Epigenetics to clinicopathological features: a bibliometric analysis of H3 G34-mutant diffuse hemispheric glioma literature.

PURPOSE: Pediatric-type diffuse high-grade gliomas are the leading cause of cancer-related morbidity and mortality in children. More than 30% of diffuse hemispheric gliomas (DHG) in adolescents harbor histone H3 G34 mutations and are recognized by the World Health Organization as a distinct tumor entity. By reporting bibliometric characteristics of the most cited publications on H3 G34-mutant DHG (H3 G34 DHG), we provide an overview of emerging literature and speculate where future research efforts may lead. METHODS: One hundred fourteen publications discussing H3 G34 DHG were identified, categorized as basic science (BSc), clinical (CL), or review (R), and ranked by citation number. Various bibliometric parameters were summarized, and a comparison between article types was performed. RESULTS: Articles within this study represent principal investigators from 15 countries and were published across 63 journals between 2012 and 2024, with 36.84% of articles originating in the United States. Overall median values were as follows: citation count, 20 (range, 0-2591), number of authors, 9 (range, 2-78), and year of publication, 2020 (range, 2012-2024). Among the top ten most cited articles, BSc articles accounted for all ten reports. Compared to CL and R articles, BSc articles were published in journals with higher impact factors. CONCLUSION: We establish variability in bibliometric parameters for the most cited publications on H3 G34 DHG. Our findings demonstrate a paucity of high-impact and highly cited CL reports and acknowledge an unmet need to intersect basic mechanism with clinical data to inform novel therapeutic approaches.

Patients with non-ischemic cardiomyopathy and mid-wall striae have similar arrhythmic outcomes as ischemic cardiomyopathy.

PURPOSE: While implantable cardioverter-defibrillator (ICD) therapy provides clear benefit in patients with ischemic cardiomyopathy (ICM), this is less clear in patients with non-ischemic cardiomyopathy (NICM). Mid-wall striae (MWS) fibrosis is an established cardiovascular magnetic resonance (CMR) risk marker observed in patients with NICM. We evaluated whether patients with NICM and MWS have similar risk of arrhythmia-related cardiovascular events as patients with ICM. METHODS: We studied a cohort of patients undergoing CMR. The presence of MWS was adjudicated by experienced physicians. The primary outcome was a composite of implantable cardioverter-defibrillator (ICD) implant, hospitalization for ventricular tachycardia, resuscitated cardiac arrest, or sudden cardiac death. Propensity-matched analysis was performed to compare outcomes for patients NICM with MWS and ICM. RESULTS: A total of 1,732 patients were studied, 972 NICM (706 without MWS, 266 with MWS) and 760 ICM. NICM patients with MWS were more likely to experience the primary outcome versus those without MWS (unadjusted subdistribution hazard ratio (subHR) 2.26, 95% confidence interval [CI] 1.51-3.41) with no difference versus ICM patients (unadjusted subHR 1.32, 95% CI 0.93-1.86). Similar results were seen in a propensity-matched population (adjusted subHR 1.11, 95% CI 0.63-1.98, p = 0.711). CONCLUSION: Patients with NICM and MWS demonstrate significantly higher arrhythmic risk compared to NICM without MWS. After adjustment, the arrhythmia risk of patients with NICM and MWS was similar to patients with ICM. Accordingly, physicians could consider the presence of MWS when making clinical decisions regarding arrhythmia risk management in patients with NICM.

Evaluating the effects of minimum unit pricing in Scotland on the prevalence of harmful drinking: a controlled interrupted time series analysis.

