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Diabetes and Obesity and Treatment Effect of Early Rhythm Control vs Usual Care in Patients With Atrial Fibrillation
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The EAST-AFNET 4 randomized clinical trial demonstrated that early rhythm control therapy added to anticoagulation therapy and therapy of concomitant conditions reduces the primary composite outcome of cardiovascular death, stroke, hospitalization because of heart failure, or acute coronary syndrome compared to usual care. However, the impact of body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) and diabetes on outcomes in EAST-AFNET 4 is not known.
Objective
To assess the effects of BMI and diabetes on outcomes in EAST-AFNET 4.
Design, Setting, and Participants
EAST-AFNET 4 is an international, investigator-initiated, parallel-group, open, blinded outcome assessment randomized clinical trial conducted in 11 European countries. Patients who had early atrial fibrillation (AF, diagnosed ≤1 year before enrollment) and cardiovascular conditions were eligible for inclusion. The current analysis is a prespecified secondary analysis of the EAST-AFNET 4 trial performed in the final, locked dataset assigning patients to therapy group on the basis of randomization (intention-to-treat population). EAST-AFNET 4 was conducted from June 2010 to May 2020, and this secondary analysis of the final locked data base was performed in 2024.
Intervention
EAST-AFNET 4 randomly assigned patients to either early rhythm control or usual care.
Main Outcomes and Measure
The primary outcome of this analysis and the EAST-AFNET 4 trial is a composite of cardiovascular death, stroke, hospitalization because of heart failure, or acute coronary syndrome.
Results
There were 1086 patients with obesity (BMI ≥30; mean [SD] BMI 34.5 [4.2]) and 1690 patients without obesity (BMI <30; mean [SD] BMI 25.9 [2.6]). Overall mean patient age was 70 years, and 1293 patients (46.6%) were female. Patients with obesity were younger (mean [SD] age, 68 [8.6] vs 72 [7.7] years) and had more frequently nonparoxysmal AF patterns (31% vs 24%) than patients without obesity. There was no difference in mean (SD) CHA2DS2-VASc score (3.4 [1.3] vs 3.3 [1.3]). Obesity did not change the effect of early rhythm control therapy on the first primary outcome (hazard rate point estimates: BMI <30, 0.84; BMI ≥30, 0.69; P for interaction = .22). Patients with diabetes were younger (mean [SD] age, 69 [8.6] vs 71 [8.2] years; P = .001) and had a higher mean CHA2DS2-VASC score (4.06 vs 3.11; P < .001). Diabetes did not interact with the treatment effect of early rhythm control (diabetes: hazard ratio [HR], 0.77; 95% CI, 0.57-1.05 vs no diabetes: HR, 0.78; 95% CI, 0.64-0.96; P for interaction = .93). There was no difference in safety outcomes between patients with and without diabetes (64 of 351 patients [18.2%] vs 167 of 1039 patients [16.1%]; P for interaction = .99).
Conclusions and Relevance
This secondary analysis of the EAST-AFNET 4 randomized clinical trial shows that early rhythm control therapy retains its effectiveness and safety in patients with and without diabetes and patients with and without obesity.
Trial Registration
ClinicalTrials.gov Identifier: NCT0128835
Validation of the self-report quantified Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders Checklist (TAND-SQ)
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Tuberous Sclerosis Complex (TSC) is a rare multi-system genetic disorder characterised by benign growths in multiple body systems. TSC-Associated Neuropsychiatric Disorders (TAND) are very common in individuals with TSC, but families often struggle to access appropriate clinical care. To address this gap, the new TAND-SQ Checklist allows individuals with TSC or their caregivers to self-report and quantify characteristics of TAND. The 33 items make up seven natural TAND clusters and an eighth cluster reflecting psychosocial difficulties in individuals with TSC and their caregivers. Respondents rate items as having ever been present to generate cluster scores (CS), and rate item severity (over the last month) on a 10-point scale to generate cluster severity scores (CSSmean) and a total TAND severity score (TTSSmean). The purpose of this study was to determine the reliability and validity of the CS, CSSmean and TTSSmean of the TAND-SQ.
