bluuebunny/crossref_metadata_2025 huggingface dataset:
Unravelling sex disparities in statin dose titration patterns in primary care
Authors: Kiss P , Uijl A , Duk T , Grobbee D , Hollander M , Smits E , Sturkenboom M , Peters S
Published: June 2024

Introduction

Statins are widely recommended by clinical guidelines for the prevention and management of cardiovascular disease. While guidelines make no sex-specific recommendations, studies have shown that women are less likely than men to be prescribed high-intensity statins at initiation and to achieve cholesterol target values. However, the existing literature lacks evidence in sex comparison of statin treatment patterns in real-world clinical practice.

Purpose

This study aims to examine sex differences in titration patterns of statin therapy over a ten-year period in a Dutch primary care setting.

Methods

Data on statin dispensing was extracted from electronic healthcare data banks between 2011-2020. Poisson regression with robust standard errors was used to estimate risk ratios (RR) with 95% confidence intervals (CI) of sex differences in statin uptitration (defined as an increase in statin intensity or the addition of ezetimibe to statin therapy). Analyses were adjusted for age, socio-economic status and Low-Density Lipoprotein (LDL) cholesterol levels at initiation and were stratified by age group, history of cardiovascular disease at initiation and intensity of the first dispensed statin. Missing data were imputed with multiple imputation.

Results

We identified 72,110 new users of statin therapy (46% women) with a mean age of 65 years old. Most patients were dispensed a moderate-intensity statin at initiation (87% of women; 84% of men), followed by high-intensity (8% of women; 13% of men) and low-intensity statins (5% of women; 3% of men). Overall, 17% of women and 19% of men were uptitrated, with median times to uptitration of 535 days (Interquartile range (IQR) 181 – 1216) in women and 559 days (187 – 1240) in men. The adjusted RR of being uptitrated in women versus men was 0.92 (95% CI 0.87 – 0.97) for those without a history of CVD and 0.82 (0.73 – 0.92) for those with a history of CVD (pvalue for interaction = 0.02). Sex differences in statin uptitration were 0.90 (0.84 – 0.97) in those 40-60 years old, 0.91 (0.84 – 0.97) in those 60-70 years old, and 0.95 (0.93 – 1.00) in the older age category (70-99 years old).

Conclusion

Among new-statin users, women receive lower statin intensities than men and are less likely to be uptitrated than men.
Lipoprotein(a) and referrals to a specialist lipid clinic
Authors: Kennedy C , Malone R , Hennessy M , O'connor P
Published: June 2024

Background

Lp(a) is raised in approximately 1 in 5 of the population. Thresholds indicating a raised Lp(a) level vary; >70nmol/L for our assay, >125nmol/L in some studies; with a level >430nmol/L described in guidance as conferring a ASCVD risk equivalent to heterozygous familial hypercholesterolemia (hFH). Higher Lp(a) levels increase measured LDL level.[1] This may lead to increased referrals to a specialist lipid clinic and increased testing for hFH.

Purpose

To determine if raised Lp(a) levels are reflected in referrals as well as downstream investigations and treatment.

Methods

An ethically approved retrospective cohort study was performed including consecutive adult patients attending a specialist lipid clinic over a six-month period. Patient data analyzed included demographics, clinical characteristics, treatments and biochemical profiles. Those with a level >70nmol/L were considered to have raised Lp(a). Groups were compared using Chi-squared tests and t-tests.

Results

330 patients had a Lp(a) result available. 39% had a Lp(a) level >70nmol/L, 33% with >125nmol/L and 5% with >430nmol/L [Figure 1]. 55% of those with a Lp(a) >70nmol/L were female and their mean age was 49 years (SD+/-13), both consistent with the cohort as a whole. The percentages referred due to ‘high cholesterol’ or ‘assessment for familial hypercholesterolemia’ was equivalent for the raised versus normal Lp(a) groups (50% v 47%; p=0.42). The groups were also similar in terms of; family history of early CVD (40% each), baseline cholesterol levels (8.2 v 7.8mmol/L; p=0.12), baseline LDL levels (5.7 v 5.5mmol/L; p=0.34), genetic testing for hFH (61% v 58%; p=0.59), positive hFH genotypes (17% v 21%; p=0.57) and treatment with a high-intensity statin (34% v 30%; p=0.26).

Conclusions

The high proportion of patients with raised Lp(a) in this cohort indicates raised Lp(a) increases the likelihood of referral to a lipid clinic. While limited by the moderate cohort size, increased levels were not reflected by differences in reasons for referral, baseline cholesterol levels, tests for hFH or treatment. Cohort stratified by Lp(a) level.
Increased low-density lipoprotein cholesterol predict the risk of progressive structural but not functional cardiac damage in youth: a 7-year follow-up study
Authors: Agbaje A O
Published: June 2024

Background

Childhood low-density lipoprotein cholesterol (LDL-c) has been associated with cardiovascular events in mid-adulthood. Recent evidence suggests that cumulative LDL-c may not contribute to sub-clinical atherosclerosis progression during growth from mid-adolescence through young adulthood. However, whether increasing LDL-c associate with premature cardiac damage in youth remains unclear.

Purpose

To investigate the longitudinal association of changes in LDL-c with the risk of progressive structural and functional cardiac damage in youth.