OBJECTIVES: In May 2018, the Scottish Government introduced a minimum unit price (MUP) for alcohol of £0.50 (1 UK unit = 8 g ethanol) to reduce alcohol consumption, particularly among people drinking at harmful levels. This study aimed to evaluate MUP's impact on the prevalence of harmful drinking among adults in Scotland. STUDY DESIGN: This was a controlled interrupted monthly time series analysis of repeat cross-sectional data collected via 1-week drinking diaries from adult drinkers in Scotland (N = 38,674) and Northern England (N = 71,687) between January 2009 and February 2020. METHODS: The primary outcome was the proportion of drinkers consuming at harmful levels (>50 [men] or >35 [women] units in diary week). The secondary outcomes included the proportion of drinkers consuming at hazardous (≥14-50 [men] or ≥14-35 [women] units) and moderate (<14 units) levels and measures of beverage preferences and drinking patterns. Analyses also examined the prevalence of harmful drinking in key subgroups. RESULTS: There was no significant change in the proportion of drinkers consuming at harmful levels (ß = +0.6 percentage points; 95% confidence interval [CI] = -1.1, +2.3) or moderate levels (ß = +1.4 percentage points; 95% confidence interval = -1.1, +3.8) after the introduction of MUP. The proportion consuming at hazardous levels fell significantly by 3.5 percentage points (95% CI = -5.4, -1.7). There were no significant changes in other secondary outcomes or in the subgroup analyses after correction for multiple testing. CONCLUSIONS: Introducing MUP in Scotland was not associated with reductions in the proportion of drinkers consuming at harmful levels but did reduce the prevalence of hazardous drinking. This adds to previous evidence that MUP reduced overall alcohol consumption in Scotland and consumption among those drinking above moderate levels.

Paradigm Shifts in Cardiac Pacing: Where Have We Been and What Lies Ahead?

The history of cardiac pacing dates back to the 1930s with externalized pacing and has evolved to incorporate transvenous, multi-lead, or even leadless devices. Annual implantation rates of cardiac implantable electronic devices have increased since the introduction of the implantable system, likely related to expanding indications, and increasing global life expectancy and aging demographics. Here, we summarize the relevant literature on cardiac pacing to demonstrate the enormous impact it has had within the field of cardiology. Further, we look forward to the future of cardiac pacing, including conduction system pacing and leadless pacing strategies.

A large outbreak of the Kappa mutation of COVID-19 in Cork, Ireland, April-May 2021.

BACKGROUND: In May 2021, the B.1.617 variant of SARS-CoV-2 emerged in Ireland, and both Delta and Kappa sub-lineages were initially deemed variants of concern (VOCs) on a precautionary basis. We describe a large outbreak of SARS-CoV-2 B.1.617.1 (Kappa mutation) linked to a private gathering among third level students in Cork, Ireland. METHODS: Surveillance data were available from the Health Service Executive COVID Care Tracker. The epidemiological sequence of infection for each new case in this outbreak was tracked and whole genome sequencing was requested on all linked cases. Enhanced public health control measures were implemented by the Department of Public Health HSE-South to contain onward spread of VOCs, including retrospective contact tracing, lengthy isolation and quarantine periods for cases and close contacts. Extensive surveillance efforts were used to describe and control onward transmission. RESULTS: There were 146 confirmed SARS-CoV-2 cases linked to the outbreak. All sequenced cases (53/146; 36%) confirmed Kappa mutation. The median age was 21 years (range 17-65). The majority (88%) had symptoms of SARS-CoV-2 infection. There were 407 close contacts; the median was 3 per case (range 0-14). There were no known hospitalisations, ICU admissions or deaths. Vaccination data was unavailable, but the outbreak pre-dated routine availability of COVID-19 vaccines among younger adults in Ireland. CONCLUSION: Enhanced public health control measures for new and emerging variants of SARS-CoV-2 may be burdensome for cases and close contacts. The overall public health benefit of enhanced controls may only become apparent when evidence on disease transmissibility and severity becomes more complete.

A Far-Red Molecular Rotor Fluorogenic Trehalose Probe for Live Mycobacteria Detection and Drug-Susceptibility Testing.

Increasing the speed, specificity, sensitivity, and accessibility of mycobacteria detection tools are important challenges for tuberculosis (TB) research and diagnosis. In this regard, previously reported fluorogenic trehalose analogues have shown potential, but their green-emitting dyes may limit sensitivity and applications in complex settings. Here, we describe a trehalose-based fluorogenic probe featuring a molecular rotor turn-on fluorophore with bright far-red emission (RMR-Tre). RMR-Tre, which exploits the unique biosynthetic enzymes and environment of the mycobacterial outer membrane to achieve fluorescence activation, enables fast, no-wash, low-background fluorescence detection of live mycobacteria. Aided by the red-shifted molecular rotor fluorophore, RMR-Tre exhibited up to a 100-fold enhancement in M. tuberculosis labeling compared to existing fluorogenic trehalose probes. We show that RMR-Tre reports on M. tuberculosis drug resistance in a facile assay, demonstrating its potential as a TB diagnostic tool.

