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The Spectrum of Neurologic Phenotypes Associated With NUS1 Pathogenic Variants: A Comprehensive Case Series
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A growing body of evidence indicates a strong genetic overlap between developmental and epileptic encephalopathies (DEEs) and movement disorders. De novo loss‐of‐function variants in NUS1 have been recently identified in DEE cases. Herein, we report a large cohort of cases with pathogenic NUS1 variants and describe their clinical presentation and the details of the associated epilepsy and movement disorders.
Methods
Cases with NUS1‐related disorders were identified through a multicentric international collaboration made possible by the GeneMatcher platform. Clinical data were acquired through retrospective case‐note review.
Results
We identified 41 subjects carrying 38 different pathogenic or likely pathogenic heterozygous NUS1 variants. The majority of cases displayed developmental delays and intellectual disability of variable severity. Epilepsy was present in 68.3% of cases (28/41) with onset typically in early childhood. Strikingly, 87.8% of cases (36/41) presented with movement disorders and for 13 of these cases the movement disorder was not accompanied by epilepsy. The phenomenology of the movement disorders was complex with myoclonus observed in 68.3% of cases (28/41), either in isolation or in combination with dystonia, ataxia, and/or parkinsonism. Seven cases that otherwise did not have prominent movement disorders had mild incoordination and intention tremor, suggestive of cerebellar dysfunction. There was no observed genotype–phenotype correlation, suggesting that other genetic or acquired factors impact the clinical presentation.
Interpretation
Heterozygous NUS1 pathogenic variants cause a complex neurological disorder, variably featuring developmental and epileptic encephalopathies and a broad spectrum of movement disorders, which represent the major source of neurological disability for most cases. ANN NEUROL 202
The maternal postnatal six-week check in women with epilepsy: Does the prevalence or subsequent postpartum health differ from the general postnatal population?
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To examine the prevalence of the maternal postnatal six-week check (SWC) in women with epilepsy compared to a sample of the postnatal population without epilepsy, and assess whether the SWC is associated with health outcomes in the first year postpartum.
Methods
Clinical Practice Research Datalink Aurum and Hospital Episode Statistics data were used to identify births between January1998-March2020 to women with epilepsy (n = 23,533) and a random sample of births to women without epilepsy (n = 317,369). The adjusted risk ratio (aRR) for not having a SWC in women with compared to without epilepsy was estimated using modified Poisson regression. The association between receiving a SWC and postpartum health outcomes was assessed using Cox regression.
Results
The likelihood of not having a SWC did not differ between those with and without epilepsy (42.7% vs 43.4%, aRR = 1.01, 95%CI = 0.99–1.03). Among all women, not having a SWC was associated with a lower subsequent likelihood of being prescribed prophylactic (aHR = 0.59, 95%CI = 0.58–0.60) and emergency (aHR = 0.95, 95%CI = 0.91–0.99) contraception and having urinary and/or faecal incontinence (aHR = 0.67, 95%CI = 0.61–0.73) or dyspareunia, perineal and/or pelvic pain (aHR = 0.70, 95%CI = 0.65–0.75) recorded in the year postpartum, with no evidence these associations differed according to whether a woman had epilepsy. Not having a SWC was also associated with a lower likelihood of having depression and/or anxiety recorded in the first year postpartum among those without (aHR = 0.86, 95%CI = 0.84–0.89) but not with epilepsy (aHR = 1.01, 95%CI = 0.93–1.09). The SWC was not associated with epilepsy relevant outcomes (Accident and emergency visits or unplanned hospital admission for epilepsy, mortality).
Conclusions
Around 2 in every 5 women had no evidence of a maternal SWC, with no evidence epileptic women had a different prevalence to the general postnatal population. The maternal SWC may play a role in increasing the use of contraception and the detection or treatment of adverse health outcomes in the first year postpartum
Deep brain stimulation for epilepsy: A systematic review and meta-analysis of randomized and non-randomized studies of thalamic targeting
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Deep Brain Stimulation (DBS) of the thalamus for drug-resistant epilepsy (DRE) is an emerging treatment modality. This systematic review and meta-analysis sought to evaluate the efficacy of stimulating different targets within the thalamus.