Methods
A descriptive group design was used. Two convenience samples with existing clinical data were recruited from the TSC Alliance Natural History Database (NHD) in the USA (n = 69), and from the Developmental Synaptopathies Consortium Rare Diseases Clinical Research Network (RDCRN) study based at Boston and Cincinnati Children's Hospitals (n = 23), totalling 92 participants.
Results
Analyses showed good internal consistency for CS (Cronbach’s alphas: 0.67–0.89) and CSSmean (0.76–0.95) with the exception of the eat/sleep cluster. Within the TAND-SQ, most CS and all CSSmean were significantly correlated to corresponding self-reported clinical diagnoses, and the TTSSmean was significantly correlated to a global self-rating of TAND burden (ρ = 0.75; p < .001). Significant correlations were observed between the CS and CSSmean and a range of relevant standardised behavioural measures in the RDCRN cohort. The TTSSmean was significantly correlated with global measures of adaptive behaviour (ρ = − 0.75; p < .001) and emotional/behavioural difficulties (ρ = 0.71; p = .001). All CS were significantly correlated with corresponding diagnoses of autism, ADHD, anxiety disorder, depressive disorder, scholastic difficulties, and neuropsychological difficulties where reported in the RDCRN and NHD cohorts.
Conclusions
Findings provide support for the reliability and validity of the CS, CSSmean and TTSSmean of the TAND-SQ and support their use in clinical decision-making for TAND management and in further research
Outcomes of specialist physiotherapy for functional motor disorder: the Physio4FMD RCT
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Functional motor disorder often causes persistent disabling symptoms that are associated with high healthcare costs. In recent years, specialist physiotherapy, informed by an understanding of functional motor disorder, has emerged as a promising treatment, but there is an absence of evidence of its effectiveness from large randomised controlled trials.
Methods
We conducted a pragmatic, multicentre, randomised controlled trial, comparing specialist physiotherapy for functional motor disorder to treatment as usual, which was defined as community neurological physiotherapy. The primary outcome was the Short Form questionnaire-36 items Physical Functioning domain at 12 months (scale range 0–100, with 100 indicating optimum health). The trial was powered to detect a 9-point difference in the primary outcome with 90% power at the 5% level of significance. Secondary domains of measurement included a patient perception of improvement, health-related quality of life, mobility, anxiety, depression and illness perception. We also completed a health economic analysis with the primary aim of calculating the mean incremental cost per quality-adjusted life-year over 12 months. In prespecified analysis plans, we excluded participants from the primary analysis if they were unable to receive their trial-allocated treatment due to COVID-19 lockdown restrictions. Sensitivity analysis explored the impact of this decision.
Results
Between 19 October 2018 and 31 January 2022, 355 adults with functional motor disorder were randomised (1 : 1) to specialist physiotherapy (n = 179) and treatment as usual (n = 176). Eighty-nine participants were excluded due to COVID-19 disruptions. Retention for the primary analysis was 90% for both groups, leaving 241 participants in the primary analysis. At 12 months, there was no between-group difference in the primary outcome (adjusted mean difference 3.5, 95% confidence interval −2.3 to 9.3). However, several secondary outcomes favoured specialist physiotherapy, including the participant perception of improvement, Short Form questionnaire-36 items Mental Health domain, confidence in the diagnosis and two subscales (Personal Control and Illness Coherence) of the Revised Illness Perception Questionnaire. There were no differences in the remaining outcomes. At 6 months, the following outcome measures were significantly different, in favour of specialist physiotherapy: participant perception of improvement, the Short Form questionnaire-36 items Physical Role Limitations, Short Form questionnaire-36 items Social Functioning, Short Form questionnaire-36 items Mental Health, EuroQol-5 Dimensions five-level version utility score, confidence in the diagnosis and three subscales (Timeline Cyclical, Personal Control and Treatment Control) of the Revised Illness Perception Questionnaire. No outcomes significantly favoured treatment as usual. In the health economic analysis, the incremental cost per quality-adjusted life-year gained from a health and social care cost perspective was £4133 with an 86% probability that specialist physiotherapy is cost-effective compared to treatment as usual at a cost-effectiveness threshold of £20,000 per quality-adjusted life-year gained. There were no adverse events related to physiotherapy.