Evaluation of the impact of PEPFAR transition on retention in care in South Africa's Western Cape Province.

BACKGROUND: Research on the impact of the US President's Emergency Plan for AIDS Relief (PEPFAR) transition in South Africa (SA) in 2012 found varying results in retention in care (RIC) of people living with HIV (PLWH). OBJECTIVES: To investigate the factors that impacted RIC during the PEPFAR transition in Western Cape Province, SA, in 2012. METHODS: We used aggregate data from 61 facilities supported by four non-governmental organisations from 2007 to 2015. The main outcome was RIC 12 months after antiretroviral therapy initiation for two periods - during PEPFAR and post PEPFAR. We used adjusted quantile regression to estimate the effect of the PEPFAR pull-out on RIC. RESULTS: Regression models (50th quantile) for 12-month RIC showed a 4.0% (95% CI -7.7 - -0.4%) decline in RIC post-direct service. Facilities supported by Anova/Kheth'impilo fared worst post PEFPAR, with a decline in RIC of -4.9% (95% CI -8.8 - -1.0%), while TB, HIV/AIDS, Treatment Support, and Integrated Therapy (that'sit) fared best (3.6% increase in RIC; 95% CI: -0.2 - 7.3%). There was a decrease in RIC when comparing urban with rural areas (-7.8%; 95% CI -12.8 - -2.9%). City of Cape Town combined with Western Cape Government health facilities showed a substantial decrease (-6.1%; 95% CI -10.6 - -1.7%), while community health clinic (v. central day clinics) declined (-6.4; 95% CI -10.6 - -2.1%) in RIC. We observed no RIC difference by facility size and a slight increase when two or more human resources transitioned from PEPFAR to the government. CONCLUSION: When PEPFAR funding decreased in 2012, there was a decrease in RIC. To ensure the continuity of HIV care when a major funder withdraws sufficient and stable transition resources, investment in organisations that understand the local context, joint planning and co-ordination are required.

Clinical Updates in Cardiac Pacing-The Future Is Bright.

The history of cardiac pacing has been defined by many innovation milestones starting in the early 1960s [...].

The impact of glycaemic load on cognitive performance: A meta-analysis and guiding principles for future research.

The effect of breakfast glycaemic load (GL) on cognition was systematically examined. Randomised and non-randomised controlled trials were identified using PubMed, Scopus, and Cochrane Library (up to May 2022). 15 studies involving adults (aged 20 - 80 years) were included. Studies had a low risk, or some concerns, of bias. A random-effects meta-analysis model revealed no effect of GL on cognition up to 119 min post-consumption. However, after 120 min, immediate episodic memory scores were better following a low-GL compared to a high-GL (SMD = 0.16, 95% confidence interval [CI] = -0.00 to 0.32, p = 0.05, I2 = 5%). Subgroup analyses indicated that the benefit was greater in younger adults (<35 years) and those with better GT. A qualitative synthesis of 16 studies involving children and adolescents (aged 5 - 17 years) suggested that a low-GL breakfast may also benefit episodic memory and attention after 120 min. Methodological practises were identified which could explain a failure to detect benefits in some studies. Consequently, guiding principles were developed to optimise future study design.

Functional connectivity of the world's protected areas.

Global policies call for connecting protected areas (PAs) to conserve the flow of animals and genes across changing landscapes, yet whether global PA networks currently support animal movement-and where connectivity conservation is most critical-remain largely unknown. In this study, we map the functional connectivity of the world's terrestrial PAs and quantify national PA connectivity through the lens of moving mammals. We find that mitigating the human footprint may improve connectivity more than adding new PAs, although both strategies together maximize benefits. The most globally important areas of concentrated mammal movement remain unprotected, with 71% of these overlapping with global biodiversity priority areas and 6% occurring on land with moderate to high human modification. Conservation and restoration of critical connectivity areas could safeguard PA connectivity while supporting other global conservation priorities.

Covid-19 Epidemic Impact on Clinical Training in Irish GP Training.