Methods
A systematic search of four databases was conducted. Rates for overall seizure reduction (SR), responder rate (RR ≥50 % SR), and seizure freedom (SF) were evaluated at a minimum time point of 12 months post-stimulation commencement in the anterior (ANT) and centro-median (CMN) thalamic nuclei. Subgroup analyses for a minimum 24 months follow up, sensitivity analyses, and funnel plots to assess for publication bias were also performed. Risk of bias was assessed using the ROBINS-I tool.
Results
Fourty-nine articles met the inclusion criteria. The mean seizure reduction (SR) across 21 studies was 62.31 % (95 % CI: 55.99–68.62, p < 0.01). Specifically, SR was 64.28 % for ANT (95 % CI: 57.55–71.01, p < 0.01) and 69.11 % for CMN (95 % CI: 58.14–80.09, p < 0.01). Meta-analyses of 41 ANT studies and 12 CMN studies reported a response rate (RR) of 61.51 % (95 % CI: 54.11–68.9, p < 0.01) and 69.09 % (95 % CI: 54.01–84.16, p < 0.01), respectively. Overall seizure freedom (SF) was 3.57 % % for ANT (95 % CI: 1.86–5.28, p = 0.45) and 1.32 % for CMN(95 % CI: 0–4.45, p = 0.81). For ANT, RR was 67.63 % (95 % CI: 61.04–74.23) for follow-up periods longer than 24 months, and 44.05 % (95 % CI: 26.73–61.38) for periods shorter than 24 months. The SF rate for ANT was 3 % (95 % CI: 1–4 %) for follow-up under 12 months. For CMN, RR was 70 % (95 % CI: 53–87 %) for periods over 24 months, and 68 % (95 % CI: 31–100 %) for periods under 24 months. The SF rate for CMN was 1 % (95 % CI: 0–4 %) for periods under 12 months. There was no strong evidence of publication bias based on funnel plot analysis, and results were consistent across sensitivity analyses. Insufficient data precluded meta-analysis for other nuclei.
Conclusion
These findings demonstrate efficacy of ANT and CMN DBS for patients with DRE, defined by responder rate and seizure reduction. Further research is required to optimize patient selection, predict individual response, and assess non-seizure related outcomes
Optimizing Diagnostic Strategies for Sudden Arrhythmic Death Syndrome Families; Time to Focus on Age and Sex differences?
No full textAge-stratified effects of intravenous ferric derisomaltose in heart failure with iron deficiency: insights from the IRONMAN trial.
Get PDFBACKGROUND: Intravenous iron therapy with ferric derisomaltose (FDI) has been shown to improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF) and iron deficiency. However, its effects across different age groups remain unclear. This analysis of the Effectiveness of Intravenous Iron Treatment versus Standard Care in Patients with Heart Failure and Iron Deficiency (IRONMAN) trial explored the efficacy and safety of FDI across age groups. METHODS: The IRONMAN trial was a prospective, open-label, blinded end point randomised controlled trial enrolling patients with HFrEF and iron deficiency. This prespecified analysis stratified the population into four quarters by age group: 79 years. The primary outcome was a composite of recurrent heart failure hospitalisations and cardiovascular death. Secondary outcomes included changes in haemoglobin and quality of life. Clinical outcomes comparing FDI versus usual care in each age subgroup were analysed by the method of Lin et al for recurrent events and Cox proportional hazards model for time to first event. Interactions between age and treatment effects were explored. RESULTS: Among 1137 randomised patients (median age 73 years), the primary outcome rate ratio (FDI vs usual care) was 0.87 (95% CI 0.61 to 1.23) in patients 79 years (p-interaction=0.38). Improvements in haemoglobin and quality of life scores at 4 months did not differ statistically across age groups (p-interaction=0.92 and 0.64, respectively). Older patients were more symptomatic at baseline, with higher N-terminal-pro B-type natriuretic peptide levels and poorer renal function, but safety outcomes did not differ across age groups. CONCLUSIONS: We found no evidence that the effects of FDI on heart failure hospitalisations, cardiovascular death, haemoglobin and quality of life differed by age. These findings support its use in patients with HFrEF and iron deficiency, including older adults. TRIAL REGISTRATION NUMBER: NCT02642562
Impact of COVID-19 pandemic on the prescribing pattern of oral anticoagulants in the English primary care setting: a population-based segmented interrupted time series analysis of over 53 million individuals.