Conclusion
Specialist physiotherapy was not superior to treatment as usual for the primary outcome, the Short Form questionnaire-36 items Physical Functioning domain at 12 months. However, a number of secondary outcome measures favoured specialist physiotherapy at 6 and 12 months. There is a high probability that specialist physiotherapy is cost-effective.
Limitations
Participants in treatment as usual waited longer to start physiotherapy, which resulted in a shorter time between concluding treatment and completing the primary outcome. Most outcome measures, including the primary outcome, were participant reported, which may have been biased by perceptions of the randomised treatment allocation.
Future work
Future work should identify or develop more suitable outcome measures for functional motor disorder research, explore who is most likely to benefit from specialist physiotherapy and identify alternative interventions for those unlikely to benefit from this treatment. Additional work is needed to adapt treatment to meet the needs of minority groups and young people.
Funding
This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/31/63
Effects of anticoagulation in patients with device-detected atrial fibrillation and multiple stroke risk factors: a win ratio analysis of the NOAH-AFNET 6 trial
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Patients with device-detected atrial fibrillation (DDAF) have a lower stroke risk than those with ECG-diagnosed AF, requiring careful evaluation of oral anticoagulation benefits vs. its inherent bleeding risk.
Methods and results
An unmatched win ratio analysis was performed of the NOAH-AFNET 6 trial dataset, using components of the primary efficacy and safety outcomes of the trial. The primary analysis used this hierarchical order: (1) all-cause death, (2) stroke, (3) systemic or pulmonary embolism/myocardial infarction, and (4) major bleeding. Two additional analyses replaced all-cause death with cardiovascular death or included patient-reported outcomes. Win odds were calculated to account for undecided comparisons. Among 2534 patients 77 ± 7 years old, 947 (37%) women, median CHA2DS2-VA score 3 [interquartile range (IQR), 3–4], median follow-up 21 months (IQR, 10–38) 1 605 280 win ratio pairs were analyzed. The win ratio comparing edoxaban to no anticoagulation was 0.87 (95% CI: 0.68–1.10; P = 0.23). Most comparisons resulted in no clear winner (undecided pairs 84.9%). In the remaining comparisons, edoxaban won in 46% of the cases, placebo in 54%. Death and major bleeding were the most common events. The win odds was 0.98 (95% CI: 0.94–1.01; P = 0.23).
Conclusions
This hypothesis-generating win ratio analysis, integrating death, thrombotic events, and major bleeds with and without quality of life, did not find an advantage of anticoagulation with edoxaban over no anticoagulation in patients with DDAF. The most common events were death and major bleeding
Implementation of surgical site infection prophylaxis in children – a cross-sectional prospective study
Get PDFBACKGROUND: Surgical site infections (SSIs) are a common cause of morbidity and mortality in both adults and children. In paediatric surgery, evidence on specific prevention measures is lacking, and practices mainly depend on local guidelines and the preferences of the treating team. AIM: To investigate current practices for children undergoing surgery with respect to SSI prevention using a standardized surveillance tool. METHODS: Nine Swiss paediatric surgery centres participated in a standard period prevalence study. SSI prevention measures were recorded in these hospitals over 7 consecutive days in October 2022 for any paediatric surgical procedure resulting in a surgical wound. The SSI prevention measures of interest were drawn from the most recent World Health Organization guidelines. FINDINGS: In total, 351 procedures were included. All Swiss language regions were represented. Traumatologic/orthopaedic surgeries were most common. Surgical antibiotic prophylaxis was administered in 161/351 (46%) cases, although in 33/161 (21%) cases, there was no indication for the administration of antibiotics. Alcohol-based or iodine-based solutions were most often used for surgical skin preparation. Antimicrobial-coated sutures were only used in 84/351 (24%) cases. Regional differences in prevention measures were noted between participating centres for skin preparation solution, suture material, wound dressing, and implementation of warming devices. CONCLUSION: This study provides an overview of current SSI prevention practices in Swiss paediatric surgery centres, identifies targets for improvement, and highlights areas of clinical uncertainty requiring further investigation. The findings underscore the need for standardized guidelines to ensure consistent and evidence-based SSI prevention strategies in paediatric surgery
