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A composite subunit vaccine confers full protection against Buruli ulcer disease in the mouse footpad model of Mycobacterium ulcerans infection.
Get PDFBuruli ulcer (BU) disease, a neglected necrotizing tropical skin infection caused by Mycobacterium ulcerans, is the third most common mycobacterial disease after tuberculosis and leprosy. Infections mostly occur in remote, rural areas of Central and West Africa, but also in Australia, Japan and Papua New Guinea. There is currently no vaccine against Buruli ulcer disease and all previous attempts using closely related bacteria and subunit proteins have been partially successful only. Here, we tested in mice a composite subunit formulation incorporating the Mycobacterium ulcerans toxin mycolactone as the immunomodulator, and the antigens Ag85A and Polyketide Synthase Enzyme Ketoreductase A (KRA), formulated with Quil-A adjuvant ('Burulivac'). Burulivac induced Ag85A and KRA antigen-specific antibodies, T cells and a mixed pro- and anti-inflammatory cytokine responses, which conferred absolute protection against Buruli ulcer disease in the mouse footpad model over a 14-week period of observation. This was superior to both live attenuated mycobacterial vaccines, that is, BCG and an avirulent M. ulcerans strain that lacks the mycolactone toxin (MuΔ). Interleukin 10 was found to be strongly associated with protection. We suggest that Burulivac is a promising vaccine candidate against Buruli ulcer disease that warrants further exploration
The relationship between prenatal anxiety and gestational age: A systematic review
Get PDFPreterm birth poses a significant risk to short- and long-term infant health, and can have significant negative effects on maternal mental health. Increased levels of anxiety during pregnancy might be related to gestational age. Identifying potential risk factors for preterm birth may offer the opportunity for early intervention and reduce adverse outcomes. Ten databases, including empirical and grey literature, were searched. Articles were screened at title, abstract, and full-text review by two independent reviewers, and were quality assessed using the JBI critical appraisal tools. Forty-one studies were identified for inclusion in the review, published between 1990 and 2022. Data were narratively synthesised due to heterogeneity in study designs. Results of the data synthesis indicate there is an inverse relationship between anxiety and gestational age or preterm birth. This relationship may be dependent upon timing of assessment, and measure of anxiety used. Assessing anxiety at a single timepoint may not be as accurate as assessments across all three trimesters. Concerted efforts should be made to distinguish between spontaneous preterm birth and medically indicated preterm birth, as anxieties during pregnancy may present differently between the two groups. Future studies should consider the assessment of anxiety across trimesters to assess change in mood, as well as the use of pregnancy-specific measures alongside general measures to support intervention during pregnancy
Lost opportunities for young people with ASC under early intervention: A service evaluation from a central London Forensic CAMHS service
Get PDFBackground
Little is known about the needs and risk behaviours of children and young people (CYP) with Autistic Spectrum Condition (ASC) referred to Community Forensic Child and Adolescent Mental Health Services (C-FCAMHS).
Methods
A retrospective service evaluation considering all CYP (n = 444) referred to a C-FCAMHS in London from mid-2018 to December 2022. We considered demographic and family background data, comorbid diagnoses, service involvement and reasons for North West London Community Forensic Child and Adolescent Mental Health Services (NWLFCAMHS) referral and NWLFCAMHS input and risk assessment of CYP with and without ASC.
Results
At referral, close to one-quarter (22.8 %; male n = 88, 25.7 %; females n = 8, 18.9 %) of referred CYP had a diagnosis of ASC; a third of these had a co-occurring neurodevelopmental disorder. A further 25 CYP were awaiting ASC assessment, of which six CYP individuals were subsequently given an ASC diagnosis. Of the CYP with ASC, close to four-fifths were open to CAMHS (78.1 %) and social care (79.2 %) on referral. Over two-fifths (42.5 %) of CYP with ASC were referred due to violent behaviours and 59.2 % were considered at moderate risk to others.
