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A 5-transcript signature for discriminating viral and bacterial etiology in pediatric pneumonia.
Pneumonia stands as the primary cause of death among children under five, yet current diagnosis methods often result in inadequate or unnecessary treatments. Our research seeks to address this gap by identifying host transcriptomic biomarkers in the blood of children with definitive viral and bacterial pneumonia. We performed RNA sequencing on 192 prospectively collected whole blood samples, including 38 controls and 154 pneumonia cases, uncovering a 5-transcript signature (genes FAM20A, BAG3, TDRD9, MXRA7, and KLF14) that effectively distinguishes bacterial from viral pneumonia (area under the curve (AUC): 0.95 [0.88-1.00]). Initial validation using combined definitive and probable cases yielded an AUC of 0.87 [0.77-0.97], while full validation in a new prospective cohort of 32 patients achieved an AUC of 0.92 [0.83-1.00]. This robust signature holds significant potential to enhance diagnostics accuracy for pediatric pneumonia, reducing diagnostic delays and unnecessary treatments and potentially transforming clinical practice.
A diagnostic host-specific transcriptome response for Mycoplasma pneumoniae pneumonia to guide pediatric patient treatment.
Mycoplasma pneumoniae causes atypical pneumonia in children and young adults. Its lack of a cell wall makes it resistant to beta-lactams, which are the first-line treatment for typical pneumonia. Current diagnostic tests are time-consuming and have low specificity, leading clinicians to administer empirical antibiotics. Using a LASSO regression simulation approach and blood microarray data from 107 children with pneumonia (including 30 M. pneumoniae) we identify eight different transcriptomic signatures, ranging from 3-10 transcripts, that differentiate mycoplasma pneumonia from other bacterial/viral pneumonias with high accuracy (AUC: 0.84-0.95). Additionally, we demonstrate that existing signatures for broadly distinguishing viral/bacterial infections and viral/bacterial pneumonias are ineffective in distinguishing M. pneumoniae from viral pneumonia. The new signatures are successfully validated in an independent RNAseq cohort of children with pneumonia, demonstrating their robustness. The high sensibility of these signatures presents a valuable opportunity to guide the treatment and management of M. pneumoniae pneumonia patients.
Epidemiology of Group B Streptococcus: Maternal Colonization and Infant Disease in Kampala, Uganda
Abstract Background Child survival rates have improved globally, but neonatal mortality due to infections, such as group B Streptococcus (GBS), remains a significant concern. The global burden of GBS-related morbidity and mortality is substantial. However, data from low and middle-income countries is lacking. Vaccination during pregnancy could be a feasible strategy to address GBS-related disease burden. Methods We assessed maternal rectovaginal GBS colonization and neonatal disease rates in a prospective cohort of 6062 women-infant pairs. Surveillance for invasive infant disease occurred in parallel at two Kampala hospital sites. In a nested case-control study, we identified infants <90 days of age with invasive GBS disease (iGBS) (n=24) and healthy infants born to mothers colonized with GBS (n=72). We measured serotype-specific anti-capsular immunoglobulin G in cord blood/infant sera using a validated multiplex Luminex assay. Results We found a high incidence of iGBS (1.0 per 1,000 live births) within the first 90 days of life across the surveillance sites, associated with a high case fatality rate (18.2%). Maternal GBS colonization prevalence was consistent with other studies in the region (14.7%; 95% confidence interval 13.7-15.6%). IgG geometric mean concentrations were lower in cases than controls for serotypes Ia (0.005 vs 0.12 µg/mL; p=0.05), III (0.011 vs 0.036 µg/mL; p=0.07) and in an aggregate analysis of all serotypes, (0.014 vs 0.05 µg/mL; p=0.02). Conclusions We found that GBS is an important cause of neonatal and young infant disease in Uganda and confirmed that maternally derived antibodies were lower in early-onset GBS cases than in healthy exposed controls.
Biodistribution of therapeutic extracellular vesicles.
The field of extracellular vesicles (EVs) has seen a tremendous paradigm shift in the past two decades, from being regarded as cellular waste bags to being considered essential mediators in intercellular communication. Their unique ability to transfer macromolecules across cells and biological barriers has made them a rising star in drug delivery. Mounting evidence suggests that EVs can be explored as efficient drug delivery vehicles for a range of therapeutic macromolecules. In contrast to many synthetic delivery systems, these vesicles appear exceptionally well tolerated in vivo. This tremendous development in the therapeutic application of EVs has been made through technological advancement in labelling and understanding the in vivo biodistribution of EVs. Here in this review, we have summarised the recent findings in EV in vivo pharmacokinetics and discussed various biological barriers that need to be surpassed to achieve tissue-specific delivery.
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.