Methods

From Avon Longitudinal Study of Parents and Children (ALSPAC), UK birth cohort, 1595 adolescents aged 17 years who had fasting plasma LDL-c estimated with Friedewald equation at 17- and 24-year clinic visits were included. Repeated echocardiography measured LVM indexed for height2.7 (LVMI2.7), relative wall thickness (RWT), LV diastolic function from mitral E/A ratio (LVDF), and LV filling pressure from E/e´ ratio (LVFP) were available at baseline and follow-up. LVMI2.7 ≥51g/m2.7, RWT ≥0.44, LVDF <1.5, and LVFP ≥8 were categorised as LV hypertrophy, high RWT, LVD dysfunction, and high LVFP, respectively. Multivariable adjusted associations were examined using generalized linear mixed-effect models and generalized logit mixed-effect models and adjusted for sex, and time-varying covariates measured at both baseline and follow-up such as age, insulin, high-sensitivity C-reactive protein, heart rate, systolic blood pressure, glucose, fat mass, lean mass, smoking status, family history of hypertension/diabetes/high cholesterol/vascular disease, socioeconomic status, sedentary time, light physical activity, moderate-to-vigorous physical activity, high-density lipoprotein cholesterol, and triglyceride.

Results

Among 1595 adolescents (mean [SD] age at baseline, 17.74 [0.38] years; 955 [59.8%] females]) LDL-c increased in males from 1.97 mmol/L to 2.37 mmol/L and in females from 2.23 mmol/L to 2.37 mmol/L, over 7 years. The prevalence of LV hypertrophy increased in males from 3.6% to 11.9% and in females from 1.6% to 4% over 7 years. The prevalence of LVD dysfunction increased in males from 7.8% to 16.6% and in females from 10.3% to 15.4%. In a fully adjusted model, a 1-mmol/L increase in LDL-c was significantly associated with higher odds of LVH progression (odds ratio 1.19; [95% CI, 1.08 – 1.32]) and high RWT (1.14; [1.01 – 1.29]), but not LVD dysfunction (0.96 [0.85 – 1.09]) and high LVFP (1.07; [0.97 – 1.19]) over 7 years. Among females, a 1 mmol/L increase in LDL-c was associated with 0.005cm [0.002 – 0.007], p<0.001) increase in RWT but not in males after full adjustments. In both males and females, increased LDL-c was not significantly associated with changes in LVMI and cardiac function.

Conclusion

Increased LDL-c was associated with progressive structural but not functional cardiac damage during growth from adolescence through young adulthood.
Cardiovascular health profile of cancer survivors: real-world insights from the Polish Norwegian Study (PONS)
Authors: Vaidean G , Manczuk M
Published: June 2024

Background

The European Society of Cardiology guidelines on cardio-oncology care recommend that oncological patients receive cardiovascular prevention counseling to control cardiovascular risk factors and to promote long-term healthy lifestyle.

Purpose

To assess the attainment of cardiovascular risk factor control among adult cancer survivors in a community setting and to explore potential gender disparities.

Methods

Cross-sectional, baseline data from PONS study, a population-based cohort of adults ages 45 to 64 years. From the total sample of 12,697 participants, we analyzed data from 442 individuals (3.48%) who reported having been diagnosed with any type of cancer. Trained technicians administered structured questionnaires, performed anthropometrics and collected fasting blood samples. We performed univariate analysis to assess the prevalence of ‘Life’s essential 8’ ideal cardiovascular health factors, and multivariable logistic regression to estimate predictors of goal attainment.

Results

There were 343 (77.6%) women and 99 men (22.4%) cancer survivors, with a mean age of 57.7 years (SD 4.7) at a median (IQR) 8 (3-11) years post cancer diagnosis. Participants reported having been diagnosed with coronary heart disease (10.6%), stroke (2.0%), heart failure (9.7%), hypertension (44.1%), diabetes (7.5%), and hyperlipidemia (19.2%). Cardiovascular risk factors control was achieved as follows: not smoking currently, 82%, leisure time physical activity at least 150 min/week, 31.5%, consuming 4 ideal dietary components, 0.45%, at least 2 ideal dietary components, 63.8%, sleep duration 7-9 h, 61.5%, BMI < 25 kg/msq, 26%, blood pressure < 120/80 mmHg, 15.8%, blood pressure < 140/90 75.8%, fasting glucose < 100 mg/dl, 69.9%, LDL-C < 70 mg/dL, 5.66%, LDL-C < 190 mg/dL, 96.3%, visited a doctor within the past year, 88.5%. More men (23.2%) than women (16.6%) reported history of cardiovascular disease, while more women (90.9%) than men (79.8%) visited a doctor during the past year (p< 0.01). No cancer survivor achieved all traditional ‘essential eight’ ideal cardiovascular health factors. More women (27.9%) than men (17.7%) achieved at least three out of the 8 essential factors, OR 1.88, 95% CI 1.06-3.3. This association persisted after adjusting for age, prevalent CVD, doctor visits, education, urban/rural residence, and years post cancer diagnosis, OR= 1.92, 95% CI 1.06-3.50.

Conclusion

In this ‘real world’ community-based sample of cancer survivors, major cardiovascular risk factors remain poorly controlled, with women displaying a minor potential advantage. Our findings support the need for a more intensive risk factors management and lifestyle change counseling.
Cardiovascular risk in cancer patients treated with immune checkpoint inhibitors: challenges and future directions
Authors: Tan Sean , Nelson Adam J , Muthalaly Rahul G , Ramkumar Satish , Hamilton Joshua , Nerlekar Nitesh , Segelov Eva , Nicholls Stephen J
Published: June 2024

