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Evaluation of polygenic scores for hypertrophic cardiomyopathy in the general population and across clinical settings
Get PDFHypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality, with pathogenic variants found in about a third of cases. Large-scale genome-wide association studies (GWAS) demonstrate that common genetic variation contributes to HCM risk. Here we derive polygenic scores (PGS) from HCM GWAS and genetically correlated traits and test their performance in the UK Biobank, 100,000 Genomes Project, and clinical cohorts. We show that higher PGS significantly increases the risk of HCM in the general population, particularly among pathogenic variant carriers, where HCM penetrance differs 10-fold between those in the highest and lowest PGS quintiles. Among relatives of HCM probands, PGS stratifies risks of developing HCM and adverse outcomes. Finally, among HCM cases, PGS strongly predicts the risk of adverse outcomes and death. These findings support the broad utility of PGS across clinical settings, enabling tailored screening and surveillance and stratification of risk of adverse outcomes
Early Childhood Neurodevelopmental Outcomes After Early Infant Invasive Group B Streptococcal Infection in Uganda
Get PDFBackground
Group B streptococcal (GBS) sepsis during infancy is a leading cause of child mortality and an important contributor to long-term neurodisability. Data on outcomes among invasive GBS infection survivors in low- and middle-income countries are limited. We present 2-year neurodevelopment and growth outcomes after GBS sepsis in Uganda.
Methods
Participants were infants with culture-proven GBS sepsis <3 months of age and a gestationally matched comparison cohort of infants who did not have GBS sepsis in Kampala, Uganda. Neurodevelopmental impairment up to 24 months (corrected age) was assessed using the Bayley Scales of Infant Development and Hammersmith Infant Neurological Examination. Weight, height, mid-upper arm circumference, and occipito-frontal circumference were measured.
Results
Neurodevelopmental outcome data were available for 16 survivors of GBS sepsis and 59 comparison children. Among survivors of GBS sepsis, cognitive and language scores were lower (median difference [interquartile range], −5 [−10 to 0] and −8 [−15 to −2], respectively). Moderate to severe neurodevelopmental impairment occurred in 31% (5/16) in the GBS cohort compared with 8.5% (5/59) in the non-GBS cohort. Three children with neurodevelopmental impairment had cerebral palsy (bilateral spasticity), and 2 had global developmental delay without cerebral palsy. GBS sepsis survivors were more likely to have undernutrition compared with comparison children (25% vs 10%), largely due to severe undernutrition among those with cerebral palsy.
Conclusions
In this Sub-Saharan African population, survivors of infant GBS sepsis were more likely to have impaired neurodevelopmental and growth outcomes compared with children who did not have GBS sepsis. GBS sepsis survivors should be included in long-term follow-up programs to monitor for neurodevelopmental difficulties and initiate early referrals to support services
Antimicrobial Stewardship Program Implementation, Perceptions, and Barriers in Zambia: A Cross-Sectional Study Among Healthcare Professionals
No full textBackground/Objectives: Antimicrobial stewardship programs (ASPs) play a vital role in combating antimicrobial resistance (AMR). However, their implementation in Zambia remains variable despite some notable progress. This study assessed healthcare professionals’ awareness of the Multisectoral National Action Plan (NAP) on AMR, alongside their perceptions, barriers, and implementation practices related to ASPs. Methods: A cross-sectional survey conducted between August and December 2024 included 364 healthcare professionals (HCPs) in 58 randomly selected public healthcare facilities in Zambia. Data were analysed using IBM SPSS 25.0. Results: Findings revealed that while 75.3% of respondents were aware of the Zambian NAP on AMS, only 68.1% of the respondents reported that their hospitals had established AMS committees. Conversely only 41.2% of the respondents stated that their hospitals possessed hospital-specific treatment guidelines. Encouragingly, 97.5% believed ASPs could enhance clinical outcomes and reduce AMR. Key barriers included limited funding (75.9%), inadequate IT infrastructure (64.1%), limited access to essential data (64%), and healthcare workforce shortages (53.8%). Conclusions: Whilst HCPs in Zambia demonstrated high awareness of the NAP and supported ASP implementation, systemic challenges hindered their consistent execution across health facilities. Gaps in treatment guideline development, AMR data usage, and the integration of antimicrobial susceptibility recording systems into clinical activities must be addressed to strengthen ASP efforts nationwide
Arrhythmogenic Cardiomyopathy or “Athlete’s Heart”?: A Systematic Approach to Differential Diagnosis
Get PDFArrhythmogenic cardiomyopathy (ACM) is a heritable cardiac condition, which may lead to fatal arrhythmias, especially during intense exercise. Long-term regular exercise is associated with a spectrum of physiological cardiac adaptations, some of which may overlap with phenotypic features of ACM, thereby complicating the distinction between benign athletic remodeling and early disease expression. This overlap presents a significant diagnostic challenge, as misclassifying pathological changes as physiological can delay appropriate risk stratification and management. By contrast, overdiagnosis of cardiomyopathy in healthy athletes may lead to unnecessary restriction from sport and psychological distress. The complexities in the differential diagnosis may be mitigated by embracing a comprehensive and systematic approach, including a thorough assessment of family and personal history, and a careful interpretation of the electrocardiogram, with further investigations to be requested if suspicion of an underlying disease is raised. This review provides a comprehensive analysis of the differential diagnosis between physiological cardiac adaptations and pathological changes that raise the suspicion of ACM, highlighting red flags and benign findings to rationalize clinical management
