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Predictive testing for Huntington's disease in a digital age; patient power with potential pitfalls.
Get PDFRelationship of maternal ophthalmic artery Doppler with uterine artery Doppler, hemodynamic indices and gestational age: prospective MATERA study.
Get PDFOBJECTIVES: To examine the relationship of ophthalmic artery (OA) Doppler indices with uterine artery (UtA) Doppler indices, selected maternal hemodynamic parameters and gestational age, and to evaluate the intraobserver reproducibility of OA Doppler indices. METHODS: This was a prospective cohort study of women recruited between 11 + 0 and 23 + 6 weeks' gestation using a stratified and random sampling approach to ensure adequate distribution across the gestational-age range. OA pulsatility index (PI), first peak systolic velocity (PSV1), second peak systolic velocity (PSV2) and peak systolic velocity ratio (PSV ratio), calculated as PSV2/PSV1, were measured twice in each eye by the same observer. UtA-PI was also measured twice on each side by the same observer. Maternal hemodynamic assessment was undertaken using an ultrasonic cardiac output monitor (USCOM 1A). Pearson's and Spearman's rank correlation coefficients were used to assess the correlations between variables, and Bland-Altman plots were used to evaluate the intraobserver reproducibility of OA Doppler indices. RESULTS: Of 194 women invited to participate in the study, 169 were eligible for inclusion, of whom 16 were excluded following an obstetric ultrasound scan and a further three owing to inadequate or incomplete OA or UtA Doppler assessment, leaving 150 women in the final analysis. Log UtA-PI had a weak correlation with both OA-PI (r = -0.19 (95% CI, -0.34 to -0.03), P = 0.021) and OA-PSV ratio (r = 0.31 (95% CI, 0.15-0.45), P < 0.001). The correlation between gestational age and OA-PI was non-significant (r = 0.14 (95% CI, -0.03 to 0.29), P = 0.097), and that between gestational age and OA-PSV ratio was weak (r = -0.23 (95% CI, -0.38 to -0.07), P = 0.004), as opposed to the strong correlation between gestational age and UtA-PI (r = -0.68 (95% CI, -0.76 to -0.58), P < 0.001). No strong correlations were observed between OA-PI or OA-PSV ratio and maternal hemodynamic indices. The correlations were unaltered by adjustment for maternal age and body mass index. The intraobserver reproducibility of OA-PI and OA-PSV ratio in the same eye was high. The correlation between the right and left eyes was moderate for OA-PI (r = 0.63 (95% CI, 0.53-0.72), P < 0.001) and strong for OA-PSV ratio (r = 0.81 (95% CI, 0.75-0.86), P < 0.001). CONCLUSIONS: OA-PI and OA-PSV ratio had a weak or no correlation with UtA-PI and maternal hemodynamic parameters, meaning that they can be used as independent predictors for pre-eclampsia. Gestational age had no clinically relevant effect on OA-PI and OA-PSV ratio, suggesting that these indices could be measured without adjustment at any time between 11 and 23 weeks' gestation. OA Doppler indices had high intraobserver reproducibility and were strongly correlated between the right and left eyes. © 2025 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology
Immunogenicity and safety of a group B Streptococcus vaccine (GBS-AlpN) in pregnant women and their infants: a phase 2, multicentre, observer-blind, randomised, placebo-controlled study
No full textBACKGROUND: GBS-AlpN is a novel group B streptococcus maternal vaccine, based on the N-terminal domains of the alpha-like proteins AlphaCN, RibN, Alp1N, and Alp2/3N, which are responsible for 99% of invasive group B streptococcus strains. We aimed to assess the safety and immunogenicity of GBS-AlpN in pregnant women receiving vaccination or placebo. METHODS: This phase 2, observer-blind, randomised, placebo-controlled study was done in ten health-care facilities in South Africa, Denmark, and the UK. Eligible participants were healthy women carrying a singleton pregnancy without detectable congenital abnormalities at 21 weeks and 0 days to 23 weeks and 