Aim To describe the effect of the Covid pandemic on the general practice workplace based learning of GP training in Ireland. Methods A prospective national survey of GP trainees who were in their GP practice placements on three separate occasions throughout the winter pandemic of 2020/2021 Results The average response rate to the three surveys was 19.4%. As the pandemic worsened, the number of face to face consultations dropped so that 51% (n=41) of trainees were seeing less than 5 patients face to face by the third survey. Conversely, the number of telephone/video consultations rose so that by the third survey 54% (n=44) of trainees were conducting more than 16 consultations per day remotely. Examinations and GP presentations expected to be daily occurrences diminished as the pandemic grew more severe, such that by the third survey 24-25% of trainees had not conducted a respiratory examination or dealt with new/unexpected hypertension in the previous month. Conclusion This study demonstrates abrupt change to the normal course of their training which was experienced by Irish GP trainees as a result of Covid, with examples from clinical practice. Adaptions of the training programme helped mitigate against the effects of the pandemic.

Differential impacts of economic and demographic variables on substance use patterns during the COVID-19 pandemic.

Background: The COVID-19 pandemic and subsequent economic crisis has provided a unique opportunity to investigate the effects of economic shifts on substance use. Existing literature on this relationship is limited and conflicting, warranting further exploration.Objective: This study aimed to identify relationships between socioeconomic status (SES), demographic variables, and substance use patterns before and after government-mandated business closures due to COVID-19.Methods: Participants were recruited based on self-reported substance use through Amazon's Mechanical Turk (MTurk). Qualifying participants (N = 315, 43% female, mean age = 35.35) reported their substance use and SES for two-week periods before and after pandemic-related business closures. Regression models analyzed relationships between substance use and study variables.Results: Regression models found that, during COVID-19 closures, greater financial strain predicted decreased benzodiazepine (ß = -1.12) and tobacco (ß = 1.59) use. Additionally, certain predictor variables (e.g., participants' age [ß = 1.22], race [ß = -4.43], psychiatric disorders including ADHD [ß = -2.73] and anxiety [ß = 1.53], and concomitant substance use [ß = 3.38]) predicted changes in substance use patterns; however, the directionality of these associations varied across substances.Conclusion: Specific substance use patterns were significantly and differentially impacted by economic strain, psychiatric diagnoses, and concomitant substance use. These results can help direct harm reduction efforts toward populations at greatest risk of harmful substance use following the pandemic.

Clinical risk prediction model for 30-day all-cause re-hospitalisation or mortality in patients hospitalised with heart failure.

BACKGROUND: This study aimed to develop a risk prediction model (AUS-HF model) for 30-day all-cause re-hospitalisation or death among patients admitted with acute heart failure (HF) to inform follow-up after hospitalisation. The model uses routinely collected measures at point of care. METHODS: We analyzed pooled individual-level data from two cohort studies on acute HF patients followed for 30-days after discharge in 17 hospitals in Victoria, Australia (2014-2017). A set of 58 candidate predictors, commonly recorded in electronic medical records (EMR) including demographic, medical and social measures were considered. We used backward stepwise selection and LASSO for model development, bootstrap for internal validation, C-statistic for discrimination, and calibration slopes and plots for model calibration. RESULTS: The analysis included 1380 patients, 42.1% female, median age 78.7 years (interquartile range = 16.2), 60.0% experienced previous hospitalisation for HF and 333 (24.1%) were re-hospitalised or died within 30 days post-discharge. The final risk model included 10 variables (admission: eGFR, and prescription of anticoagulants and thiazide diuretics; discharge: length of stay>3 days, systolic BP, heart rate, sodium level (<135 mmol/L), >10 prescribed medications, prescription of angiotensin converting enzyme inhibitors or angiotensin receptor blockers, and anticoagulants prescription. The discrimination of the model was moderate (C-statistic = 0.684, 95%CI 0.653, 0.716; optimism estimate = 0.062) with good calibration. CONCLUSIONS: The AUS-HF model incorporating routinely collected point-of-care data from EMRs enables real-time risk estimation and can be easily implemented by clinicians. It can predict with moderate accuracy risk of 30-day hospitalisation or mortality and inform decisions around the intensity of follow-up after hospital discharge.

Puberty enables oestradiol-induced progesterone synthesis in female mouse hypothalamic astrocytes.

