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Acceptability of the gonorrhoea human challenge model to accelerate vaccine development in UK men.
BACKGROUND: 281 million people worldwide were diagnosed with a bacterial sexually transmitted infection (STI) in 2020. Antimicrobial therapy for bacterial STIs is a key contributor to antimicrobial resistance (AMR) and multidrug resistant gonorrhoea is an urgent global health threat. Development of an efficacious gonorrhoea vaccine is a global health priority to address AMR. The controlled human infection model for gonorrhoea (GC-CHIM) could accelerate gonorrhoea vaccine development. This work sought to assess the acceptability of the urogenital model to UK men. METHODS: A mixed-methods study of UK men aged 18-35 years old was undertaken to assess acceptability of the urogenital GC-CHIM to UK men and attitudes to STI research, vaccines and AMR. Participants completed an online survey indicating their agreement with a series of statements using a Likert scale. Semi-structured interviews were performed on a subset of participants to gain insight into their survey responses. RESULTS: Survey responses from 72 participants and 13 interviewees highlighted stigma associated with STIs as a key barrier to, and perceived risk of, participation in STI research and GC-CHIM studies. Financial reimbursement was an important motivator, and some felt this should include compensation for intimate procedures, potential embarrassment and sexual abstinence. Individuals willing to participate in a GC-CHIM study were more likely to have personal experience of STIs, be educated to postgraduate level and describe their sexuality as gay or bisexual than those who were ambivalent or opposed to participation. CONCLUSIONS: Recruitment of participants to UK urogenital GC-CHIM studies is feasible. Sexual abstinence can be a significant inconvenience for individuals that could be recognised via reimbursement. Care should be taken generalising results from STI vaccine research where participants may not be representative of the general population. Investigators in STI research should recognise stigmatisation as a potential risk for participants and promote their STI research sensitively as a means to counter misinformation and stigma.
Long-term non-progression in children living with HIV: estimates from international cohort data.
OBJECTIVES: To estimate the probability of long-term nonprogression (LTNP) in the absence of antiretroviral treatment (ART) in children with perinatally acquired HIV, and the impact of LTNP definitions on these estimates. DESIGN: Analysis of longitudinal routine care data (follow-up to 2016) collected through a collaboration of cohorts of children in routine HIV care across Europe and Thailand. METHODS: LTNP was defined as reaching age 8 years without disease progression (defined as an AIDS diagnosis or immunosuppression based on WHO immunosuppression-for-age thresholds, age-adjusted CD4+z-scores or CD4+ counts). ART initiation was treated as a competing risk (children initiating ART before age 8 were not considered to have LTNP). We included children born domestically in six national HIV cohorts (n = 2481). Additional analyses included domestic-born children enrolled in national cohorts in infancy (aged <12 months, n = 1144, six cohorts), or all domestic-born children in national and nonnational cohorts (n = 4542, 18 cohorts). Results were stratified by birth year. RESULTS: Among children born domestically in national cohorts in 2004-2007, the probability [95% confidence interval (CI)] of LTNP at age 8 years was 10% (6-15%) based on WHO immunosuppression-for-age criteria. This was lower for children born earlier when ART use was less frequent. Results were similar using other immunosuppression thresholds. Estimates were lower when restricted to domestic-born children in national cohorts enrolled in infancy, and higher when including all domestic-born children. CONCLUSION: Up to 10% of children born during 2004-2007 had LTNP at age 8. Our findings may help identify participants with LTNP for research into posttreatment control and HIV cure.
Contribution of autosomal rare and de novo variants to sex differences in autism
Autism is four times more prevalent in males than females. To study whether this reflects a difference in genetic predisposition attributed to autosomal rare variants, we evaluated sex differences in effect size of damaging protein-truncating and missense variants on autism predisposition in 47,061 autistic individuals using a liability model with differing thresholds. Given the sex differences in the rates of cognitive impairment among autistic individuals, we also compared effect sizes of rare variants between individuals with and without cognitive impairment or motor delay. Although these variants mediated different likelihoods of autism with versus without cognitive or motor difficulties, their effect sizes on the liability scale did not differ significantly by sex exome wide or in genes sex-differentially expressed in the cortex. De novo mutations were enriched in genes with male-biased expression in the adult cortex, but these genes did not show a significant sex difference on the liability scale, nor did the liability conferred by these genes differ significantly from other genes with similar loss-of-function intolerance and sex-averaged cortical expression. Exome-wide female bias in de novo protein-truncating mutation rates on the observed scale was driven by high-confidence and syndromic autism-predisposition genes. In summary, autosomal rare and damaging coding variants confer similar liability for autism in females and males.