Cardiovascular disease is the leading cause of non-cancer related mortality and morbidity among people living with or cured from cancer. Immune checkpoint inhibitors (ICIs) are systemic anti-cancer therapies that have revolutionized the treatment of numerous cancers, even achieving durable long-term responses among patients with metastatic disease. However, the pro-inflammatory effects of ICIs have been postulated to increase the risk of atherosclerotic cardiovascular disease (ASCVD) in cancer survivorship. Standard modifiable cardiovascular risk factors can further contribute to ASCVD risk during cancer survivorship but are not routinely screened and are often untreated in patients with cancer. With the expanding use of ICIs leading to improved cancer survivorship, cardiovascular risk identification and prevention will be paramount in the care of patients with cancer. This review highlights the practical challenges associated with ASCVD prevention among the growing number of patients treated with ICIs for cancer, including balancing competing mortality risks from cancer and ASCVD, the lack of ICI-specific cardiovascular risk stratification tools, potential interactions between cardiovascular and oncological therapies, and barriers to implementation of cardiovascular screening and prevention within existing healthcare systems.
MACCABI-RED, community emergency care at the press of a button: a descriptive study
Authors: Bar-Yishay Mattan , Adler Limor , Bar El Alon , Boker Faran Limor , Mizrahi Reuveni Miri , Sternberg Shelley A , Schejter Eduardo , Radomyslsky Zorian , Segal Yakov , Azuri Joseph , Yehoshua Ilan
Published: June 2024

Background

Maccabi-RED is a new service developed in Israel that allows primary care staff to direct urgent cases to specialists in the community for evaluation in their local clinics on the same day as an alternative to an emergency department (ED) visit. A primary care physician or a nurse can activate the service, and all nearby specialists receive “a call” and can decide if they are willing to accept it, thus allowing the patient to avoid an unnecessary visit to the ED.

Aim

To quantify and characterize the medical care provided by this service in a large national healthcare system.

Design and Setting

Multicenter, community-based, retrospective cohort study.

Methods

All Maccabi-RED visits recorded between September 2021 and August 2022 were included. Patient characteristics were compared to national demographics. Descriptive statistics were used to present data regarding recorded diagnoses, treating physicians, treatments or referrals provided, and subsequent emergency department admissions or hospitalizations.

Results

31831 visits were recorded. Most frequent diagnoses were musculoskeletal pain (12.1%), otitis or otalgia (7.8%), contusions (7.6%), fractures (7.1%), foreign body (6.7%), pregnancy-related symptoms (6.3%), and upper-respiratory or unspecified viral infection (6.3%). The most common treatments reported were foreign body removal (5%) and cast application (3.5%). Only 7.8% of visits resulted in emergency department admission within seven days (any cause). The average time from patient request to physician treatment was 91 min.

Conclusions

Maccabi-RED is being widely used by patients nationwide. Additional studies are needed to investigate whether Maccabi-RED reduces emergency department visits and costs.
The WUSCHEL-related homeobox transcription factor CsWOX3 negatively regulates fruit spine morphogenesis in cucumber (Cucumis sativus L.)
Authors: Xu Shuo , Wang Yaru , Yang Songlin , Fan Shanshan , Shi Kexin , Wang Fang , An Menghang , Qi Yu , Wang Mingqi , Feng Min , Li Zhifang , Liu Xingwang , Ren Huazhong
Published: June 2024

Cucumber (Cucumis sativus L.) is a widely cultivated crop with rich germplasm resources, holding significant nutritional value. It also serves as an important model for studying epidermal cell fate and sex determination. Cucumbers are covered with multicellular and unbranched trichomes, including a specific type called spines found on the surface of the fruit. The presence and density of these fruit spines determine the visual quality of cucumber fruits. However, the key regulatory genes and mechanisms underlying cucumber fruit spine development remain poorly understood. In this study, we identified a WUSCHEL-related homeobox (WOX) family gene CsWOX3, which functioned as a typical transcriptional repressor and played a negative role in fruit spine development. Spatial–temporal expression analysis revealed that CsWOX3 exhibited a relatively high expression level in the cucumber female floral organs, particularly in the fruit exocarp. Knockout of CsWOX3 using CRISPR/Cas9 resulted in a significant 2-to-3-fold increase in the diameter of fruit spines base, while overexpression led to a 17% decrease in the diameter compared to the wild-type. A SQUAMOSA PROMOTER BINDING PROTEIN-LIKE transcription factor CsSPL15 could directly bind and activate the expression of CsWOX3, thereby suppressing the expression of downstream auxin-related genes, such as CsARF18. Additionally, the RING-finger type E3 ubiquitin ligase CsMIEL1-like interacted with the HD domain of CsWOX3, which might result in the ubiquitination and subsequent alteration in protein stability of CsWOX3. Collectively, our study uncovered a WOX transcription factor CsWOX3 and elucidated its expression pattern and biological function. This discovery enhances our comprehension of the molecular mechanism governing cucumber fruit spine morphogenesis.
NREM Slow-Wave Activity in Adolescents Is Differentially Associated With ADHD Levels and Normalized by Pharmacological Treatment
Authors: Reicher Vivien , Szalárdy Orsolya , Bódizs Róbert , Vojnits Blanka , Magyar Tárek Zoltán , Takács Mária , Réthelyi János M , Bunford Nóra
Published: June 2024

Background

A compelling hypothesis about attention-deficit/hyperactivity disorder (ADHD) etiopathogenesis is that the ADHD phenotype reflects a delay in cortical maturation. Slow-wave activity (SWA) of non-rapid eye movement (NREM) sleep electroencephalogram (EEG) is an electrophysiological index of sleep intensity reflecting cortical maturation. Available data on ADHD and SWA are conflicting, and developmental differences, or the effect of pharmacological treatment, are relatively unknown.