Conclusion
There are higher prevalence rates of ASC in referrals to our C-FCAMHS than in the general adolescent population, with disproportionally higher rates in girls and those from racialised backgrounds. Missed opportunities for support to reduce development of risk behaviours were noted, including insufficient individual support plans in education, social care and CAMHS. There is much need to support early identification of ASC across all demographically diverse groups to enable early support from services and prevent escalation to high-risk behaviours
A template tool for the evaluation of vaccines for emerging pathogens to be used for pregnant and breast-feeding women
Get PDFVaccination during pregnancy provides effective protection against pathogens that increase the risk of maternal and infant morbidity and mortality for mothers and their infants. The SARS-CoV-2 pandemic demonstrated the need for the inclusion of pregnant and breast-feeding women in research and development of vaccines for emerging pathogens, such as Ebola, Zika, Lassa fever, Chikungunya, and influenza virus of pandemic potential. The COVID-19 Vaccines Global Access (COVAX) Maternal Immunization Working Group (MIWG), in collaboration with the Coalition for Epidemic Preparedness Innovation and the Safety Platform for Emergency Vaccines (CEPI-SPEAC) developed a standardized template with key considerations to guide the assessment of vaccines against emerging pathogens in pregnant and breast-feeding women. The aim of this tool is to enable key stakeholders to perform an early structured assessment of the overall potential benefit and risk for maternal immunization against an emerging pathogen. It can also be used to support risk management and pharmacovigilance planning, communication strategies, policy development, and acceptance of vaccination during pregnancy in future pandemics
Small Bowel Motility Quantified by Cine MRI to Predict Longer-Term Response in Patients with Crohn’s Disease Commencing Biological Therapy: The Motility Study
Get PDFBackground
Small bowel Crohn’s disease (SBCD) is increasingly treated with biological therapies. Predicting response or remission (RoR) for individual patients is difficult and complicates treatment strategy. We aimed to determine if motility magnetic resonance imaging (mMRI) is superior to CRP and fecal calprotectin (FC) for the prediction of RoR at 1 year in patients commencing biologics for SBCD.
Methods
Prospective, multicenter (n = 13) cohort study of patients with active non-stricturing SBCD requiring anti-TNFα or anti-IL-12/23 treatment. We measured mMRI and CRP at baseline and post-induction (visit 2: 12-30 weeks), and FC in a subset. RoR was assessed at 1 year using clinical and structural magnetic resonance enterography parameters. We compared sensitivity, specificity, and area under the receiver operating characteristic curve (ROC-AUC) of changes in mMRI and CRP to predict RoR at 1 year. Secondary outcomes compared mMRI with FC, and prediction of improved quality of life (QoL).
Results
Eighty-six participants completed all assessments. Stable or improved mMRI at visit 2 was more sensitive than normalization of CRP for RoR (mMRI:71.0%, 95%CI 52.0-85.8; CRP:45.2%, 95%CI 27.3-64.0%, P = .008) but less specific (mMRI:30.9%, 95%CI 19.1-44.8; CRP:67.3%, 95%CI 53.3-79.3%, P < .001). There was no significant difference in ROC-AUC (mMRI:0.48; CRP:0.53, P = .65). Similar results were obtained for FC. None of mMRI, CRP, or FC predicted patient QoL at 1 year.
Conclusions
Although improved mMRI is more sensitive than CRP and FC to predict RoR at 1 year, it is less specific. No factor predicted patient QoL. Motility MRI remains a marker of disease activity at given timepoints
Multicenter Case–Control Study of Behavioral, Environmental, and Geographic Risk Factors for Talaromycosis, Vietnam
Get PDFTalaromycosis is a life-threatening fungal disease that primarily affects immunocompromised persons in Southeast Asia. We conducted a multicenter, case-control study recruiting participants with advanced HIV disease in Vietnam; 205 case-patients with culture-confirmed talaromycosis were matched to 405 control-patients by age, sex, and CD4 count. Occupational exposure to tropical plants (odds ratio [OR] 1.73 [95% CI 1.10-2.73]; p = 0.017) and to farmed animals (OR 2.07 [95% CI 1.20-3.55]; p = 0.009) were independent risk factors for talaromycosis. Talaromycosis risk was higher in participants from highland regions than in persons from lowland regions (p<0.05). Participants from lowland regions who had lived or traveled to highland regions had a higher risk for talaromycosis (OR 3.15 [95% CI 1.49-6.64]; p = 0.003). This study confirms the epidemiologic correlation between talaromycosis and soil exposure and demonstrates an epidemiologic link between talaromycosis and residence in or travel to highland regions of Vietnam
Concomitant Aficamten and Disopyramide in Symptomatic Obstructive Hypertrophic Cardiomyopathy
Get PDFBackground
Disopyramide, used in obstructive hypertrophic cardiomyopathy (oHCM) for its negative inotropic properties mediated by its reduction in cytosolic calcium, has been recommended for decades as an option to relieve resistant obstruction. Aficamten is a selective cardiac myosin inhibitor that reduces hypercontractility directly by reducing myosin-actin interaction.
Objectives
This study aims to investigate the safety and efficacy of concomitant use and withdrawal of disopyramide in patients with symptomatic oHCM receiving aficamten.