Dystrophin isoform deficiency and upper-limb and respiratory function in Duchenne muscular dystrophy.
AIM: To investigate the associations between mutations expected to differentially affect Dp140 expression and long-term trajectories of respiratory and upper-limb motor outcomes in Duchenne muscular dystrophy (DMD). METHOD: In a retrospective analysis of population-based longitudinal data from three real-world and natural history data sources, individuals with DMD aged 5 years to 18 years were subdivided according to the predicted effects of the participants' DMD mutation on dystrophin isoform expression (group 1, Dp427 absent, Dp140/Dp71 present; group 2, Dp427/Dp140 absent, Dp71 present). RESULTS: A total of 459 participants were studied, with upper-limb outcomes assessed in 71 (27 in group 1 and 44 in group 2) and forced vital capacity percentage predicted (%pred) assessed in 434 (224 in group 1 and 210 in group 2). Mean grip strength %pred was on average 7.1 percentage points lower in group 2 than in group 1 (p = 0.03). Mean pinch strength %pred was on average 9.2 percentage points lower in group 2 than in group 1 (p = 0.04). Mean forced vital capacity %pred was on average 4.3 percentage points lower in group 2 than in group 1 (p = 0.01). INTERPRETATION: In individuals with DMD, DMD mutations predicted to affect Dp140 expression were associated with more severe trajectories of respiratory and upper-limb motor outcomes.
X-linked myotubular myopathy: an untreated treatable disease.
INTRODUCTION: X-linked myotubular myopathy (XLMTM) is a life-threatening congenital disorder characterized by severe respiratory and motor impairment. This disease presents significant therapeutic challenges, with various strategies being explored to address its underlying pathology. Among these approaches, gene replacement therapy has demonstrated substantial functional improvements in clinical trials. However, safety issues emerged across different therapeutic approaches, highlighting the need for further research. AREAS COVERED: This review provides a comprehensive analysis of the data gathered from natural history studies, preclinical models and clinical trials, with a particular focus on gene replacement therapy for XLMTM. The different therapeutic strategies are addressed, including their outcomes and associated safety concerns. EXPERT OPINION: Despite the encouraging potential of gene therapy for XLMTM, the occurrence of safety challenges emphasizes the urgent need for a more comprehensive understanding of the disease's complex phenotype. Enhancing preclinical models to more accurately mimic the full spectrum of disease manifestations will be crucial for optimizing therapeutic strategies and reducing risks in future clinical applications.
Newborn screening programs for spinal muscular atrophy worldwide in 2023.
BACKGROUND: Spinal muscular atrophy is a rare, genetic neuromuscular disorder. Disease-modifying therapies, when administered early, have shown improved outcomes, leading to the implementation of numerous newborn screening programs for spinal muscular atrophy. OBJECTIVE: The aim of this study was to evaluate the progress in implementing newborn screening for spinal muscular atrophy and therapy accessibility worldwide, after the first paper published in 2021. METHODS: We conducted a survey, contacted experts from 143 countries worldwide, gathered responses from 86 experts from 80 countries. RESULTS: By 2023, 31 countries reported established programs, 33 in the beginning of the year 2024; identifying approximately 1176 cases of spinal muscular atrophy. Additionally, the availability of disease-modifying therapies has expanded. At least one therapy is now accessible in 62 countries. Challenges, such as lack of governmental support, resource constraints, and varying healthcare priorities continue to impede implementation in some countries. CONCLUSIONS: The data shows a significant increase in the implementation of newborn screening programs since 2021. The experts are still expressing a strong need for equitable access to standard of care for all the patients globally. Despite all setbacks, collaborative efforts have played a crucial role in newborn screening for spinal muscular atrophy implementation and currently 7% of world newborns are being screened, projections indicate an estimated 18% screening rate by 2028.