Methods

We examined, in samples (Mage = 16.4, SD = 1.2), of ever-medicated adolescents at risk for ADHD (n = 18; 72% boys), medication-naïve adolescents at risk for ADHD (n = 15, 67% boys), and adolescents not at risk for ADHD (n = 31, 61% boys) matched for chronological age and controlling for non-ADHD pharmacotherapy, whether ADHD pharmacotherapy modulates the association between NREM SWA and ADHD risk in home sleep.

Results

Findings indicated medication-naïve adolescents at risk for ADHD exhibited greater first sleep cycle and entire night NREM SWA than both ever-medicated adolescents at risk for ADHD and adolescents not at risk for ADHD and no difference between ever-medicated, at-risk adolescents, and not at-risk adolescents.

Conclusions

Results support atypical cortical maturation in medication-naïve adolescents at risk for ADHD that appears to be normalized by ADHD pharmacotherapy in ever-medicated adolescents at risk for ADHD. Greater NREM SWA may reflect a compensatory mechanism in middle-later adolescents at risk for ADHD that normalizes an earlier occurring developmental delay.
Making a case for outpatient parenteral antimicrobial therapy (OPAT)
Authors: Seaton R A , Gilchrist M
Published: June 2024

In the wake of the COVID-19 pandemic, and its negative impact on both acute and elective care and decline in available inpatient resources, there is an imperative to maximize safe and effective alternatives to inpatient hospital care. Properly governed outpatient parenteral antimicrobial therapy (OPAT) services embed the principles of antimicrobial stewardship (AMS) (including use of early oral therapy) and support admission avoidance and early discharge for a growing range of patient groups with complex infections through well-organized multidisciplinary team working. Expansion of OPAT aligns with the UK’s national strategy to deliver care closer to home and cost-effectively maximize use of inpatient resources. OPAT serves as an exemplar to other ambulatory services and presents opportunities for developing and assuring AMS strategies within the rapidly developing hospital-at-home and virtual ward environments.
Monoamine oxidase-A (MAO-A) low-expression variants and increased risk of Plasmodium vivax malaria relapses
Authors: Puça Maria Carolina Silva De Barros , Rodrigues Danielle Fonseca , Salazar Yanka Evellyn Alves Rodrigues , Louzada Jaime , Fontes Cor Jesus Fernandes , Daher André , Pereira Dhélio Batista , Fernandes Vieira José Luiz , Carvalho Luzia Helena , Alves de Brito Cristiana Ferreira , Gil José Pedro , Nobrega de Sousa Tais
Published: June 2024

Objectives

Primaquine is essential for the radical cure of Plasmodium vivax malaria and must be metabolized into its bioactive metabolites. Accordingly, polymorphisms in primaquine-metabolizing enzymes can impact the treatment efficacy. This pioneering study explores the influence of monoamine oxidase-A (MAO-A) on primaquine metabolism and its impact on malaria relapses.

Methods

Samples from 205 patients with P. vivax malaria were retrospectively analysed by genotyping polymorphisms in MAO-A and cytochrome P450 2D6 (CYP2D6) genes. We measured the primaquine and carboxyprimaquine blood levels in 100 subjects for whom blood samples were available on the third day of treatment. We also examined the relationship between the enzyme variants and P. vivax malaria relapses in a group of subjects with well-documented relapses.

Results

The median carboxyprimaquine level was significantly reduced in individuals carrying low-expression MAO-A alleles plus impaired CYP2D6. In addition, this group experienced significantly more P. vivax relapses. The low-expression MAO-A status was not associated with malaria relapses when CYP2D6 had normal activity. This suggests that the putative carboxyprimaquine contribution is irrelevant when the CYP2D6 pathway is fully active.

Conclusions

We found evidence that the low-expression MAO-A variants can potentiate the negative impact of impaired CYP2D6 activity, resulting in lower levels of carboxyprimaquine metabolite and multiple relapses. The findings support the hypothesis that carboxyprimaquine may be further metabolized through CYP-mediated pathways generating bioactive metabolites that act against the parasite.
Multilateral Maritime Exercises, Grand Strategy, and Strategic Change: The American Case and Beyond
Authors: Dombrowski Peter , Reich Simon
Published: June 2024

Military exercises are largely overlooked by scholars of international security, despite the fact that exercise planning, execution, and analysis represent a huge investment of any military’s energy. Nonetheless, they offer the possibility of a rich research program about what states prioritize and how they adjudge their relationship to other state and non-state actors. We examine the role that multilateral maritime exercises (MMEs) play in the implementation of grand strategy in three regions—Europe, the Middle East, and the Indo-Pacific. Our central proposition is that as American policymakers and military leaders’ perception of a strategic threat increases, the purpose, numbers, and participants in MMEs will change. MMEs will move from a focus on peacetime operations to those designed for military crisis response or management, or for preparation for war.
Integration of QTL and transcriptome approaches for the identification of genes involved in tomato response to nitrogen deficiency
Authors: Desaint Henri , Héreil Alexandre , Belinchon-Moreno Javier , Carretero Yolande , Pelpoir Esther , Pascal Michel , Brault Marie , Dumont Doriane , Lecompte François , Laugier Patricia , Duboscq Renaud , Bitton Frederique , Grumic Mara , Giraud Christophe , Ferrante Paola , Giuliano Giovanni , Sunseri Francesco , Causse Mathilde
Published: June 2024