Methods
Patients with oHCM enrolled in REDWOOD-HCM Cohort 3 (open-label), SEQUOIA-HCM (placebo-controlled), and FOREST-HCM (open-label) were analyzed. The authors identified 4 groups, each with patients symptomatic despite background therapy with disopyramide who received: 1) disopyramide plus aficamten and subsequent aficamten withdrawal per protocol (Diso-Afi Withdrawal); 2) disopyramide plus placebo (Diso-Pbo); 3) aficamten plus disopyramide with subsequent disopyramide withdrawal (Afi-Diso Withdrawal); and 4) continued both disopyramide and aficamten (Diso+Afi Continuous). Assessments were performed at baseline, after aficamten or placebo add-on therapy, and after washout (except at week 24 for Diso+Afi Continuous group).
Results
Overall, 50 unique patients from 3 trials enrolled, resulting in 93 subjects (segments) across 4 groups: Diso-Afi Withdrawal (n = 29), Diso-Pbo (n = 20), Afi-Diso Withdrawal (n = 17), and Diso+Afi Continuous (n = 27); mean disopyramide dose was 331 ± 146 mg/d. The addition of aficamten to disopyramide alleviated left ventricular outflow tract (LVOT) obstruction (resting: change [Δ] in least squares mean −27.0 ± 3.6, Valsalva: Δ least squares mean −39.2 ± 5.0, both P < 0.0001), symptoms (≥1 NYHA functional class improvement: 77.8% [95% CI: 61.0-94.5]; P < 0.0001; Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score: 12.3 ± 3.3 [P < 0.001]), and reduced N-terminal pro–B-type natriuretic peptide ratio: 0.35 [95% CI: 0.26-0.48]; P < 0.0001, and there was no significant change with placebo. Withdrawal of aficamten while on disopyramide resulted in return of LVOT obstruction, worsening of symptoms, and increase in NT-proBNP to baseline values. Conversely, withdrawal of disopyramide while on aficamten did not impact efficacy. There were no safety events associated with aficamten or disopyramide withdrawal, and no episodes of atrial fibrillation after disopyramide withdrawal.
Conclusions
In this cohort of patients with symptomatic oHCM with persistent LVOT obstruction, combination therapy with aficamten and disopyramide was safe and well tolerated but did not enhance clinical efficacy vs aficamten alone. For such oHCM patients, aficamten treatment may be considered with an option to discontinue disopyramide. (Dose-finding Study to Evaluate the Safety, Tolerability, PK, and PD of CK-3773274 in Adults With HCM [REDWOOD-HCM]; NCT04219826) (Aficamten vs Placebo in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy [SEQUOIA-HCM]; NCT05186818) (Open-label Extension Study to Evaluate the Long-term Safety and Tolerability of Aficamten in Adults With HCM [FOREST-HCM]; NCT04848506
Cardiac resynchronization therapy for enabling guideline‐directed medical therapy optimization in heart failure
Get PDFAims
We aimed to assess whether cardiac resynchronization therapy (CRT) might serve as an enabler for guideline‐directed medical therapy (GDMT) optimization.
Methods and results
Patients with heart failure with reduced ejection fraction (HFrEF) enrolled in the Swedish Heart Failure Registry between January 2009 and August 2022 were considered. Patients receiving a CRT close to the index registration were the cases, whereas controls had not received a CRT despite having an indication. Overall, 1543 (25%) HFrEF cases and 4537 (75%) controls were analysed in the intention‐to‐treat analysis. At baseline, beta‐blockers, angiotensin‐converting enzyme inhibitor (ACEi), angiotensin receptor blocker (ARB) or angiotensin receptor–neprilysin inhibitor (ARNi), mineralocorticoid receptor antagonist (MRA) and loop diuretic use was 84% versus 86%, 89% versus 88%, 57% versus 46% and 62% versus 59% in patients receiving versus not receiving CRT, respectively. At 1.5‐year follow‐up, patients receiving a CRT more likely experienced an improved use/dose of beta‐blocker therapy (46% vs. 35%) and decreased loop diuretic use/dose (30% vs. 24%) versus controls. These associations were consistent after adjustments (odds ratio [OR] 1.83, 95% confidence interval [CI] 1.58–2.13, and OR 1.26, 95% CI 1.07–1.48, respectively), and confirmed in the per‐protocol analysis (i.e. after excluding controls who received a CRT during follow‐up). A significant association between CRT and the likelihood of ACEi/ARB/ARNi and MRA optimization (OR 1.22, 95% CI 1.04–1.44, and OR 1.25, 95% CI 1.05–1.50, respectively) was observed in the per‐protocol analysis.