6 days of gestation at first vaccination. Participants were randomly assigned (2:2:2:2:1) via an electronic case report to receive two GBS-AlpN vaccine doses and one placebo dose (groups 1, 2, and 3), one GBS-AlpN vaccine dose and two placebo doses (group 4), or no vaccine doses and three placebo doses (group 5). Randomisation was stratified by site and within site using blocks of nine. Participants received 0·5 mL GBS-AlpN or placebo (saline) intramuscularly at 22 (placebo), 26 (vaccine), and 30 (vaccine) weeks' gestational age (group 1); 22 (vaccine), 26 (vaccine), and 30 (placebo) weeks' gestational age (group 2); 22 (vaccine), 26 (placebo), and 30 (vaccine) weeks' gestational age (group 3); 22 (placebo), 26 (vaccine), and 30 (placebo) weeks' gestational age (group 4); and 22 (placebo), 26 (placebo), and 30 (placebo) weeks' gestational age (group 5). All individuals (study staff and participants) were masked to group allocation, except those administering vaccines. The primary endpoint was the concentration of AlphaCN, RibN, Alp1N, and Alp2/3N protein-specific IgG in umbilical cord blood or blood obtained from infants within 72 h of birth and the proportion of infants with AlpN-specific IgG concentrations above a range of prespecified descriptive thresholds (0·1, 0·2, 0·5, 1·0, 2·0, 4·0, and 8·0 μg/mL). Safety endpoints were evaluated in participants who received at least one vaccination, and their infants. Immunogenicity analyses included participants in the safety population who provided an evaluable sample following first GBS-AlpN or placebo. This trial is registered with ClinicalTrials.gov, NCT05154578, and is closed to enrolment. FINDINGS: Between Feb 17 and Nov 22, 2022, 400 participants were screened for eligibility, of whom 272 were randomly assigned (group 1 n=61; group 2 n=60; group 3 n=59; group 4 n=62; group 5 n=30). 269 participants received at least one dose of GBS-AlpN or placebo (group 1 n=61; group 2 n=59; group 3 n=59; group 4 n=60; and group 5 n=30). The highest serum IgG concentrations at birth were observed in group 1, followed by the other two dose vaccine groups (groups 2 and 3). Lower IgG concentrations were observed in group 4, although these were at least 21-fold higher than in group 5 (placebo only). The proportion of infants with IgG concentrations greater than 1·0 μg/mL in umbilical cord blood ranged from 33 (87%) of 38 to 34 (94%) of 36 in group 1, 30 (67%) of 45 to 43 (91%) of 47 in group 2, 37 (82%) of 45 to 38 (93%) of 41 in group 3, and 22 (61%) of 36 to 28 (80%) of 35 in group 4. No infants in the placebo group had antibody concentrations greater than 1·0 μg/mL for any of the AlpN proteins. Treatment-emergent adverse events were reported by 56 (92%) of 61 maternal participants in group 1, 54 (92%) of 59 in group 2, 57 (97%) of 59 in group 3, 56 (93%) of 60 in group 4, and 26 (87%) of 30 in group 5; most events were mild-moderate. Nine infant fatalities were reported; none were considered related to vaccination. INTERPRETATION: GBS-AlpN had an acceptable safety profile and was immunogenic when administered to pregnant women, supporting its progression to phase 3 trials, with a flexible two-dose schedule allowing dosing intervals of 4-8 weeks. FUNDING: MinervaX
Epstein-Barr Virus Central Nervous System Infections and Mortality Risk in Patients Presenting With Suspected Meningitis: Results From the Botswana National Meningitis Survey and the Harare Meningitis Aetiology Study
Get PDFBackground
Epstein-Barr virus (EBV) central nervous system (CNS) infection in immunocompromised hosts and among meningitis cohorts is well recognized. The clinical significance of EBV CNS infection, however, is poorly understood.
Methods
Data were collected as part of the Botswana National Meningitis Survey and the Harare Meningitis Aetiology Study. The prevalence of EBV CNS infection (EBV DNA detected in cerebrospinal fluid [CSF] by means of quantitative polymerase chain reaction) was determined, alongside associations with baseline covariates and the in-hospital mortality rate.
