Authors: Li Yuanyuan , Wang Chunhui , Wang Haiyang , Sun Kunhui , Lu Siyu , Wang Yahui , Zhang Lei , Jing Su , Cordes Thorben
Published: May 2024

Modified commercial fluorophores are essential tools for optical imaging and biomedical research. Their synthetic modification to incorporate new functions, however, remains a challenging task. Conventional strategies rely on linear synthesis in which a parent framework is gradually extended. We here designed and synthesized a versatile library of functional fluorophores via a scaffold-based Ugi four-component reaction (U-4CR). The adaptability of the scaffold is achieved through modification of starting materials. This allows to use a small range of starting materials for the creation of fluorogenic probes that can detect reactive-oxygen species and where the localization into subcellular organelles or membranes can be controlled. We present reaction yields ranging from 60% to 90% and discovered that some compounds can even function as imaging and therapeutic agents via Fenton chemistry inducing pyroptosis in living cancer cells. Our study underlines the potential of scaffold-based synthesis for versatile creation of functional fluorophores and their applications.
Characterization of sleep in a mouse model of CLN3 disease revealed sex-specific sleep disturbances
Authors: Kane Kelby M. , Iradukunda Diane , McLouth Christopher J. , Guo Landys Z. , Wang Jun , Subramoniam Anjana , Huffman Dillon , Donohue Kevin , O’Hara Bruce F. , Sunderam Sridhar , Wang Qing Jun
Published: May 2024

The neuronal ceroid lipofuscinoses (NCLs) are a group of recessively inherited neurodegenerative diseases characterized by lysosomal storage of fluorescent materials. CLN3 disease, or juvenile Batten disease, is the most common NCL that is caused by mutations in theCeroid Lipofuscinosis, Neuronal 3(CLN3) gene. Sleep disturbances are among the most common symptoms associated with CLN3 disease, yet this is understudied and has not been delineated in an animal model of the disease. The current study utilized a non-invasive, automated piezoelectric motion sensing system (PiezoSleep) to classify sleep and wakefulness in aCln3ϕ..ex1–6/ϕ..ex1–6(Cln3KO) mouse model and age- and sex-matched wild-type (WT) controls. The sleep-wake classification by PiezoSleep was found to be about 90% accurate when validated against simultaneous gold standard polysomnographic recordings including electroencephalography (EEG) and electromyography (EMG) in a small cohort of WT andCln3KO mice. Our large cohort PiezoSleep study reveals sleep abnormalities during the light period (LP) in maleCln3KO mice compared to WT male, and more subtle differences inCln3KO female mice throughout the dark period (DP) compared to WT female, recapitulating sleep abnormalities seen in CLN3 disease patients. Our characterization of sleep in a mouse model of CLN3 disease contributes to a better understanding of the sleep disturbances commonly reported for CLN3 disease and other NCLs, which will facilitate the development of new disease treatment and management strategies.
A fully synthetic three-dimensional human cerebrovascular model based on histological characteristics to investigate the hemodynamic fingerprint of the layer BOLD fMRI signal formation
Authors: Báez-Yáñez Mario Gilberto , Schellekens Wouter , Bhogal Alex A. , Roefs Emiel C.A. , van Osch Matthias J.P. , Siero Jeroen C.W. , Petridou Natalia
Published: May 2024

Recent advances in functional magnetic resonance imaging (fMRI) at ultra-high field (≥7 tesla), novel hardware, and data analysis methods have enabled detailed research on neurovascular function, such as cortical layer-specific activity, in both human and nonhuman species. A widely used fMRI technique relies on the blood oxygen level-dependent (BOLD) signal. BOLD fMRI offers insights into brain function by measuring local changes in cerebral blood volume, cerebral blood flow, and oxygen metabolism induced by increased neuronal activity. Despite its potential, interpreting BOLD fMRI data is challenging as it is only an indirect measurement of neuronal activity.

Computational modeling can help interpret BOLD data by simulating the BOLD signal formation. Current developments have focused on realistic 3D vascular models based on rodent data to understand the spatial and temporal BOLD characteristics. While such rodent-based vascular models highlight the impact of the angioarchitecture on the BOLD signal amplitude, anatomical differences between the rodent and human vasculature necessitate the development of human-specific models. Therefore, a computational framework integrating human cortical vasculature, hemodynamic changes, and biophysical properties is essential.

Here, we present a novel computational approach: a three-dimensional VAscular MOdel based on Statistics (3D VAMOS), enabling the investigation of the hemodynamic fingerprint of the BOLD signal within a model encompassing a fully synthetic human 3D cortical vasculature and hemodynamics. Our algorithm generates microvascular and macrovascular architectures based on morphological and topological features from the literature on human cortical vasculature. By simulating specific oxygen saturation states and biophysical interactions, our framework characterizes the intravascular and extravascular signal contributions across cortical depth and voxel-wise levels for gradient-echo and spin-echo readouts. Thereby, the 3D VAMOS computational framework demonstrates that using human characteristics significantly affects the BOLD fingerprint, making it an essential step in understanding the fundamental underpinnings of layer-specific fMRI experiments.
APP-KI mice do not display the hallmark age-dependent cognitive decline of amyloid diseases
Authors: Blackmer-Raynolds Lisa , Lipson Lyndsey D. , Fraccaroli Isabel , Krout Ian N. , Chang Jianjun , Sampson Timothy Robert
Published: May 2024

APP knock-in (KI) mice serve as an exciting new model system to understand amyloid beta (Aβ) pathology, overcoming many of the limitations of previous overexpression-based model systems. The APPSAAmouse model (containing the humanized APP with three familial Alzheimer’s disease mutations) and the APPWTcontrol are the first commercially available APP KI mice within the United States. While APPSAAmice have been shown to develop progressive Aβ pathology and neuroinflammation, behavioral changes, particularly in cognitive functions, have yet to be described. Therefore, we performed an in-depth longitudinal study over 12 months, assessing cognition in these two strains, as well as assessments of motor and GI function. We surprisingly note no overt, progressive cognitive impairment or motor deficits. However, we do observe a significant increase in fecal output in APPSAAmice compared to APPWTat 12 months old. These data provide a baseline for these models’ behavioral attributes.

Highlights

APPSAAand APPWTknock-in mice do not display age related cognitive decline

Fecal output appears altered by APP genotype, but no other measure of GI function is impacted.

Both genotypes behave equally in motor function tests