Optimizing plant nitrogen (N) usage and inhibiting N leaching loss in the soil–crop system is crucial to maintaining crop yield and reducing environmental pollution. This study aimed at identifying quantitative trait loci (QTLs) and differentially expressed genes (DEGs) between two N treatments in order to list candidate genes related to nitrogen-related contrasting traits in tomato varieties. We characterized a genetic diversity core-collection (CC) and a multi-parental advanced generation intercross (MAGIC) tomato population grown in a greenhouse under two nitrogen levels and assessed several N-related traits and mapped QTLs. Transcriptome response under the two N conditions was also investigated through RNA sequencing of fruit and leaves in four parents of the MAGIC population. Significant differences in response to N input reduction were observed at the phenotypic level for biomass and N-related traits. Twenty-seven QTLs were detected for three target traits (leaf N content, leaf nitrogen balance index, and petiole NO3− content), 10 and six in the low and high N condition, respectively, while 19 QTLs were identified for plasticity traits. At the transcriptome level, 4752 and 2405 DEGs were detected between the two N conditions in leaves and fruits, respectively, among which 3628 (50.6%) in leaves and 1717 (71.4%) in fruit were genotype specific. When considering all the genotypes, 1677 DEGs were shared between organs or tissues. Finally, we integrated DEG and QTL analyses to identify the most promising candidate genes. The results highlighted a complex genetic architecture of N homeostasis in tomato and novel putative genes useful for breeding tomato varieties requiring less N input.
Immuno-electron microscopy localizes Caenorhabditis elegans vitellogenins along the classic exocytosis route
Authors: Zhai Chao , Zhang Nan , Li Xi-Xia , Tan Xue-Ke , Sun Fei , Dong Meng-Qiu
Published: June 2024

Vitellogenins (VITs) are the most abundant proteins in adult hermaphrodite Caenorhabditis elegans. VITs are synthesized in the intestine, secreted to the pseudocoelom, matured into yolk proteins, and finally deposited in oocytes as nutrients for progeny development. How VITs are secreted out of the intestine remains unclear. Using immuno-electron microscopy (immuno-EM), we localize intestinal VITs along an exocytic pathway consisting of the rough endoplasmic reticulum (ER), the Golgi, and the lipid bilayer-bounded VIT vesicles (VVs). This suggests that the classic exocytotic pathway mediates the secretion of VITs from the intestine to the pseudocoelom. We also show that pseudocoelomic yolk patches (PYPs) are membrane-less and amorphous. The different VITs/yolk proteins are packed as a mixture into the above structures. The size of VVs can vary with the VIT levels and the age of the worm. On adult Day 2 (AD 2), intestinal VVs (~200 nm in diameter) are smaller than gonadal yolk organelles (YOs, ~500 nm in diameter). VVs, PYPs, and YOs share a uniform medium electron density by conventional EM. The morphological profiles documented in this study serve as a reference for future studies of VITs/yolk proteins.
Simba-C: the evolution of the thermal and chemical properties in the intragroup medium
Authors: Hough Renier T , Shao Zhiwei , Cui Weiguang , Loubser S Ilani , Babul Arif , Davé Romeel , Rennehan Douglas , Kobayashi Chiaki
Published: June 2024

The newly updated GIZMO and Simba based simulation, Simba-C, with its new stellar feedback, chemical enrichment, and recalibrated AGN feedback, allows for a detailed study of the intragroup medium X-ray properties. We discuss the impact of various physical mechanisms, e.g. stellar and AGN feedback, and chemical enrichment, on the composition and the global scaling relations of nearby galaxy groups. We also study the evolution (z = 2 to 0) of the global properties for the $1\, \mathrm{keV}$ temperature groups. Simba-C shows improved consistent matching with the observations of all X-ray scaling relations compared to Simba. It is well known that AGN feedback has a significant influence on LX, 0.5–2.0–Tspec, corr, S500/2500–Tspec, corr, and gas mass fractions, with our Simba-C results consistent with it. Our recalibrated AGN feedback strength also showed an additional improvement in gas entropy, which now aligns with CLoGS observations. The updated stellar feedback and chemical enrichment model is shown to play an important role in our understanding of the chemical abundance ratios and their evolution within galaxy groups. In particular, we find that Simba-C produces an increase in the amount of heavier elements (specifically Si and Fe) relative to O, compared to Simba.
Diagnosing the massive-seed pathway to high-redshift black holes: statistics of the evolving black hole to host galaxy mass ratio
Authors: Scoggins Matthew T , Haiman Zoltán
Published: June 2024

Supermassive black holes (SMBHs) with masses of ∼109 M⊙ within the first billion year of the universe challenge our conventional understanding of black hole formation and growth. One pathway to these SMBHs proposes that supermassive stars born in pristine atomic cooling haloes yield massive seed BHs evolving to these early SMBHs. This scenario leads to an overly massive BH galaxy (OMBG), in which the BH to stellar mass ratio is initially Mbh/M* ≥ 1, well in excess of the typical values of ∼10−3 at low redshifts. Previously, we have investigated two massive seed BH candidates from the Renaissance simulation and found that they remain outliers on the Mbh–M* relation until the OMBG merges with a much more massive halo at z = 8. In this work, we use Monte-Carlo merger trees to investigate the evolution of the Mbh–M* relation for 50 000 protogalaxies hosting massive BH seeds, across 10 000 trees that merge into a 1012 M⊙ halo at z = 6. We find that up to 60 per cent (depending on growth parameters) of these OMBGs remain strong outliers for several 100 Myr, down to redshifts detectable with JWST and with sensitive X-ray telescopes. This represents a way to diagnose the massive-seed formation pathway for early SMBHs. We expect to find ∼0.1–1 of these objects per JWST Near Infrared Camera (NIRCam) field per unit redshift at z ≳ 6. Recently detected SMBHs with masses of ∼107 M⊙ and low-inferred stellar-mass hosts may be examples of this population.
SUN5 interacts with nuclear membrane LaminB1 and cytoskeletal GTPase Septin12 mediating the sperm head-and-tail junction
Authors: Zhang Yunfei , Liu Gang , Huang Lihua , He Xiyi , Su Yuyan , Nie Xinmin , Mao Zenghui , Xing Xiaowei
Published: June 2024