Results
A total of 581 participants with suspected meningitis were recruited. Of these, 54% were male, the median age (interquartile range) was 38 (29–46) years, and 76% were persons living with human immunodeficiency virus (HIV). Cryptococcal meningitis was the most common microbiologically confirmed infectious meningitis (12.0%), and 6.4% of participants had definite tuberculous meningitis. EBV CNS infection was common (26% [152 of 581]) and was associated with older age, being HIV positive, and CSF pleocytosis (P &lt; .001). It was also associated with increased in-hospital mortality rate (odds ratio, 1.64, [95% confidence interval, 1.10–2.43]; P = .01), but after adjustment for sex, age, and HIV status, there was no longer evidence of an association (adjusted odds ratio, 1.29 [.84–1.98]; P = .25). In subgroup analyses, there was an indication that the association between EBV CNS infection and mortality rate may differ by meningitis subgroup.
Conclusions
EBV CNS infection was common among our cohort, and it was strongly associated with CSF pleocytosis. Following multivariable analyses, EBV CNS infection overall was not associated with in-hospital mortality rate. EBV CNS infection in the context of meningitis is most likely a “bystander” virus that reflects heightened CSF inflammation
Effect of Behavior-change Interventions on Daily Physical Activity in Patients with Intermittent Claudication: The OPTIMA Systematic Review with Meta-Analysis.
Get PDFAIMS: The study aimed to synthesize evidence of daily physical activity (PA) following Behavior-change technique (BCT)-based interventions compared to any control in individuals with peripheral arterial disease/intermittent claudication (PAD/IC); and examine the relationship between BCTs and daily PA. METHODS: Systematic search of 11 databases from inception to 30/11/2022 was conducted, plus weekly email alerts of new literature until 31/8/2023. Studies comparing BCT-based interventions with any control were included. Primary analysis involved a pairwise random-effects meta-analysis. Risk of bias was assessed using the Cochrane-RoB-2 and ROBINS-I tools. Certainty of evidence was evaluated with the GRADE system. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline was followed. Outcome measures were short-term (<6 months) change in daily PA, and maintenance of the daily PA (6 months or longer) reported as standardized mean differences (SMDs) with 95% confidence intervals (95%CIs). RESULTS: Forty-one studies (4,339 patients; 26 RCTs/3,357 patients; 15 non-RCTs/982 patients; study mean age 60.3 to 73.8, 29.5% female) were included. Eleven RCTs (15 comparisons, 952 participants) suggested that BCT-based interventions increased daily PA in the short term compared to non-SET [increase of 0.20 SMD (95%CI: 0.07 to 0.33), ∼473 steps/day] with high certainty. Evidence of maintenance of daily PA (≥6 months) is unclear [increase of 0.12 SMD (95%CI: -0.04 to 0.29); ∼288 steps/day; 6RCTs, 8 comparisons, 899 participants], with moderate certainty. For daily PA, compared to SET it was inconclusive both for < 6months change [-0.13 SMD, 95%CI: -0.43 to 0.16); 3RCTs, 269 participants; low certainty] and ≥6months [-0.04 SMD, 95%CI: -0.55 to 0.47); 1 RCT, 89 participants; very low certainty]. It was unclear whether the number of BCTs or any BCT domain were independently related to an increase in PA. CONCLUSION: BCT-based interventions improve short-term daily PA in people with PAD/IC compared to non-SET controls. Evidence for maintenance of the improved PA at 6 months or longer and comparison with SET is uncertain. BCT-based interventions are effective choices for enhancing daily PA in PAD/IC
Oral Regimens for Rifampin-Resistant, Fluoroquinolone-Susceptible Tuberculosis.