Conclusions
In this large nationwide real‐world population with HFrEF, CRT implantation was associated with enabled use/dose of heart failure GDMT and decreased loop diuretic need (use/dose)
Personalisation at the Core of Success: Process Evaluation of the LISTEN Randomised Controlled Trial Evaluating a Personalised Self‐Management Support Intervention for People Living With Long Covid
Get PDFBackground
The development and evaluation of rehabilitation interventions designed to support people with Long Covid (LC) remains an important ongoing priority. Many people with LC experience episodic, debilitating symptoms that can reduce their ability to engage in all areas of activity. The Long CovId personalised Self‐managemenT support co‐design and EvaluatioN (LISTEN) trial co‐designed and evaluated a personalised self‐management support intervention to build confidence and support people to live better with LC. This paper describes the context, implementation, mechanisms of impact and impacts from the LISTEN intervention, in comparison with usual LC services accessed within the National Health Service (NHS).
Methods
A mixed methods process evaluation was nested within the LISTEN pragmatic, multi‐site, randomised controlled trial. Data were collected from sites in England and Wales between September 2022 and January 2024. Observations and focus groups with healthcare practitioners (HCPs) delivering the intervention were conducted to assess fidelity. Standardised implementation measures, focussed on intervention feasibility, acceptability and appropriateness, were gathered from HCPs and intervention participants. Semi‐structured interviews were undertaken with a subset of participants across both trial arms. Data were analysed independently using descriptive statistics, or reflexive thematic analyses, and subsequently integrated, drawing upon the Consolidated Framework for Implementation Research v2.
Findings
Thirty‐six HCPs participated in the process evaluation, and 197 intervention participants completed standardised implementation measures. Across both trial arms, 49 participants took part in semi‐structured interviews. Six integrated themes were constructed from all data sources describing and illustrating links between the context, implementation, mechanisms of impact and impacts: ‘Delivery during uncertainty and ambiguity’, ‘Diversity and consistency of usual care’, ‘Drivers for self‐care and the impact of self‐generated expertise’, ‘Appropriate if unexpected support’, ‘Personalisation at the core of success’ and ‘A spectrum of change’.
Conclusion
The LISTEN intervention is an appropriate, feasible intervention for participants and HCPs. The intervention can be delivered to a high level of fidelity following training and with ongoing HCP support. Access, receipt and perceptions of NHS LC services were variable. Personalised, relational interventions, such as LISTEN, can foster favourable impacts on confidence, knowledge and activity and are acceptable and strongly recommended within LC rehabilitation services.
Patient or Public Contribution
The study was supported by a patient and public involvement and engagement (PPIE) group from project conception to study end. Using their lived expertise, seven people with LC supported accessible recruitment (e.g., materials), data collection (e.g., topic guides), data interpretation (e.g., theme construction and reviewing findings) and dissemination activities (e.g., online webinars).
Trial Registration
ISRCTN36407216, registered 27/01/2022
Point Prevalence Survey of Antibiotic Use in Level 1 hospitals in Zambia: Future Prospects for Antimicrobial Stewardship Programs
Get PDFIntroduction: The inappropriate prescribing and use of antibiotics have contributed to the emergence and spread of antimicrobial resistance (AMR). In Zambia, there is a paucity of information on the prescribing patterns and use of antibiotics among hospitalized patients in level 1 hospitals. This study investigated antibiotic use in five level 1 hospitals in Lusaka, Zambia.
Methods: This cross-sectional study utilized the World Health Organization (WHO) Point Prevalence Survey (PPS) methodology among in-patients admitted in level 1 hospitals before 08:00 a.m. on the survey day in August 2024. Data were analysed using IBM SPSS version 23.0.
Results: The prevalence of antibiotic use among inpatients was 59.0%, with ceftriaxone being the most prescribed. Antibiotics were prescribed mainly for paediatrics and male inpatients. This study found that 53.0% of prescribed antibiotics were from the Access group while 38.2% were from the Watch group of the World Health Organization Access, Watch, and Reserve (AWaRe) classification. Adherence to national treatment guidelines was 36.0%, with most antibiotics prescribed empirically without evidence of culture and sensitivity tests.
Conclusion: This study found a high use of antibiotics and low adherence to treatment guidelines in level 1 hospitals in Lusaka, Zambia. The findings of this study demonstrate the need to establish and strengthen antimicrobial stewardship programs and strengthen laboratory capacity to aid clinicians in diagnosing, treating, and managing patients across level 1 hospitals in Zambia
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