The development of oestrogen positive feedback is a hallmark of female puberty. Both oestrogen and progesterone signalling are required for the functioning of this neuroendocrine feedback loop but the physiological changes that underlie the emergence of positive feedback remain unknown. Only after puberty does oestradiol (E2) facilitate progesterone synthesis in the rat female hypothalamus (neuroP), an event critical for positive feedback and the LH surge. We hypothesize that prior to puberty, these astrocytes have low levels of membrane oestrogen receptor alpha (ERα), which is needed for facilitation of neuroP synthesis. Thus, we hypothesized that prepubertal astrocytes are unable to respond to E2 with increased neuroP synthesis due a lack of membrane ERα. To test this, hypothalamic tissues and enriched primary hypothalamic astrocyte cultures were acquired from prepubertal (postnatal week 3) and post-pubertal (week 8) female mice. E2-facilitated neuroP was measured in the hypothalamus pre- and post-puberty, and hypothalamic astrocyte responses were measured after treatment with E2. Prior to puberty, E2-facilitated neuroP synthesis did not occur in the hypothalamus, and mERα expression was low in hypothalamic astrocytes, but E2-facilitated neuroP synthesis in the rostral hypothalamus and mERα expression increased post-puberty. The increase in mERα expression in hypothalamic astrocytes corresponded with a post-pubertal increase in caveolin-1 protein, PKA phosphorylation, and a more rapid [Ca2+ ]i flux in response to E2. Together, results from the present study indicate that E2-facilitated neuroP synthesis occurs in the rostral hypothalamus, develops during puberty, and corresponds to a post-pubertal increase in mERα levels in hypothalamic astrocytes.

High-Throughput Activity Assay for Screening Inhibitors of the SARS-CoV-2 Mac1 Macrodomain.

Macrodomains are a class of conserved ADP-ribosylhydrolases expressed by viruses of pandemic concern, including coronaviruses and alphaviruses. Viral macrodomains are critical for replication and virus-induced pathogenesis; therefore, these enzymes are a promising target for antiviral therapy. However, no potent or selective viral macrodomain inhibitors currently exist, in part due to the lack of a high-throughput assay for this class of enzymes. Here we developed a high-throughput ADP-ribosylhydrolase assay using the SARS-CoV-2 macrodomain Mac1. We performed a pilot screen that identified dasatinib and dihydralazine as ADP-ribosylhydrolase inhibitors. Importantly, dasatinib inhibits SARS-CoV-2 and MERS-CoV Mac1 but not the closest human homologue, MacroD2. Our study demonstrates the feasibility of identifying selective inhibitors based on ADP-ribosylhydrolase activity, paving the way for the screening of large compound libraries to identify improved macrodomain inhibitors and to explore their potential as antiviral therapies for SARS-CoV-2 and future viral threats.

Management of vasovagal syncope.

Vasovagal syncope (VVS) is a very common form of fainting. Treatment begins with patient education about the mechanism of fainting, and the non-lethal nature of vasovagal syncope. In this article, we review several non-pharmacological approaches that form the foundation of our current treatments. These include increases in dietary salt and water intake, the use of compression garments, physical counter-maneuvers and tilt-training. When these approaches are inadequate, medications can sometimes be effective. While the evidence base for the pharmacological treatment of VVS is modest, recent trial data have found drugs to be useful in placebo-controlled randomized trials. For select patients, and those patients more refractory to medications, procedural treatments may be an option. In this review, we discuss the current state of evidence for the non-pharmacological and pharmacological treatments for VVS, as well as some novel, emerging therapies for VVS.

Bridging the age gap in breast cancer: impact of omission of breast cancer surgery in older women with oestrogen receptor-positive early breast cancer on quality-of-life outcomes.