Acephalic spermatozoa syndrome (ASS) is a severe teratospermia with decaudated, decapitated, and malformed sperm, resulting in male infertility. Nuclear envelope protein SUN5 localizes to the junction between the sperm head and tail. Mutations in the SUN5 gene have been identified most frequently (33–47%) in ASS cases, and its molecular mechanism of action is yet to be explored. In the present study, we generated Sun5 knockout mice, which presented the phenotype of ASS. Nuclear membrane protein LaminB1 and cytoskeletal GTPases Septin12 and Septin2 were identified as potential partners for interacting with SUN5 by immunoprecipitation–mass spectrometry in mouse testis. Further studies demonstrated that SUN5 connected the nucleus by interacting with LaminB1 and connected the proximal centriole by interacting with Septin12. The binding between SUN5 and Septin12 promoted their aggregation together in the sperm neck. The disruption of the LaminB1/SUN5/Septin12 complex by Sun5 deficiency caused separation of the Septin12-proximal centriole from the nucleus, leading to the breakage of the head-to-tail junction. Collectively, these data provide new insights into the pathogenesis of ASS caused by SUN5 deficiency.
Single-cell proteomics reveals decreased abundance of proteostasis and meiosis proteins in advanced maternal age oocytes
Authors: Galatidou Styliani , Petelski Aleksandra A , Pujol Aïda , Lattes Karinna , Latorraca Lais B , Fair Trudee , Popovic Mina , Vassena Rita , Slavov Nikolai , Barragán Montserrat
Published: June 2024

Advanced maternal age is associated with a decline in oocyte quality, which often leads to reproductive failure in humans. However, the mechanisms behind this age-related decline remain unclear. To gain insights into this phenomenon, we applied plexDIA, a multiplexed data-independent acquisition, single-cell mass spectrometry method, to analyze the proteome of oocytes from both young women and women of advanced maternal age. Our findings primarily revealed distinct proteomic profiles between immature fully grown germinal vesicle and mature metaphase II oocytes. Importantly, we further show that a woman’s age is associated with changes in her oocyte proteome. Specifically, when compared to oocytes obtained from young women, advanced maternal age oocytes exhibited lower levels of the proteasome and TRiC complex, as well as other key regulators of proteostasis and meiosis. This suggests that aging adversely affects the proteostasis and meiosis networks in human oocytes. The proteins identified in this study hold potential as targets for improving oocyte quality and may guide future studies into the molecular processes underlying oocyte aging.
Magnesium biology
Authors: Kröse Jana L , de Baaij Jeroen H F
Published: June 2024

Magnesium (Mg2+) is essential for energy metabolism, muscle contraction and neurotransmission. As part of the Mg–ATP complex, it is involved in over 600 enzymatic reactions. Serum Mg2+ levels are tightly regulated between 0.7 and 1.1 mmol/L by interplay of intestinal absorption and renal excretion. In the small intestine, Mg2+ is absorbed paracellularly via claudin-2 and -12. In the colon, transcellular absorption of Mg2+ is facilitated by TRPM6/7 and CNNM4. In the kidney, the proximal tubule reabsorbs only 20% of the filtered Mg2+. The majority of the filtered Mg2+ is reabsorbed in the thick ascending limb, where the lumen-positive transepithelial voltage drives paracellular transport via claudin-16/-19. Fine-tuning of Mg2+ reabsorption is achieved in the distal convoluted tubule (DCT). Here, TRPM6/7 tetramers facilitate apical Mg2+ uptake, which is hormonally regulated by insulin and epidermal growth factor. Basolateral Mg2+ extrusion is Na+ dependent and achieved by CNNM2 and/or SLC41A3. Hypomagnesemia (serum Mg2+ <0.7 mmol/L) develops when intestinal and/or renal Mg2+ (re)absorption is disturbed. Common causes include alcoholism, type 2 diabetes mellitus and the use of pharmacological drugs, such as proton-pump inhibitors, calcineurin inhibitors and thiazide diuretics. Over the last decade, research on rare genetic and acquired Mg2+ disorders have identified Mg2+ channel and transporter activity, DCT length, mitochondrial function and autoimmunity as mechanisms explaining hypomagnesemia. Classically, treatment of hypomagnesemia depended on oral or intravenous Mg2+ supplementation. Recently, prebiotic dietary fibers and sodium-glucose cotransporter 2 inhibitors have been proposed as promising new therapeutic pathways to treat hypomagnesemia.
Discrepancy between medical conditions self-reported by bus drivers and medical records
Authors: McCollum E
Published: June 2024

Background

Medical incapacity at the wheel is a rare but high-profile factor in accident causation. The UK Driver and Vehicle Licensing Agency (DVLA) does not require a review of medical records on the application for a bus licence, but applicants sign a self-declaration of medical history. There is debate over what, if any, verification of medical information is required for doctors who complete the medical assessment.

Aims

To assess how self-declaration compares against General Practitioner (GP) patient records for a series of bus drivers undergoing driver licensing assessment in a 12-month period.

Methods

Review of GP reports received for bus driver medicals undertaken in a 12-month period between 1 July 2022 and 30 June 2023.

Results

Of the 145 medicals undertaken, 12 (8.3%) GP reports contained undeclared medical conditions that required further evaluation and may have impacted on fitness to drive.