Get PDFBACKGROUND: For decades, poor treatment options and low-quality evidence plagued care for patients with rifampin-resistant tuberculosis. The advent of new drugs to treat tuberculosis and enhanced funding now permit randomized, controlled trials of shortened-duration, all-oral treatments for rifampin-resistant tuberculosis. METHODS: We conducted a phase 3, multinational, open-label, randomized, controlled noninferiority trial to compare standard therapy for treatment of fluoroquinolone-susceptible, rifampin-resistant tuberculosis with five 9-month oral regimens that included various combinations of bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C), and pyrazinamide (Z). Participants were randomly assigned (with the use of Bayesian response-adaptive randomization) to receive one of five combinations or standard therapy. The primary end point was a favorable outcome at week 73, defined by two negative sputum culture results or favorable bacteriologic, clinical, and radiologic evolution. The noninferiority margin was -12 percentage points. RESULTS: Among the 754 participants who underwent randomization, 699 were included in the modified intention-to-treat analysis, and 562 in the per-protocol analysis. In the modified intention-to-treat analysis, 80.7% of the patients in the standard-therapy group had favorable outcomes. The risk difference between standard therapy and each of the four new regimens that were found to be noninferior in the modified intention-to-treat population was as follows: BCLLfxZ, 9.8 percentage points (95% confidence interval [CI], 0.9 to 18.7); BLMZ, 8.3 percentage points (95% CI, -0.8 to 17.4); BDLLfxZ, 4.6 percentage points (95% CI, -4.9 to 14.1); and DCMZ, 2.5 percentage points (95% CI, -7.5 to 12.5). Differences were similar in the per-protocol population, with the exception of DCMZ, which was not noninferior in that population. The proportion of participants with grade 3 or higher adverse events was similar across the regimens. Grade 3 or higher hepatotoxic events occurred in 11.7% of participants overall and in 7.1% of those receiving standard therapy. CONCLUSIONS: Consistent results across all the analyses support the noninferior efficacy of three all-oral shortened regimens for the treatment of rifampin-resistant tuberculosis. (Funded by Unitaid and others; endTB ClinicalTrials.gov number, NCT02754765.)
The Healthcare Needs of Children With Down Syndrome in the First Year of Life: An Analysis of the EUROlinkCAT Data Linkage Study.
Get PDFBACKGROUND: Globally, Down syndrome is the most common chromosomal anomaly, often co-occurring with cardiac or gastrointestinal anomalies. There is a lack of robust data on specific healthcare needs of children with Down syndrome compared to children with other major congenital anomalies. OBJECTIVES: To quantify the healthcare needs of children with Down syndrome in the first year of life compared to children with major congenital anomalies in a large population-based cohort across Europe. METHODS: The EUROlinkCAT study was a multicentre data linkage study between congenital anomaly registries in Europe and hospital and mortality databases. Children born between 1st January 1997 and 31st December 2014 were included. Summary statistics were used to compare differences between children (those with Down syndrome compared to all major anomalies) and regions. Random-effects meta-analysis was used to pool results related to survival, need for intensive care and ventilation support. RESULTS: A total of 3554 children were born with Down syndrome out of 89,081 children with major congenital anomalies. The pooled 1-year survival was 95.4%. In every region, > 80% of children with Down syndrome had a hospital admission excluding the birth admission. Hospital length of stay in the first year was higher for children with Down syndrome compared to those with all anomalies (median: 14 versus 7 days). Despite having similar need for ventilation support (9.7% vs. 8.4%), children with Down syndrome had higher rates of intensive care admission than all children with anomalies (24.8% vs. 13.0%). CONCLUSIONS: There is a high need for hospital care for children born with Down syndrome in the first year of life. Future work should continue to explore the long-term prognosis for children with Down syndrome to ensure their care needs are met
Cortico-thalamic tremor circuits and their associations with deep brain stimulation effects in essential tremor.