BACKGROUND: Primary endocrine therapy may be an alternative treatment for less fit women with oestrogen receptor (ER)-positive breast cancer. This study compared quality-of-life (QoL) outcomes in older women treated with surgery or primary endocrine therapy. METHODS: This was a multicentre, prospective, observational cohort study of surgery or primary endocrine therapy in women aged over 70 years with operable breast cancer. QoL was assessed using European Organisation for Research and Treatment of cancer QoL questionnaires QLQ-C30, -BR23, and -ELD14, and the EuroQol Five Dimensions 5L score at baseline, 6 weeks, and 6, 12, 18, and 24 months. Propensity score matching was used to adjust for baseline variation in health, fitness, and tumour stage. RESULTS: The study recruited 3416 women (median age 77 (range 69-102) years) from 56 breast units. Of these, 2979 (87.2 per cent) had ER-positive breast cancer; 2354 women had surgery and 500 received primary endocrine therapy (125 were excluded from analysis due to inadequate data or non-standard therapy). Median follow-up was 52 months. The primary endocrine therapy group was older and less fit. Baseline QoL differed between the groups; the mean(s.d.) QLQ-C30 global health status score was 66.2(21.1) in patients who received primary endocrine therapy versus 77.1(17.8) among those who had surgery plus endocrine therapy. In the unmatched analysis, changes in QoL between 6 weeks and baseline were noted in several domains, but by 24 months most scores had returned to baseline levels. In the matched analysis, major surgery (mastectomy or axillary clearance) had a more pronounced adverse impact than primary endocrine therapy in several domains. CONCLUSION: Adverse effects on QoL are seen in the first few months after surgery, but by 24 months these have largely resolved. Women considering surgery should be informed of these effects.

Multiple deprivation and geographic distance to community physical activity events - achieving equitable access to parkrun in England.

OBJECTIVES: To evaluate geographic access to free weekly outdoor physical activity events ('parkrun') in England, with a particular focus on deprived communities, and to identify optimal locations for future events to further maximise access. STUDY DESIGN: This study is a cross-sectional ecological analysis of the socio-economic disparities in geographic access to parkrun events in England in late 2018. METHODS: We combined geolocation data on all English Lower Layer Super Output Areas and parkrun events to calculate geodesic distances to the nearest event for more than 32,000 communities in England. We use this measure of geographic access to summarise the relationship between access and socio-economic deprivation, measured using the index of multiple deprivation. We then used geographic coordinates of public green spaces in England to conduct a simple location-allocation analysis to identify 200 locations for future event locations that would maximise access. RESULTS: In England, 69% of the population live within 5 km of one of the 465 parkrun events. There is a small negative correlation between distance and deprivation, indicating that access is slightly better in more socio-economically deprived areas. Setting up an additional 200 events in optimal locations would improve access: the average distance to the nearest parkrun event would improve by 1.22 km, from 4.65 km to 3.43 km, and approximately 82% of the English population would live within 5 km of a parkrun event. CONCLUSION: Over two-thirds of the English population live within 5 km of a parkrun event, and contrary to our expectation, we find that geographic access is slightly better for those living in more deprived communities. Creating additional events may improve geographic access, but effective strategies will still be needed to increase engagement in new and existing events by those living in socio-economically deprived areas.

The Pneumococcal Iron Uptake Protein A (PiuA) Specifically Recognizes Tetradentate FeIIIbis- and Mono-Catechol Complexes.

Streptococcus pneumoniae (Spn) is an important Gram-positive human pathogen that causes millions of infections worldwide with an increasing occurrence of antibiotic resistance. Fe acquisition is a crucial virulence determinant in Spn; further, Spn relies on exogenous FeIII-siderophore scavenging to meet nutritional Fe needs. Recent studies suggest that the human catecholamine stress hormone, norepinephrine (NE), facilitates Fe acquisition in Spn under conditions of transferrin-mediated Fe starvation. Here we show that the solute binding lipoprotein PiuA from the piu Fe acquisition ABC transporter PiuBCDA, previously described as an Fe-hemin binding protein, binds tetradentate catechol FeIII complexes, including NE and the hydrolysis products of enterobactin. Two protein-derived ligands (H238, Y300) create a coordinately saturated FeIII complex, which parallel recent studies in the Gram-negative intestinal pathogen Campylobacter jejuni. Our in vitro studies using NMR spectroscopy and 54Fe LC-ICP-MS confirm the FeIII can move from transferrin to apo-PiuA in an NE-dependent manner. Structural analysis of PiuA FeIII-bis-catechol and GaIII-bis-catechol and GaIII-(NE)2 complexes by NMR spectroscopy reveals only localized structural perturbations in PiuA upon ligand binding, largely consistent with recent descriptions of other solute binding proteins of type II ABC transporters. We speculate that tetradentate FeIII complexes formed by mono- and bis-catechol species are important Fe sources in Gram-positive human pathogens, since PiuA functions in the same way as SstD from Staphylococcus aureus.