Conclusions

Studies into the contribution of medical incapacity at the wheel to vehicle accidents are sparse, as, thankfully, are the events themselves. Nevertheless, given the updated General Medical Council guidance to doctors on confidentiality and public protection responsibilities, and evidence to suggest that doctors’ knowledge of the DVLA guidelines is poor, it might be pertinent for the DVLA to reconsider its approach to driver self-reporting in some circumstances, given the discrepancy highlighted here.
Impact of fatigue on work productivity and health-related job loss
Authors: Macfarlane G J , D’Angelo S , Ntani G , Walker-Bone K
Published: June 2024

Background

Fatigue is commonly reported in population surveys and has been identified in patients with health conditions as a key co-morbidity which makes remaining in work challenging. Such patients, however, rarely have access to programmes to help them manage their fatigue.

Aims

To quantify the relationship between fatigue, work impairment and health-related job loss.

Methods

We use data from the Health and Employment After Fifty study, a longitudinal study of people aged 50–64 years when recruited through general practices in England in 2013–14. During follow-up, fatigue was measured using the Fatigue Assessment Scale, work impairment was assessed using the Work Productivity and Activity Impairment scale, and changes in employment status were recorded.

Results

A total of 2743 participants were eligible for the current analysis; 23% satisfied criteria for being fatigued. People who were fatigued were less likely to have a partner, university degree, be physically active and were more likely to be obese. Their job was more likely to involve shifts, be perceived as insecure, have reported difficulties coping with job demands, and be unsatisfying. After adjustment for socio-economic, lifestyle and work-related factors, they were almost twice as likely to report both work impairment (relative risk 1.8; 95% confidence interval [CI] 1.6, 2.1) and future health-related job loss, although the latter effect was only in those with other morbidities (incidence rate ratio 1.96; 95% CI 1.03–3.72).

Conclusions

Providing evidence-based support for workers with health conditions who experience fatigue may have an important impact at a population level in terms of extending working lives.
Efficacy of Fecal Microbiota, Live-jslm (REBYOTA®), Among Patients Exposed to Non–Clostridioides difficile Infection Antibiotics: Post Hoc Subgroup Analysis of a Phase 2 Open-Label Study
Authors: Reveles Kelly R , Gonzales-Luna Anne J , Golan Yoav , Alonso Carolyn D , Guthmueller Beth , Tan Xing , Bidell Monique R , Pokhilko Victoria , Crawford Carl V , Skinner Andrew M
Published: June 2024

Background

Antibiotic use is a major risk factor for recurrent Clostridioides difficile infection (CDI) due to the associated disruption in gut microbiota. Fecal microbiota, live-jslm (REBYOTA®; RBL, previously RBX2660), is the first microbiota-based live biotherapeutic approved by the US Food and Drug Administration to prevent recurrent CDI in adults following standard-of-care antibiotic treatment. To investigate the impact of non-CDI antibiotics on the durability of RBL, a subgroup analysis was conducted on PUNCH™ Open-Label study participants who received non-CDI antibiotics during the period between RBL administration and up to 2 years after.

Methods

Participants in PUNCH™ Open-Label who received non-CDI antibiotics after RBL administration were included in this subgroup analysis. Treatment response was defined as the absence of CDI diarrhea needing retreatment at the last evaluable time point (8 weeks, 6 months, 1 year, or 2 years) after RBL administration.

Results

Among participants from PUNCH™ Open-Label, 43 received non-CDI antibiotics after RBL administration but before CDI recurrence as evaluated over a 2-year period. Across all evaluable time points, 86% (37/43) of participants had a treatment response regardless of when non-CDI antibiotic exposure occurred. Treatment response was sustained for a median 470 days (IQR, 212–648) from the first day of non-CDI antibiotic use. Most participants (5/6) with CDI recurrences received a high-risk antibiotic.

Conclusions

RBL remained efficacious in participants with a history of recurrent CDI after subsequent non-CDI antibiotic exposure.

Clinical Trials Registration

NCT02589847 (https://clinicaltrials.gov/study/NCT02589847).
The association between physical intervention use and treatment outcomes in patients participating in an online and psychologically informed pain management program
Authors: McNaughton David T , Hancock Mark J , Bisby Madelyne A , Scott Amelia J , Jones Michael P , Dear Blake F
Published: June 2024

Background

The availability of multidisciplinary care for the management of chronic pain is uncommon outside specialist clinics. The present study aims to determine the physical intervention use of patients participating in an online psychological pain management program and whether exposure to physical interventions in these patients alters treatment outcomes compared with patients who do not access physical interventions.

Methods

Data were obtained from 2 previously published randomized controlled trials of an online psychological pain management program. Physical intervention exposure (categories: none, 1–3 sessions, 4+ sessions) was assessed at baseline, after treatment, and at 3-month follow-up. Primary outcomes included depression, anxiety, pain intensity, and pain-related disability. Generalized estimating equation models were used to compare treatment outcomes among those with different physical intervention frequencies and periods of exposure. We assessed whether changes in primary outcomes differed (moderated) by the period and category of physical intervention exposure.

Results

Of the patients (n = 1074) who completed the baseline questionnaire across both randomized controlled trials, 470 (44%) reported physical intervention use at baseline, 383 (38%) reported physical intervention use after treatment, and 363 (42%) reported physical intervention use at 3-month follow-up. On average, there were moderate–large reductions from baseline to after treatment with respect to all outcomes (Cohen’s d = 0.36–0.82). For all outcomes, the interaction of time by physical intervention exposure was statistically nonsignificant.

