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Clinical and regulatory development strategies for GBS vaccines intended for maternal immunisation in low- and middle-income countries
Get PDFGroup B Streptococcus (GBS) is a leading cause of infant mortality, particularly in low- and middle-income countries (LMICs). Several maternal GBS vaccine candidates, aimed at protecting infants, are progressing through clinical trials. The World Health Organisation (WHO) aims to ensure equitable access to safe, effective, and affordable vaccines of assured quality in LMICs, by facilitating regulatory pathways. An alternate approval pathway, based on safety and an immunological endpoint thought to predict clinical benefit (commonly referred to as serological threshold of risk reduction [SToRR]), is being considered for GBS maternal vaccines. Since this approach is new to many LMICs regulators and policymakers, WHO organized consultative meetings at national, regional, and global levels to discuss the feasibility and potential challenges of approving a GBS vaccine based on safety and immunogenicity data alone. These consultations focused on evidence supporting SToRR, their use as endpoints to infer protection, and post-licensure requirements. The aim of the consultations was to reduce the delay between vaccine development, licensure, policy recommendations and use in high-burden LMICs
Role of von Willebrand factor, platelets, and aberrant flow in the initiation of venous thrombosis
Get PDFDeep vein thrombosis is a major cause of morbidity and mortality worldwide. However, because of the absence of overt blood vessel damage, how venous thrombosis is actually initiated remains unclear. Using endothelialized fluidic devices, we show that aberrant flow patterns that may occur in venous valve pockets of individuals with common stasis-related risk factors can cause the formation of von Willebrand factor–platelet tangles that are resistant to ADAMTS13 removal. These von Willebrand factor–bound platelets specifically recruit neutrophils in a manner that is dependent on platelet-activated αIIbβ3, neutrophil SLC44A2, and endothelial P-selectin. The interaction of SLC44A2 with activated αIIbβ3 promotes formation of prothrombotic neutrophil extracellular traps. These data provide molecular and cellular insights into the proclivity for venous thrombosis to develop in venous valve pockets and suggest an alternative strategy to protect against the initiation of venous thrombosis
Which factors predict outcome from specialist physiotherapy for functional motor disorder? Prognostic modelling of the Physio4FMD intervention
Get PDFObjectives
Physiotherapy is considered part of first line treatment for functional motor disorder (FMD) although not all patients benefit. Predictors of treatment outcome may help to inform triage decisions. We aimed to determine which baseline variables predicted treatment outcome in the pragmatic multicentre Physio4FMD randomised controlled trial of specialist physiotherapy for FMD.
Methods
Participants randomised to the specialist physiotherapy arm of the trial were included in the analysis. Treatment outcome was dichotomised into improvement vs no improvement, based on two measures, Short Form 36 Physical Functioning (SF36 PF) and participant-rated Clinical Global Impression Scale of Improvement (CGI-I). Predictors of outcome were selected from baseline variables. Univariate logistic regression was used to calculate the odds ratio of improvement for each variable. Variables associated with improvement at p < 0.1 were considered for inclusion in a multiple logistic regression model.
Results
A greater perception of having control over recovery predicted improvement on the CGI-I (OR 1.18, 95 % CI 1.07, 1.31). Predictors of lack of improvement were an increased perception of the permanence of symptoms, predicting lack of improvement on the SF36 PF (OR 0.91, 95 % CI 0.84, 0.99) and older age, predicting lack of improvement on the CGI-I (OR 0.97, 95 % CI 0.95, 0.998).
Conclusions
Age and perceptions of symptom control were weak predictors of outcome from specialist physiotherapy. In contrast, a number of factors commonly believed to predict poorer treatment response, including illness duration and levels of pain and fatigue, were not related to the outcomes measured in this study
Identifying modifiable factors that influence walking in patients undergoing surgery for neurogenic claudication: a prospective longitudinal study.