Development and validation of the Oxford Benchmark Scale for Rating Vaccine Technologies (OBSRVT), a scale for assessing public attitudes to next-generation vaccine delivery technologies.
Next-generation vaccine delivery technologies may provide significant gains from both a technical and behavioral standpoint, but no scale has yet been developed to assess public attitudes to novel vaccine delivery technologies. We therefore performed a cross-sectional validation study that included 1,001 demographically representative participants from the UK and US to develop and validate a novel scale, the Oxford Benchmark Scale for Rating Vaccine Technologies (OBSRVT). A sample of 500 UK participants was used to perform exploratory factor analysis with categorical variables (using a polychoric correlation matrix) followed by promax oblique factor rotation to develop the initial model. This yielded a 15-item 4-domain scale with domains including acceptance (6 items), effectiveness (4 items), comfort (3 items), and convenience (2 items). This model was tested for robustness on a 501-participant demographically representative sample from the US. A confirmatory factor analysis with a Satorra-Bentler scaled test statistic was performed, which demonstrated adequate goodness of fit statistics including the root mean squared error of approximation (0.057), standardized root mean squared residual (0.053), and comparative fit index (0.938). Reliability as internal consistency was excellent (alpha = 0.92). Convergent validity with the Oxford Needle Experience Scale was supported by an adequate correlation (r = 0.31, p
Statistical analysis plan for the Petal trial: the effects of parental touch on relieving acute procedural pain in neonates.
BACKGROUND: Infants undergo multiple clinically-required painful procedures during their time in hospital, and there is an increasing desire from both parents and clinical staff to have parents directly involved in their newborn's pain relief. To avoid biases due to selective analysis and reporting, a clinical trial's statistical analysis plan (SAP) should be finalised and registered prior to dataset lock and unblinding. Here, we outline the SAP for the Petal trial, which was registered on the ISRCTN registry prior to dataset lock and unblinding. METHODS: The Petal trial is a multicentre, individually randomised, parallel-group interventional superiority trial. The study involves in-patient neonates born at or after 35+0 weeks gestation with a postnatal age of ≤7 days, in two hospital research sites (John Radcliffe Hospital, Oxford, UK; Royal Devon and Exeter Hospital, Exeter, UK). The primary objective is to investigate the potential efficacy of a non-pharmacological parent-led stroking intervention on reducing the magnitude of neonates' noxious stimulus-evoked brain activity. The primary outcome is the neonate's brain activity recorded using electroencephalography (EEG) in response to a heel lance blood sampling procedure. Secondary outcomes include neonatal clinical pain scores and tachycardia, and parental anxiety. The study hypothesis is neonates' pain responses and parents' anxiety scores are lower in the intervention group. Randomisation will be via a minimisation algorithm to maintain balance in five prognostic factors. CONCLUSIONS: Paediatric pain trials have been highlighted by regulatory bodies as an important and challenging topic, with interest increasing in brain imaging outcomes. The Petal trial, to which this SAP relates, is part of a larger effort of establishing a brain-based EEG outcome measure of infant pain for use in clinical trials. This SAP is thus likely to be of interest to those in academia, pharmaceutical companies, and regulatory bodies. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04901611, 25/05/2021; ISRCTN: ISRCTN14135962, 23/08/2021).