Conclusion

A substantial proportion of patients who participated in a psychologically informed pain management program were establishing, continuing, or stopping additional physical interventions. The frequency of and period of exposure to physical interventions did not appear to moderate treatment outcomes.

Clinical trial registration

Australian and New Zealand Clinical Trials Registry (ACTRN12613000252718 and ACTRN12615001003561). The website for registration information is https://www.anzctr.org.au
Emergent scale-free networks
Authors: Lynn Christopher W , Holmes Caroline M , Palmer Stephanie E
Published: June 2024

Many complex systems—from the Internet to social, biological, and communication networks—are thought to exhibit scale-free structure. However, prevailing explanations require that networks grow over time, an assumption that fails in some real-world settings. Here, we explain how scale-free structure can emerge without growth through network self-organization. Beginning with an arbitrary network, we allow connections to detach from random nodes and then reconnect under a mixture of preferential and random attachment. While the numbers of nodes and edges remain fixed, the degree distribution evolves toward a power-law with an exponent γ=1+1p that depends only on the proportion p of preferential (rather than random) attachment. Applying our model to several real networks, we infer p directly from data and predict the relationship between network size and degree heterogeneity. Together, these results establish how scale-free structure can arise in networks of constant size and density, with broad implications for the structure and function of complex systems.
Generic Diagonal Conic Bundles Revisited
Authors: Skorobogatov Alexei N , Sofos Efthymios
Published: June 2024

We prove a stronger form of our previous result that Schinzel’s Hypothesis holds for 100% of n-tuples of integer polynomials satisfying the usual necessary conditions, where the primes represented by the polynomials are subject to additional constraints in terms of Legendre symbols, as well as upper and lower bounds. We establish the triviality of the Brauer group of generic diagonal conic bundles over the projective line. Finally, we give an explicit lower bound for the probability that diagonal conic bundles in certain natural families have rational points.
Predictive validity of Lupus Patient-Reported Outcome for damage accrual in patients with systemic lupus erythematosus: the LUNA Registry
Authors: Nose Yoko , Onishi Akira , Nishimura Keisuke , Yamamoto Yuzuru , Sada Ken-ei , Ichinose Kunihiro , Yoshimi Ryusuke , Ohno Shigeru , Yanai Ryo , Kajiyama Hiroshi , Sato Shuzo , Shimojima Yasuhiro , Fujiwara Michio , Kida Takashi , Miyawaki Yoshia , Matsuo Yusuke , Tsuji Hideaki , Morinobu Akio , Saegusa Jun
Published: June 2024

Objectives

The predictive validity of disease-specific quality of life (QOL) remains unknown in patients with systemic lupus erythematosus (SLE), although disease-specific measures are equally or more responsive to changes than generic QOL. We aimed to examine the predictive validity of the Lupus Patient-Reported Outcome (PRO) for damage accrual.

Methods

Patients with SLE and ≥2 measurements over time were included in the Japanese nationwide multicentre registry (LUNA). The Lupus PRO questionnaire contains both health-related (HR) and non-HR QOL measures. Damage accrual was evaluated using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). We examined the association between the Lupus PRO score at baseline and longitudinal SDI scores using mixed-effects models adjusted for prognostic factors.

Results

Among 1295 patients, those with higher HR-QOL of Lupus PRO at baseline demonstrated a significantly lower increase in SDI (−0.005/year, 95% confidence interval [CI]: −0.007 to −0.004, P < 0.001). According to the categorization of HR-QOL based on tertile, a similar dose-dependent effect of HR-QOL on longitudinal SDI was identified (second vs first tertile category: −0.101/year, 95% CI: −0.172 to −0.030; third tertile category: −0.211/year, 95% CI: −0.281 to −0.142). Non-HR-QOL was not significantly associated with the SDI scores. Among the HR-QOL domains, cognition, procreation and physical health were significantly associated with the total SDI scores over time. HR-QOL was associated with corticosteroid-dependent and -independent SDI scores.

Conclusion

A higher HR-QOL of Lupus PRO was associated with a lower increase in SDI scores. Our findings imply the importance of disease-specific HR-QOL measurements in assessing prognosis.
Potential association between suicide risk, aggression, impulsivity, and the somatosensory system
Authors: Lee Yoojin , Gilbert Jessica R , Waldman Laura R , Zarate  Carlos A , Ballard Elizabeth D
Published: June 2024

Aggression and impulsivity are linked to suicidal behaviors, but their relationship to the suicidal crisis remains unclear. This magnetoencephalography (MEG) study investigated the link between aggression, impulsivity, and resting-state MEG power and connectivity. Four risk groups were enrolled: high-risk (HR; n = 14), who had a recent suicidal crisis; lower-risk (LR; n = 41), who had a history of suicide attempts but no suicide attempt or ideation in the past year; clinical control (CC; n = 38), who had anxiety/mood disorders but no suicidal history; and minimal risk (MR; n = 28), who had no psychiatric/suicidal history. No difference in resting-state MEG power was observed between the groups. Individuals in the HR group with high self-reported aggression and impulsivity scores had reduced MEG power in regions responsible for sensory/emotion regulation vs. those in the HR group with low scores. The HR group also showed downregulated bidirectional glutamatergic feedback between the precuneus (PRE) and insula (INS) compared to the LR, CC, and MR groups. High self-reported impulsivity was linked to reduced PRE to INS feedback, whereas high risk-taking impulsivity was linked to upregulated INS to postcentral gyrus (PCG) and PCG to INS feedback. These preliminary findings suggest that glutamatergic-mediated sensory and emotion-regulation processes may function as potential suicide risk markers.