Associations between life course exposure to ambient air pollution with cognition and later-life brain structure: a population-based study of the 1946 British Birth Cohort
Get PDFBACKGROUND: Previous research has linked higher exposure to air pollution to increased cognitive impairment at older ages. We aimed to extend the existing evidence in this area by incorporating exposures across the life course in addition to measures of cognition and brain structural imaging in participants at midlife to older age. METHODS: For this population-based study, we used data from the Medical Research Council National Survey of Health and Development (NSHD; also known as the 1946 British Birth Cohort) and a neuroimaging substudy of the NSHD known as Insight 46. Participants were recruited after birth in a single week during March, 1946. Our objectives were to assess whether exposure to air pollutants in midlife (age 45-64 years) was associated with poorer processing speed and poorer verbal memory between the ages of 43 years and 69 years, and whether exposures were associated with poorer cognitive state and brain structure outcomes at age 69-71 years. Air pollution exposure data were available for nitrogen dioxide (NO2; ages 45-64 years); particulate matter with diameter less than 10 μm (PM10; ages 55-64 years); and nitrogen oxides (NOx) and particulate matter with diameters less than 2·5 μm (PM2·5) and between 2·5 μm and less than 10 μm (PMcoarse) and particulate matter absorbance (PM2·5abs) as a measure of black carbon absorption (ages 60-64 years), with adjustments for early-life exposures to black smoke and sulphur dioxide. Verbal memory was tested with a 15-item recall task and processing speed with a visual search task at ages 43, 53, 60-64, and 69 years. The Addenbrooke's Cognitive Examination III (ACE-III), a measure of cognitive state, was conducted at age 69 years. Whole-brain, ventricular, hippocampal, and white matter hyperintensity volumes were assessed by MRI at age 69-71 years. Generalised linear models and generalised mixed linear models were used to explore associations between pollution exposure, cognitive measures, and brain structural outcomes, adjusted for sociodemographic factors including smoking status and neighbourhood deprivation. FINDINGS: Between the ages of 43 years and 69 years, we included 1534 NSHD participants in the verbal memory and processing speed analysis. Of 2148 participants who underwent testing during the wave of follow-up in 2015-16, at age 69 years, 1761 were included in the ACE-III analysis. Of the 502 NSHD participants recruited into the Insight 46 substudy, 453 were included in the analysis. Higher exposure to NO2 and PM10 was associated with slower processing speed between the ages of 43 years and 69 years (NO2 β -8·121 [95% CI -10·338 to -5·905 per IQR increase in exposure]; PM10 β -4·518 [-6·680 to -2·357]). Higher exposure to all tested pollutants was associated with lower ACE-III score at age 69 years (eg, NO2 β -0·589 [-0·921 to -0·257]). Higher exposure to NOx was associated with smaller hippocampal volume (β -0·088 [-0·172 to -0·004]) and higher exposure to NO2 and PM10 was associated with larger ventricular volume (NO2 β 2·259 [0·457 to 4·061]; PM10 β 1·841 [0·013 to 3·669]) at age 69-71 years. INTERPRETATION: Acknowledging the probable effects of exposure early in life, higher exposure to nitrogen dioxide, nitrogen oxides, and coarse particulate matter in midlife to older age was associated with poorer cognition, processing speed, and brain structural outcomes, strengthening evidence for the adverse effects of air pollution on brain function in older age. FUNDING: The National Institute for Health and Care Research, the Medical Research Council (MRC), Alzheimer's Research UK, the Alzheimer's Association, MRC Dementias Platform UK, and Brain Research UK
A mix of views: Perspectives on pregnant women's participation in maternal vaccine trials