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The COVID-19 pandemic disrupted healthcare delivery, impacting oral anticoagulants (OAC) prescribing due to increased thromboembolic risks, Vaccine-induced immune thrombotic thrombocytopenia, and guidelines favoring Direct Oral Anticoagulants (DOACs) over warfarin. Previous studies were limited to short-term analyses.
Research design and methods
A segmented interrupted time series analysis was conducted using the English primary care Prescription Cost Analysis data from March/2018-March/2024 to assess the impact of the first and second COVID-19 lockdowns in March and November 2020, respectively. Trends in OAC utilisation were measured using number of items per 1,000 inhabitants (NIT) and defined daily dose per 1,000 inhabitants per day (DTD).
Results
Overall, oral anticoagulants prescribing increased significantly. Pre-pandemic, both NIT (β1: 0.09; 95%CI: 0.02, 0.16) and DTD (β1:0.13; 95%CI: 0.09, 0.16) showed positive trends. Post-first lockdown, DTD slope declined significantly (β3:-0.22; 95%CI: -0.42, -0.03). Post-second lockdown, DTD rose in both immediate level (β4:1.39; 95%CI: 0.34, 2.45) and slope (β5: 0.20; 95%CI: 0.0015, 0.39). Warfarin usage declined initially but rebounded, while DOACs, particularly apixaban, increased substantially (β4:0.96; 95%CI: 0.11, 1.81).
Conclusions
The COVID-19 pandemic significantly impacted oral anticoagulant prescribing patterns in England. While DOAC utilisation continued to rise, warfarin use declined significantly post-first lockdown but rebounded after the second lockdown
Comparative Performance of Urine Lipoarabinomannan and Urine Xpert MTB/RIF Ultra for Diagnosing Tuberculosis in Adult Inpatients With HIV in East London, South Africa
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Urine lateral flow lipoarabinomannan (LF-LAM) is a point-of-care tuberculosis (TB) test for patients with human immunodeficiency virus (HIV). Xpert MTB/RIF Ultra (Ultra) has improved sensitivity on sputum compared with the previous generation of Xpert and may improve diagnostic yield for TB on urine-based testing.
Methods
We conducted a diagnostic accuracy study in East London, South Africa. Adults with HIV hospitalized with ≥1 W4SS (World Health Organization–recommended 4-symptom screen) or clinical concern for TB were enrolled; TB cultures were performed on blood, sputum, and urine. Unprocessed urine was tested with LF-LAM and Ultra on the pellet of 15 mL centrifuged urine. The primary outcome was sensitivity of urine Ultra compared with LF-LAM, with microbiological TB (positive TB culture or molecular test, excluding urine Ultra) as the reference. Secondary outcomes included specificity and diagnostic yield.
Results
Two hundred thirty-eight participants were enrolled with a median CD4 count of 76 cells/mm3. Microbiological TB was diagnosed in 62 (26%). Using microbiological TB as the reference, sensitivity of LF-LAM and urine Ultra was 45% (95% confidence interval, 32–58) and 70% (95% CI, 57–81; McNemar P = .0013); specificity was 93% (95% CI, 81–99) and 100% (95% CI, 92–100; McNemar P = .25). Diagnostic yields for microbiological TB were 34% for sputum Ultra, 45% for urine LF-LAM, 68 for urine Ultra, and 73% for urine LF-LAM and urine Ultra combined.
Conclusions
Combined urine-based testing (Ultra + LF-LAM) identified nearly three-quarters of medical inpatients with HIV with microbiological TB. Urine Ultra had significantly improved sensitivity compared with LF-LAM
Clinical standards in angina and non-obstructive coronary arteries: A clinician and patient consensus statement
Get PDFPatients with angina and non-obstructive coronary arteries (ANOCA) or myocardial ischaemia with non-obstructive coronary arteries (INOCA) comprise a relatively large subgroup within those with ischaemic heart disease.