Antenatal CMV screening, testing, and treatment strategies in Europe: a 2024 survey
Get PDFOBJECTIVE: Congenital cytomegalovirus (cCMV) is the most common congenital infection globally, affecting approximately 0.5% of all live births in high income settings, with long-term sequelae affecting around a fifth of infected infants. Recently, interest in antenatal CMV screening has increased but current practices and impact are unclear. Our objective was to describe policy and practice around antenatal CMV screening, testing, and treatment in Europe, including the use of universal antenatal screening, in the context of the emerging evidence base for use of valaciclovir to reduce CMV vertical transmission (VT). METHODS: A web-based survey was distributed to healthcare professionals within antenatal services with knowledge of CMV testing/treatment practices, from 29 April 2024 to 24 July 2024. Responses from Europe were analyzed. Where multiple responses were submitted from the same healthcare service, the most complete response was kept for the analysis. RESULTS: We received responses from 73 centers in 21 countries in Europe, mostly 76% (55/72) from tertiary centers. Overall, 52% (38/73) had a CMV testing policy and 61% (23/38) reported that this had been introduced or significantly updated in the last 2 years. Half of respondents (53%, 39/73, from 11/21 countries) reported routine offer of CMV testing to pregnant woman at their center (universal antenatal screening), sometimes with gestational age limits, and mostly (67%, 26/39) on an "opt-out" basis. Universal antenatal CMV screening was more common among centers with formalized testing policies than those without (84% (32/38) vs. 20% (7/35) respectively, χ2 = 30.19, p 95% of pregnant women at half (18/39) of centers. Fifty-nine percent (23/39) of centers reported routinely offering repeat testing. Of 39 centers routinely offering testing, only 69% (27/39) gave advice on reducing CMV acquisition risk routinely to pregnant women. Medication was offered for prevention of CMV VT or tertiary prevention of cCMV disease at 82% (60/73) and 78% (56/72) of centers, respectively. Of 59 sites offering treatment for secondary and/or tertiary prevention and responding to a question on frequency of treatment monitoring, 93% (55/59) reported monitoring blood tests at least monthly. Forty-three percent of centers offering treatment lacked a formal procedure for reporting adverse drug reactions. Overall, 83% (58/70) respondents supported CMV testing (49 strongly, nine moderately), but 59% (41/70) identified at least one concern/risk. CONCLUSIONS: This survey of antenatal CMV policies and practice at 73 centers in Europe highlights substantial variation in policies and practice, reflecting variation in national screening guidelines and the evolving evidence base around valaciclovir to reduce CMV VT risk. A recent opinion paper and statement have called for consideration of universal screening but also highlighted important evidence gaps around its implementation, risks, benefits, and cost-effectiveness. Responses to this survey suggested that valaciclovir is already quite widely used for prophylaxis of CMV VT in the context of maternal primary infection in early pregnancy, at participating sites. Our findings suggest that research to inform safe and equitable decisions around implementation of CMV testing and universal screening is urgently needed, in addition to epidemiological research to underpin screening decisions tailored to specific settings. Shared research priorities are needed to ensure testing and treatment are carried out in an evidence-based and equitable way
Neural mass modeling reveals that hyperexcitability underpins slow-wave sleep changes in children with epilepsy
Get PDFObjective
The relationship between sleep and epilepsy is important but imperfectly understood. We sought to understand the mechanisms that explain the differences in sleep homeostasis observed in children with epilepsy.
Methods
We used a neural mass model to replicate sleep electroencephalography (EEG) recorded from 15 children with focal lesional epilepsies and 16 healthy age-matched controls. Different parameter sets were recovered in the model for each subject.
Results
The model revealed that sleep EEG differences are driven by enhanced firing rates in the neuronal populations of patients, which arise predominantly due to enhanced excitatory synaptic currents. These differences were more marked in patients who had seizures within 72 h after the sleep recording. Furthermore, model parameters inferred from patients resided closer to model parameters inferred from a typical seizure rhythm.
Significance
These results demonstrate that brain mechanisms relating to epilepsy manifest in the interictal EEG in slow-wave sleep, and that EEG recorded from patients can be mapped to synaptic deficits that may explain their predisposition to seizures. Neural mass models inferred from sleep EEG data have the potential to generate new biomarkers to predict seizure occurrence and inform treatment decisions
Development of a diagnostic checklist to identify functional cognitive disorder versus other neurocognitive disorders
Get PDFBackground Functional cognitive disorder (FCD) poses a diagnostic challenge due to its resemblance to other neurocognitive disorders and limited biomarker accuracy. We aimed to develop a new diagnostic checklist to identify FCD versus other neurocognitive disorders.