Statistical analysis plan for the Petal trial: the effects of parental touch on relieving acute procedural pain in neonates
Background Infants undergo multiple clinically-required painful procedures during their time in hospital, and there is an increasing desire from both parents and clinical staff to have parents directly involved in their newborn’s pain relief. To avoid biases due to selective analysis and reporting, a clinical trial’s statistical analysis plan (SAP) should be finalised and registered prior to dataset lock and unblinding. Here, we outline the SAP for the Petal trial, which was registered on the ISRCTN registry prior to dataset lock and unblinding. Methods The Petal trial is a multicentre, individually randomised, parallel-group interventional superiority trial. The study involves in-patient neonates born at or after 35+0 weeks gestation with a postnatal age of ≤7 days, in two hospital research sites (John Radcliffe Hospital, Oxford, UK; Royal Devon and Exeter Hospital, Exeter, UK). The primary objective is to investigate the potential efficacy of a non-pharmacological parent-led stroking intervention on reducing the magnitude of neonates’ noxious stimulus-evoked brain activity. The primary outcome is the neonate’s brain activity recorded using electroencephalography (EEG) in response to a heel lance blood sampling procedure. Secondary outcomes include neonatal clinical pain scores and tachycardia, and parental anxiety. The study hypothesis is neonates’ pain responses and parents’ anxiety scores are lower in the intervention group. Randomisation will be via a minimisation algorithm to maintain balance in five prognostic factors. Conclusions Paediatric pain trials have been highlighted by regulatory bodies as an important and challenging topic, with interest increasing in brain imaging outcomes. The Petal trial, to which this SAP relates, is part of a larger effort of establishing a brain-based EEG outcome measure of infant pain for use in clinical trials. This SAP is thus likely to be of interest to those in academia, pharmaceutical companies, and regulatory bodies. Trial registration ClinicalTrials.gov: NCT04901611, 25/05/2021; ISRCTN: ISRCTN14135962, 23/08/2021).
Etiology and Antimicrobial Resistance of Culture-Positive Infections in Ugandan Infants: A Cohort Study of 7000 Neonates and Infants.
BACKGROUND: Epidemiological evidence about the etiology and antimicrobial resistance of neonatal infections remains limited in low-resource settings. We aimed to describe the etiology of neonatal infections in a prospective observational cohort study conducted at two hospital sites in Kampala, Uganda. METHODS: Babies admitted to either unit with risk factors or signs of sepsis, pneumonia, or meningitis had a blood culture, nasopharyngeal swab, and lumbar puncture (if indicated) collected. Basic demographics were collected, and babies were followed up until discharge or death to determine admission outcome. Blood cultures were processed using the BACTEC system and identification confirmed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Cerebrospinal fluid was processed using standard microbiological testing and swabs were processed using the multiplex real-time polymerase chain reaction assay. Antimicrobial susceptibilities of bacterial isolates to World Health Organization-recommended first-line antibiotics (ampicillin or benzylpenicillin and gentamicin) were assessed using e-tests. RESULTS: A total of 7323 infants with signs or risk factors for sepsis had blood cultures, 2563 had nasopharyngeal swabs, and 23 had lumbar punctures collected. Eleven percent of blood cultures and 8.6% of swabs were positive. Inpatient mortality was 12.1%, with 27.7% case fatality observed among infants with Gram-negative bloodstream infections. Escherichia coli (14.8%), Acinetobacter spp. (10.3%), and Klebsiella spp. (7.6%), were notable contributors to Gram-negative sepsis, whereas Group B Streptococcus was the predominant Gram-positive pathogen identified (13.5%). Almost 60% of Gram-negative pathogens were ampicillin- and gentamicin-resistant. CONCLUSIONS: Our study demonstrates high levels of antimicrobial resistance and inpatient mortality from neonatal sepsis in the first months of life in Uganda. This underscores the pressing need for revised, context-specific antimicrobial treatment guidelines that account for the evolving landscape of antimicrobial resistance in neonatal sepsis.
“Bye-Bye Germs”: Respiratory Tract Infection Prevention—An Education Intervention for Children
Becoming one of the first studies in the field to do so, specially developed educational interventions (Germ’s Journey), designed to teach children about respiratory tract infection prevention, were delivered to 273 pupils aged five to six across five primary schools in the U.K. The intervention aimed to increase understanding of pathogens and respiratory tract illness, transmission and infection prevention, and preparedness for future pandemics due to a lack of such resources for young children at present. To assess the impact of the intervention, children were asked five questions related to knowledge of pathogens, transmission of infection, and infection prevention directly before and after activity-based workshops, as well as one month later. Responses were scored for pupils’ level of knowledge; differences in the frequency of responses between the time points were analysed using Pearson’s chi-squared test. Teachers also took part in semi-structured interviews to evaluate the workshop from the educators’ points of view. Children showed increased knowledge in all three areas immediately after the workshops. This improvement was retained to a lesser or equal extent one month following the learning intervention workshop. The consistent use of teaching resources and interventions such as Germ’s Journey should be implemented in the school curriculum in order to increase understanding and reduce the transmission of respiratory tract illness. Specially designed activity-based workshops using a range of learning skills can help young children to understand the link between pathogens, and infection transmission and control.