Get PDFNeurogenic claudication, caused by lumbar spinal stenosis, is the most common reason for spinal surgery in older adults, aiming to improve pain and walking. However, most people do not increase walking post-operatively. This study aimed to identify modifiable physical and psychosocial factors that could be targeted with rehabilitation. A prospective longitudinal study recruited 97 adults, aged > 50 years, awaiting surgery for neurogenic claudication. Walking measures (six-minute walk test, daily step count, self-rated maximum walking distance) were assessed pre-surgery and 12-weeks post-surgery. Modifiable variables, mapped to a behaviour change model (COM-B; e.g. falls, lower limb performance, fear of movement, illness perceptions), were evaluated using mixed-effects regression models. All walking measures demonstrated statistically significant improvements (p < .001). However, 50% did not achieve minimum clinically important differences. The strongest correlation with post-operative walking was pre-operative walking. Cross-sectionally, lower limb performance (b:.75; 95CI .64, .86 to b:.35; 95%CI .19, .52), pre-surgery history of falls (b:-.29; 95%CI-.44,-.13), fear of falling (b:-.55; 95%CI-.69,-.41 to b:-.32; 95%CI -.48, -.15), fear of movement (b:-.48; 95%CI-.63,-.33 to -.22; 95%CI -.40, -.03), coherence of condition (b:-.23; 95%CI -.41, -.05 to b:-.17; 95%CI-.33,-.01) and perceived personal control (b:.26; 95%CI .09, .43 to b:.14; 95%CI.02,.31), were significantly associated with pre-surgical walking (p < .05). Most pre-surgical variables were not longitudinally associated with change in walking post-surgery. Six-weeks post-surgery fear of falling (b:-.35; 95%CI -.57, -.13 to b:-.18; 95%CI-.33,-.02), fear of movement (b:-.32; 95%CI-.53,-.11 to b:-.19; 95%CI -.33, -.05), and emotional response (b-.24; 95%CI -.38, -.11 to b:-.22; 95%CI -.41, -.03) were significantly associated with less improvement in walking at 12-weeks post-surgery. Prehabilitation and post-operative rehabilitation targeting walking, balance, and psychosocial factors is recommended to optimise post-surgical walking
Assessment of frailty in patients with heart failure: A new Heart Failure Frailty Score developed by Delphi consensus.
Get PDFAIMS: The Heart Failure Frailty Score (HFFS) is a novel, multidimensional tool to assess frailty in patients with heart failure (HF). It has been developed to overcome limitations of existing frailty assessment tools while being practical for clinical use. The HFFS reflects the concept of frailty as a multidimensional, dynamic and potentially reversible state, which increases vulnerability to stressors and risk of poor outcomes in patients with HF. METHODS AND RESULTS: The HFFS was developed through a Delphi consensus process involving 54 international experts. This approach involved iterative rounds of questionnaires and interviews, where a panel of experts provided their opinions on specific questions prepared by the Steering Committee. The experts were invited to vote and share their views anonymously, using a 5-point Likert scale over iterative rounds. An 80% threshold was set for agreement or disagreement for each statement. Twenty-two variables from four domains (clinical, functional, psycho-cognitive and social) have been selected for inclusion in the HFFS after the third round of the Delphi process. A shorter version (S-HFFS), including 10 variables, has also been developed for daily clinical use. CONCLUSIONS: The HFFS is a new multidimensional tool for the identification of frailty in patients with HF. It should also enables healthcare providers to identify potential 'red flags' for frailty in order to develop personalized care plans. The next step will be to validate the new score in patients with HF
Sore throat or severe threat? The teleconsultation that uncovered neutropenic sepsis.
No full textThis case report describes a telemedicine visit by a patient with fever, sore throat, and odynophagia. The patient had recently started taking propylthiouracil (PTU) for Graves disease. She was referred to the ED, where a complete blood cell count revealed agranulocytosis with a neutrophil count of 200 cells/mm3. PTU was promptly discontinued, and she received treatment with IV piperacillin-tazobactam, resulting in an improvement in her condition. With the rise of telemedicine, clinicians must prioritize thorough history-taking to detect uncommon complications of medications and to ensure patient safety
Current access, availability and use of antibiotics in primary care among key low- and middle-income countries and the policy implications
Get PDFIntroduction
Antimicrobial resistance (AMR) poses a significant threat, particularly in low- and middle-income countries (LMICs), exacerbated by inappropriate antibiotic use, access to quality antibiotics and weak antimicrobial stewardship (AMS). There is a need to review current evidence on antibiotic use, access, and AMR, in primary care across key countries.
Areas covered
This narrative review analyzes publications from 2018 to 2024 regarding access, availability, and use of appropriate antibiotics.