Get PDFEssential tremor (ET) is one of the most common movement disorders in adults. Deep brain stimulation (DBS) of the ventralis intermediate nucleus (VIM) of the thalamus and/or the posterior subthalamic area (PSA) has been shown to provide significant tremor suppression in patients with ET, but with significant inter-patient variability and habituation to the stimulation. Several non-invasive neuromodulation techniques targeting other parts of the central nervous system, including cerebellar, motor cortex, or peripheral nerves, have also been developed for treating ET, but the clinical outcomes remain inconsistent. Existing studies suggest that pathology in ET may emerge from multiple cortical and subcortical areas, but its exact mechanisms remain unclear. By simultaneously capturing neural activities from motor cortices and thalami, and hand tremor signals recorded via accelerometers in fifteen human subjects who have undergone lead implantations for DBS, we systematically characterized the efferent and afferent cortico-thalamic tremor networks. Through the comparisons of these network characteristics and tremor amplitude between DBS OFF and ON conditions, we further investigated the associations between different tremor network characteristics and the magnitude of DBS effect. Our findings implicate the thalamus, specifically the contralateral hemisphere, as the primary generator of tremor in ET, with a significant contribution of the ipsilateral hemisphere as well. Although there is no direct correlation between the cortico-tremor connectivity and tremor power or reduced tremor by DBS, the strength of connectivity from the motor cortex to the thalamus and vice versa at tremor frequency predicts baseline tremor power and effect of DBS. Interestingly, there is no correlation between these two connectivity pathways themselves, suggesting that, independent of the subcortical pathway, the motor cortex appears to play a relatively distinct role, possibly mediated through an afferent/feedback loop in the propagation of tremor. DBS has a greater clinical effect in those with stronger cortico-thalamo-tremor connectivity involving the contralateral thalamus, which is also associated with bigger and more stable tremor measured with an accelerometer. Interestingly, stronger cross-hemisphere coupling between left and right thalami is associated with more unstable tremor. Together this study provides important insights into a better understanding of the cortico-thalamic tremor generating network and its implication for the development of patient-specific therapeutic approaches for ET
Antenatal Screening for Hepatitis B Virus in Uganda: Missed Opportunities for Diagnosis and Treatment
Get PDFBackground
Hepatitis B virus (HBV) infection is a significant cause of morbidity and mortality globally. The World Health Organization estimates that just 10.5% of individuals living with HBV globally are aware of their status. Antenatal care provides an opportunity to screen pregnant women for HBV and to treat those who are eligible to reduce the risk of vertical transmission. We conducted an observational study to determine the proportion of pregnant women with active HBV infection delivering at a government-funded hospital in Kampala, Uganda, to estimate the number of missed opportunities to prevent vertical transmission.
Methods
Eligible participants were enrolled via the PROGRESS study, an observational cohort study undertaken in Kampala, Uganda, between November 2018 and April 2021. Results presented here describe data from April 2019 to November 2020. Five milliliters of venous blood was drawn shortly after delivery. Serum aliquots were analyzed for hepatitis B surface antigen (HBsAg). HBsAg-positive participants were informed of their result by telephone and referred to the gastroenterology service for specialist management.
Results
In total, 6062 women were enrolled between April 2019 and November 2020. Results were available for 6012 (99.6%) participants, among whom 131 (2.2%) were HBsAg positive. Only 10 of 131 (7.6%) HBsAg-positive participants were successfully referred to the gastroenterology service at Mulago Hospital for treatment of their infection.
Conclusions
Our study identified a number of missed opportunities to identify active HBV infection among our pregnant cohort. Additional resources are urgently required to increase the coverage of antenatal HBV screening while also improving treatment pathways for pregnant women with HBV infection in this region
Infectious Causes of Stillbirths: A Descriptive Etiological Study in Uganda
Get PDFBackground
Every year an estimated 2–3 million babies are stillborn, with a high burden in Africa. Infection is an important driver of stillbirth. There is a lack of data on the bacterial causes of stillbirth in Uganda, contributing to a lack of interventions such as effective prophylaxis and development of maternal vaccine options against the most implicated pathogens.
Methods
The PROGRESS study was an observational cohort study undertaken in Kampala, Uganda, between November 2018 and April 2021. If a woman delivered a stillborn baby, consent was sought for the collection of a heart-blood aspirate. One to three mL of blood was collected and sent for culture using the BD Bactec blood culture system. Organism identification was performed using biochemical testing and matrix-assisted laser desorption/ionization–time of flight mass spectrometry. Susceptibilities to appropriate panels of antimicrobials were determined by agar dilution.
Results
Kawempe Hospital registered 34 517 births in the study period, of which 1717 (5.0%) were stillbirths. A total of 581 (33.8%) were recruited into the study, and heart blood aspirates were performed on 569 (97.9%). Blood samples were sufficient for analysis of 476, with a total of 108 positive cultures (22.7% of sampled stillbirths). Fifty-nine of 108 blood cultures contained organisms that were considered potential pathogens, giving a pathogen positivity rate of 12.4%. Common pathogens included Enterococcus spp. (n = 14), Escherichia coli (n = 13), viridans streptococci (n = 18), Klebsiella pneumoniae (n = 6), and group B Streptococcus (n = 5). Gram-negative organisms were frequently resistant to commonly used first-line antimicrobials.
Conclusions
The high proportion of stillbirths caused by likely pathogenic bacteria in Uganda highlights the potential for prevention with prophylaxis and stresses the need for further investment in this area
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