Methods The clinical checklist was developed through mixed methods: (1) a literature review, (2) a three-round Delphi study with 45 clinicians from 12 countries and (3) a pilot discriminative accuracy study in consecutive patients attending seven memory services across the UK. Items gathering consensus were incorporated into a pilot checklist. Item redundancy was evaluated with phi coefficients. A briefer checklist was produced by removing items with >10% missing data. Internal validity was tested using Cronbach’s alpha. Optimal cut-off scores were determined using receiver operating characteristic curve analysis.
Results A full 11-item checklist and a 7-item briefer checklist were produced. Overall, 239 patients (143 FCD, 96 non-FCD diagnoses) were included. The checklist scores were significantly different across subgroups (FCD and other neurocognitive disorders) (F(2, 236)=313.3, p0.80).
Conclusions This pilot study shows that a brief clinical checklist may serve as a quick complementary tool to differentiate patients with neurodegeneration from those with FCD. Prospective blind large-scale validation in diverse populations is warranted
High intensity exercise programme in patients with hypertrophic cardiomyopathy: a randomized trial
Get PDFBackground and Aims
The feasibility and impact of high intensity exercise programmes in patients with hypertrophic cardiomyopathy (HCM) are unknown. This study was conducted to determine the feasibility of a high intensity exercise programme and explore safety and efficacy outcomes in patients with HCM.
Methods
Participants were randomized to a 12-week supervised exercise programme (n = 40) in addition to usual care, or usual care alone (n = 40). All participants underwent assessment at baseline and 12 weeks. The exercise group was re-evaluated 6 months post-programme. Feasibility was assessed by (i) recruitment, adherence, and retention rates; (ii) staffing ratios; (iii) logistics; and (iv) acceptability of the intervention. The primary exploratory safety outcome was a composite of arrhythmia-related events. Exploratory secondary outcomes included changes in (i) cardiorespiratory fitness; (ii) cardiovascular risk factors; and (iii) quality of life, anxiety, and depression scores.
Results
Overall, 67 (84%) participants completed the study (n = 34 and n = 33 in the exercise and usual care groups, respectively). Reasons for non-adherence included travel, work, and family commitments. Resource provision complied with national cardiac rehabilitation standards. There was no difference between groups for the exploratory safety outcome (P = .99). At 12 weeks, the exercise group had a greater increase in peak oxygen consumption (VO2) [+4.1 mL/kg/min, 95% confidence interval (CI) 1.1, 7.1] and VO2 at anaerobic threshold (+2.3 mL/kg/min, 95% CI 0.4, 4.1), lower systolic blood pressure (−7.3 mmHg, 95% CI −11.7, −2.8) and body mass index (−0.8 kg/m2, 95% CI −1.1, −0.4), and greater improvement in hospital anxiety (−3, 95% CI −4.3, −1.7) and depression (−1.7, 95% CI −2.9, −0.5) scores, compared to the usual care group. Most exercise gains dissipated at 6 months.
Conclusions
A high intensity exercise programme is feasible in patients with HCM, with apparent cardiovascular and psychological benefits, and no increase in arrhythmias. A large-scale study is required to substantiate findings and assess long-term safety of high intensity exercise in HCM
Adenine base editing of CFTR using receptor targeted nanoparticles restores function to G542X cystic fibrosis airway epithelial cells
Get PDFThe cystic fibrosis (CF) causing variant G542X harbours a premature translation stop signal in the cystic fibrosis transmembrane conductance regulator (CFTR) mRNA. This results in nonsense-mediated decay and loss of functional CFTR protein which leads to defective anion transport and the development of CF disease pathology. Currently available CF modulator therapies cannot be used to treat this variant. We used an adenine base editor (ABE8e Cas9) and guide RNA (sgRNA)/enhanced green fluorescent protein (EGFP) plasmids encapsulated in receptor targeted nanoparticles (RTN), delivered to Bmi-1 transduced basal human CF nasal epithelial cells harbouring the homozygous CFTR G542X variant, to convert the stop codon to G542R, a variant which is amenable to modulator therapy. ABE resulted in 17% of alleles edited to G542R and further selection of GFP fluorescent cells by FACS liberated a population with 52% G542R edited alleles with no editing of neighbouring adenines (A) and few off target edits using a gRNA homology-based approach. In cells differentiated at air–liquid-interface (ALI), 17% and 52% editing of CFTR G542X increased mRNA abundance. 52% editing alone or 17% and 52% editing of CFTR G542X plus treatment with CFTR modulators (VX-445/VX-661/VX-770; ETI/Trikafta/Kaftrio) increased epithelial CFTR protein expression, CFTR protein band C abundance, CFTR172 inhibitable anion transport, and changes in airway surface liquid height and pH in response to vasoactive intestinal peptide (VIP) stimulation. Epithelial scratch repair speed and directionality was also improved. These data provide proof-of-concept that ABE of G542X to G542R in human CF airway epithelial cells could provide a feasible therapy for this variant
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