Expert opinion
There were very few studies focussing on a lack of access to antibiotics in primary care. However, there was considerable evidence of high rates of inappropriate antibiotic use, including Watch antibiotics, typically for minor infections, across studied countries exacerbated by patient demand. The high costs of antibiotics in a number of LMICs impact on their use, resulting in short courses and sharing of antibiotics. This can contribute to AMR alongside the use of substandard and falsified antibiotics. Overall, limited implementation of national action plans, insufficient resources, and knowledge gaps affects sustainable development goals to provide routine access to safe, effective, and appropriate antibiotics.
Conclusions
There is a clear need to focus health policy on the optimal use of essential AWaRe antibiotics in primary care settings to reduce AMR in LMICs
The Epidemiology and Clinical Burdens of Human Parainfluenza Virus Infections Amongst Hospitalized Children Under 5 Years of Age in Jordan: A National Multi-Center Cross-Sectional Study.
Get PDFHuman parainfluenza virus (HPIV) is a major cause of respiratory illnesses in children under five years, with clinical manifestations ranging from mild upper respiratory tract infections to severe lower respiratory tract diseases. This multi-center, cross-sectional study investigated the burden, clinical features, and predictors of respiratory viral infections in hospitalized children across four sites in Jordan. Nasopharyngeal specimens from 1000 eligible children were analyzed. In this article, we focused on HPIV infections. The overall HPIV positivity rate was 22.6%, with HPIV-3 accounting for 90.3% of cases. Significant geographic variability was observed, with higher positivity rates in the southern region. HPIV-positive cases frequently presented with symptoms like nasal congestion, tachypnea, and poor feeding. Co-infections with respiratory syncytial virus (RSV) or influenza were associated with worse outcomes, including an increased need for invasive ventilation. The logistic regression identified male gender, asthma, and respiratory acidosis as predictors of complications. Geographic differences in HPIV prevalence and severity were notable, emphasizing the influence of environmental and socioeconomic factors. These findings underscore the urgent need for enhanced HPIV surveillance, targeted public health interventions, and vaccine development to mitigate the disease burden. This study provides critical insights that guide healthcare strategies and improve outcomes in young children at risk of severe HPIV infections
Defective Notch1 signaling in endothelial cells drives pathogenesis in a mouse model of Adams-Oliver Syndrome
Get PDFAdams-Oliver Syndrome (AOS) is a rare congenital disorder characterized by scalp, limb, and cardiovascular defects. While variants in the NOTCH1 receptor, DLL4 ligand, and RBPJ transcription factor have been implicated in AOS, the driving tissue types and molecular mechanisms by which these variants cause pathogenesis are unknown. Here, we used quantitative binding assays to show that AOS-associated RBPJ missense variants compromise DNA binding but not cofactor binding. These findings suggest that AOS-associated RBPJ variants do not function as loss-of-function alleles but instead act as dominant-negative proteins that sequester cofactors from DNA. Consistent with this idea, mice carrying an AOS-associated Rbpj allele develop dominant phenotypes that include increased lethality and cardiovascular defects in a Notch1 heterozygous background, whereas Notch1 and Rbpj compound heterozygous null alleles are well-tolerated. To facilitate studies into the tissues driving AOS pathogenesis, we employed conditional genetics to isolate the contribution of the vascular endothelium to the development of AOS-like phenotypes. Importantly, our studies show that expression of the Rbpj AOS allele in endothelial cells is both necessary and sufficient to cause lethality and cardiovascular defects. These data establish that reduced Notch1 signaling in the vasculature is a key driver of pathogenesis in this AOS mouse model
Epidemiology and aetiology of sudden cardiac death in athletes
No full textSudden cardiac death (SCD) is a devastating and tragic occurrence that may affect individuals of all ages. It is defined as an unexpected death occurring within one hour of the onset of symptoms, if witnessed, or within 24 hours of last being seen alive and well, if unwitnessed. Athletes are considered to be the healthiest of all the population, and exercise is known to reduce the risk of atherosclerotic coronary artery disease. However, both amateur and highly trained athletes do die suddenly and unexpectedly, and this gets widespread media attention as it is so shocking and unexpected. This brings SCD, its frequency and causes into the spotlight. This review focuses on the epidemiology and aetiology of SCD in athletes from a pathological perspective
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