Novel mRNA vaccines induce potent immunogenicity and afford protection against tuberculosis.
INTRODUCTION: Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), a disease with a severe global burden. The intractability of Mtb has prevented the identification of clear correlates of protection against TB and hindered the development of novel TB vaccines that are urgently required. Lipid nanoparticle (LNP)-formulated mRNA is a highly promising vaccine platform that has yet to be thoroughly applied to TB. METHODS: We selected five Mtb antigens (PPE15, ESAT6, EspC, EsxI, MetE) and evaluated their potential as LNP-formulated mRNA vaccines, both when each antigen was delivered individually, and when all five antigens were combined in a mix regimen (m-Mix). RESULTS: Each mRNA construct demonstrated unique cellular and humoral immunogenicity, and both m-Mix, as well as the single antigen EsxI, conferred significant protection in a murine Mtb challenge model. Whilst the potent immune responses of each mRNA were maintained when applied as a boost to BCG, there was no additional increase to the efficacy of BCG. Combination of m-Mix with a recombinant, replication-deficient chimpanzee adenovirus (ChAdOx1), in a heterologous prime-boost delivery (C-m-Mix), appeared to result in increased protection upon murine Mtb infection, than either regimen alone. DISCUSSION: This work warrants further investigation of LNP-formulated mRNA vaccines for TB, whilst indicating the potential of m-Mix and C-m-Mix to progress to further stages of vaccine development.
Physiological responses to retinopathy of prematurity screening: indirect ophthalmoscopy versus ultra-widefield retinal imaging.
BACKGROUND/AIMS: Retinopathy of prematurity (ROP) screening is vital for early disease detection in very premature infants but can cause physiological instability. This study compares the physiological response to binocular indirect ophthalmoscopy (BIO) with indentation and non-contact ultra-widefield (UWF) retinal imaging in non-ventilated neonates. The impact of the Dandle WRAP, a specialised swaddling aid, on UWF imaging was also assessed. METHODS: This retrospective study included 86 ROP screening events in 66 non-ventilated infants aged 35.3 weeks (range 30.6-44.6). Vital signs were continuously recorded, evaluating immediate (within 15 min) and longer-term (within 12 h) physiological responses. RESULTS: ROP screening significantly increased heart and respiratory rates and decreased oxygen saturation within 15 min of screening. No significant differences in physiological responses were found between BIO and UWF imaging, although there was a trend towards lower maximum heart rate with UWF imaging. The Dandle WRAP did not significantly alter physiological responses but improved the ease and speed of UWF imaging. CONCLUSION: UWF imaging does not increase physiological instability compared to BIO in non-ventilated infants. Specialised swaddling aids may facilitate the imaging procedure. IMPACT: ROP screening can be distressing for premature infants and induce physiological instability during and after the examination. We deployed non-contact ultra-widefield retinal imaging as the default method of ROP screening and show that it induces comparable physiological responses as traditional indirect ophthalmoscopy in non-ventilated babies. Dandle WRAP swaddling facilitated handling and speed of retinal imaging. The study demonstrates that imaging-based ROP screening is safe and efficacious in non-ventilated neonates, and continuous multimodal physiological recordings can provide detailed assessment of the effects of procedures and medications.
The ferroportin Q248H mutation protects from anemia, but not malaria or bacteremia.
Iron acquisition is critical for life. Ferroportin (FPN) exports iron from mature erythrocytes, and deletion of the Fpn gene results in hemolytic anemia and increased fatality in malaria-infected mice. The FPN Q248H mutation (glutamine to histidine at position 248) renders FPN partially resistant to hepcidin-induced degradation and was associated with protection from malaria in human studies of limited size. Using data from cohorts including over 18,000 African children, we show that the Q248H mutation is associated with modest protection against anemia, hemolysis, and iron deficiency, but we found little evidence of protection against severe malaria or bacteremia. We additionally observed no excess Plasmodium growth in Q248H erythrocytes ex vivo, nor evidence of selection driven by malaria exposure, suggesting that the Q248H mutation does not protect from malaria and is unlikely to deprive malaria parasites of iron essential for their growth.