Advances in the understanding of disease mechanisms, diagnostic tests and multidisciplinary care are improving awareness of the needs of affected individuals. However, practice variations and suboptimal management promulgate the health burden and increase health care resource consumption.
Clinical standards represent a limited number of quality statements that describe the care patients should be offered by health professionals and providers for a specific clinical condition or defined clinical pathway in line with current best evidence. Clinical standards should address implementation of this evidence along with education of patients and healthcare professionals, multidisciplinary care networks, and research.
In this consensus statement, we highlight contemporary evidence and stakeholder views, including clinicians and patients, to provide an international perspective for developing clinical standards for services involving ANOCA/INOCA patients. A clinical service for ANOCA/INOCA should “consider the whole patient” and provide a multidisciplinary, patient-centred service
Dronedarone vs Sotalol Among Patients With Atrial Fibrillation
Get PDFBACKGROUND: Dronedarone and sotalol are antiarrhythmic drugs (AADs) recommended in similar populations per atrial fibrillation (AF) guidelines; however, comparative safety data are limited. OBJECTIVES: The goal of this study was to assess the safety of dronedarone vs sotalol for treatment of AF in AAD-naive patients. METHODS: This was a prespecified noninterventional meta-analysis of 4 retrospective observational cohort studies from 4 databases (Optum Clinformatics Data Mart, Merative MarketScan, Veterans Health Administration Electronic Health Record, and the Swedish National Patient Register) conducted by using one master protocol. Each analysis emulated the target trial using an active comparator (dronedarone vs sotalol), new user design with an as-treated approach. Primary outcomes were tested hierarchically for dronedarone vs sotalol: first for statistical significance of cardiovascular (CV) hospitalization, and then for statistical significance of ventricular arrhythmias. Propensity score matching (PSM) was used for confounding control, and negative control outcomes were used to assess residual confounding. Outcomes were evaluated by using Cox proportional hazards regression; meta-analysis was performed by using fixed effects models. RESULTS: The dronedarone and sotalol cohorts were well balanced within databases before and after PSM (after PSM mean age range: 62.5-70.9 years; mean CHA2DS2-VASc score range: 1.81-3.15). Negative control outcomes exhibited little-to-no evidence of residual confounding. Meta-analysis found significantly lower rates of CV hospitalization (pooled HR: 0.91; 95% CI: 0.85-0.97) and ventricular arrhythmias (pooled HR: 0.77; 95% CI: 0.69-0.85) with dronedarone vs sotalol. CONCLUSIONS: In this retrospective meta-analysis, dronedarone exhibited significantly lower rates of CV hospitalization and ventricular arrhythmias compared with sotalol. These findings provide real-world evidence to support selection of the most appropriate first-line AAD for rhythm control in patients with AF
The impact of child and adolescent health on adult respiratory health: the evidence, gaps and priorities
Get PDFChronic respiratory diseases impart a huge global disease burden. Many cases of adult chronic respiratory disorders are recognised to originate early in life during critical phases of lung growth and development. We therefore reviewed the longitudinal evolution of common childhood respiratory diseases across the lifespan. We included studies relating childhood respiratory health (preterm birth, asthma, low lung function or bronchiectasis) to respiratory health in adolescents and adults, including COPD.
The negative impact of preterm birth (with or without bronchopulmonary dysplasia) on future respiratory health has now been quantified, with many having increasing deviation of lung function from the norm over their life course. While previous studies report children with asthma frequently “outgrow their disease” by adolescence or early adulthood, recent data describe asthma trajectories that include relapse, early-onset adult-remitting, and early-onset persistent childhood asthma. Evidence is emerging in adults of the negative impact of chronic productive cough, breathlessness and lower lung function on future respiratory and cardiovascular health and all-cause mortality. In addition, we found that in general, childhood respiratory health and adverse lung function trajectories are inextricably linked to adult respiratory health and cardiovascular events, as well as cardiovascular and all-cause mortality. Thus, we highlight the importance of pulmonary assessments in high-risk groups during childhood (e.g. preterm birth, parental smokers, early life hospitalisation for acute lower respiratory infections). Our review emphasises the importance of childhood respiratory health and the need for interventions to reduce or manage disease burden, which require a whole-of-society approach across the life course
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