No full textBACKGROUND: The aim of this study was to investigate perspectives on participation in a Group B Streptococcus (GBS) maternal vaccine trial among pregnant women, their partners, family members, friends and other stakeholders in Kampala, Uganda. METHODS: We conducted focus group discussions, in-depth interviews and key informant interviews from October 2022 to February 2023 with 56 participants: 36 pregnant or breastfeeding women, 5 women not in the trial, 5 partners of women in trial, 5 healthcare workers, and 5 community stakeholders. This cross-sectional study was embedded within a GBS maternal vaccine trial conducted at the national referral hospital. All study participants were recruited after seeking hospital administrative approval and individual consent. Women taking part in the GBS trial were contacted by phone and invited to the hospital for detailed information during their follow-up visits. Eligible pregnant women were aged 18-39, and participating in a GBS maternal vaccine trial. Their identifiers were shared with the social science team after approval. With the support of the health visitors, the women were contacted. Non-trial participants with similar characteristics were recruited through antenatal clinic staff. Both groups were purposively sampled across age brackets (18-24 years, 25-32 years, 33-39 years) for discussion groups. Women's partners were recruited through contact information provided by the women, and community stakeholders were mobilized with assistance from a Community Advisory Board member. Healthcare workers involved in the trial, including doctors, nurses, and midwives, as well as a research ethics committee member, were directly approached and invited to participate. All participants provided informed consent. RESULTS: The participants expressed various concerns about participation of pregnant women in maternal vaccine trials. While family members, partners, friends, and community members, expressed concern for the safety of pregnant women and their unborn babies, the specific nature of these concerns and the focus on vaccine intentions differed. Pregnant women primarily focused on the safety of their babies, while partners and family members worried about both maternal and fetal safety. Friends were more concerned about the vaccine itself, community members were suspicious of vaccines in general, fear of possible harm and questioned the intent for vaccine development. CONCLUSIONS: Building trust, providing accurate information, and engaging in transparent communication about the safety and intentions of maternal vaccines are crucial steps in fostering understanding and increasing participation in vaccine trials. Efforts to dispel myths, correct misconceptions, and address the underlying fears that contribute to hesitancy within these diverse stakeholder groups need to be discussed with targeted study populations
Xpert MTB/RIF® cycle threshold as a marker of TB disease severity; Implications for TB treatment stratification
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Recent trials have demonstrated that shortened four-month treatment durations are effective for the majority of people with tuberculosis (TB). However, there is a population of TB patients who require longer treatment durations. Prospectively identifying those who require shorter versus longer treatment durations would support evaluation and implementation of optimized regimens.
Methods
We analysed data from the RIFASHORT TB treatment-shortening non-inferiority trial to define a TB phenotype classification. The RIFASHORT trial primary outcome was reanalysed using the protocol-defined non-inferiority criterion of eight percentage points, stratifying by those classified as having limited or extensive disease.
Results
Xpert MTB/RIF® semiquantitative bacterial burden in combination with TB disease involvement grading on chest X-ray achieved the strongest differentiation between relapse and non-relapse. The extensive disease TB phenotype (high semiquantitative bacterial burden and extensive TB disease on X-ray) accounted for one quarter of the RIFASHORT trial population and more than half of all post-treatment TB relapses (13/23). For the limited TB disease phenotype (a semiquantitative bacterial burden other than high or no extensive TB disease on X-ray), the experimental 4-month 1200mg rifampicin-containing regimen met the protocol-defined non-inferiority criterion in both modified-intention-to-treat (adjusted risk difference: -1.3% (95% confidence interval: -6.7% to 4.0%)) and per protocol analyses (1.7% (95% CI: -3.8% to 7.1%)).
Conclusion
The TB phenotype classification derived here successfully identified three-quarters of RIFASHORT trial participants for whom a four-month 1200mg rifampicin regimen was non-inferior to the six-month standard of care. A definitive phase III randomised trial of disease-stratified rifampicin-based TB treatment is justified
Age, anticoagulants, hypertension and cardiovascular genetic traits predict cranial ischaemic complications in patients with giant cell arteritis
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This project aimed to determine whether cranial ischaemic complications at the presentation of giant cell arteritis (GCA) were associated with pre-existing cardiovascular (CV) risk factors, CV disease or genetic risk of CV-related traits.
Methods
1946 GCA patients with clinicodemographic data at GCA presentation were included. Associations between pre-existing CV-related traits (including Polygenic Risk Scores (PRS) for CV traits) and cranial ischaemic complications were tested. A model for cranial ischaemic complications was optimised using an elastic net approach. Positional gene mapping of associated PRS was performed to improve biological understanding.
Results
In a sample of 1946 GCA patients (median age=71, 68.7% female), 17% had cranial ischaemic complications at presentation. In univariable analyses, 10 variables were associated with complications (likelihood-ratio test p≤0.05). In multivariable analysis, the two variables with the strongest effects, with or without PRS in the model, were anticoagulant therapy (adjusted OR (95% CI)=0.21 (0.05 to 0.62), p=4.95×10−3) and age (adjusted OR (95% CI)=1.60 (0.73 to 3.66), p=2.52×10−3, for ≥80 years versus <60 years). In sensitivity analyses omitting anticoagulant therapy from multivariable analysis, age and hypertension were associated with cranial ischaemic complications at presentation (hypertension: adjusted OR (95% CI)=1.35 (1.03 to 1.75), p=0.03). Positional gene mapping of an associated transient ischaemic attack PRS identified TEK, CD96 and MROH9 loci.
Conclusion
Age and hypertension were risk factors for cranial ischaemic complications at GCA presentation, but in this dataset, anticoagulation appeared protective. Positional gene mapping suggested a role for immune and coagulation-related pathways in the pathogenesis of complications. Further studies are needed before implementation in clinical practice
Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine in children aged 6–17 years: Final results of a phase 2, single-blind, randomised controlled trial (COV006)
Get PDFBACKGROUND: Paediatric COVID-19 vaccination programmes were initiated in response to the coronavirus pandemic declared by the World Health Organisation (WHO) in 2020. Ten COVID-19 vaccines received WHO Emergency Use Listing, however, only five were approved for use in children. ChAdOx1 nCoV-19 (AZD1222) was approved in adults in a two-dose regimen. We previously reported interim findings of a phase 2 study of ChAdOx1 nCoV-19 in children with immunogenicity, comparable with adults. Final results after 12 month follow-up are reported. METHODS: Single-blind, randomised controlled trial across four UK centres, recruiting 261 children and adolescents (aged 6-17 years). Participants received either two doses of ChAdOx1 nCoV-19 or Bexsero vaccine (controls). The primary outcome was safety (adverse events for 28 days following vaccination and serious adverse events throughout), and secondary outcome was immunogenicity (measured by SARS-CoV-2 anti-spike enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunosorbent spot (ELISpot)). FINDINGS: Five serious adverse events and four adverse events of special interest were reported. None were related to study vaccinations, and there were no deaths. Geometric mean titres (GMTs) from an anti-spike (Wuhan) ELISA in participants aged 6-11 years were 1 EU/ml (95% CI 1-2) at baseline versus 796 EU (95% CI 161-3948, n =4) at D364. In participants aged 12-17 years, GMTs were 1 EU/ml (95% CI 1-2, n=3) at baseline versus 1432 EU/ml (95% CI 2337-6083; n=6) at D364 (2 dose regimen at 112-day interval), compared to 3 EU/ml (95% CI 0-62) at baseline versus 392 EU/ml (95% CI 24, 6493; n=3) at D364 (2 dose regimen at a 28-day interval). INTERPRETATION: A two-dose regimen of ChAdOx1 nCoV-19 was immunogenic and safe in the trial population. No vaccine-related serious adverse events were reported. Immune responses persisted to 12 months in participants who did not experience breakthrough infection, This trial was registered with ISRCTN, trial number 15638344. FUNDING: The study was funded by the Department of Health and Social Care, through the National Institute for Health Research, and AstraZeneca
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