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Rebeccah Slater has been awarded an NIHR grant to look at whether morphine can be used to effectively treat pain in babies
Safety and broad immunogenicity of HIVconsvX conserved mosaic candidate T-cell vaccines vectored by ChAdOx1 and MVA in HIV-CORE 006: a double-blind, randomised, placebo-controlled phase 1 trial in healthy adults living without HIV-1 in eastern and southern Africa
Background: Even within the context of antiretroviral treatment and prevention, an HIV-1 vaccine remains the best strategy for ending the HIV/AIDS epidemic. A vaccine is particularly needed in sub-Saharan Africa, where HIV-1 greatly affects people's lives and economy. Here, we aimed to assess the safety and immunogenicity of candidate T-cell vaccines in African populations. Methods: HIV-CORE 006 was a double-blind, randomised, placebo-controlled phase 1 trial conducted across four clinical research centres in Uganda, Kenya, and Zambia. Eligible participants were not pregnant, were living without HIV-1 or HIV-2, had a low likelihood of acquiring HIV-1, were aged 18–50 years, fully comprehended the purpose and details of this study as outlined in the participant information sheet, and passed an assessment of understanding before providing written informed consent. Participants were randomly assigned (9:2) to receive either a vaccine regimen or a placebo. The vaccine was administered as ChAdOx1.tHIVconsv1 (C1) followed by MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4) in regimen C1-M3M4. The first primary outcome was the vaccines’ safety assessment, assessed in all participants who received at least one vaccine or placebo dose. The second primary outcome evaluated the C1-M3M4 regimen's induction of HIVconsvX-specific T-cell responses by assessing the proportion of vaccine recipients who responded to the vaccination, assessed in all participants who received all doses of vaccine or placebo as per protocol. This study is registered with ClinicalTrials.gov, NCT04553016, and the Pan-African Clinical Trials Registry PACTR202006495409011, and is now closed. Findings: Between July 15, 2021, and Nov 2, 2022, 89 healthy adults living without HIV-1 were randomly assigned, with 88 receiving either the vaccine (n=72) or placebo (n=16). Of these 88 participants, 57 (65%) were male and 31 (35%) were female. The C1, M3, and M4 vaccine components were well tolerated and induced HIVconsvX-specific responses in 70 (99%) of the 71 participants who completed all vaccine doses. Vaccine-elicited T cells peaked at a median of 2310 (IQR 1080–4480) IFN-γ spot-forming units per 106 peripheral blood mononuclear cells and recognised a median of eight (five to ten) of ten peptide pools spanning the HIVconsvX immunogen. The total frequencies of elicited T cells decreased 4·6 times over a 40-week follow-up period compared with the peak responses. Upon antigenic re-exposure, T cells proliferated, exhibited multiple effector functions, and inhibited HIV-1 representatives from clades A, B, C, and D. Interpretation: Results from key sub-Saharan African populations supported the safety of the vaccine regimen previously shown in the first-in-human trial in the UK. The induction of T cells and their characteristics encourage vaccine integration into HIV-1 cure strategies, which could inform HIV-1 prevention efforts. Funding: The European and Developing Countries Clinical Trials Partnership.
Pain management in preterm infants with necrotizing enterocolitis: an international expert consensus statement
Abstract Necrotizing enterocolitis (NEC) is probably the most painful intestinal disease affecting infants born preterm. NEC is known to cause highly severe and prolonged pain that has been associated with adverse short- and long-term effects. However, research on pain management in infants with NEC is scarce. This is likely due to its low incidence and very acute occurrence. As a result, the optimal pain management for these vulnerable infants remains unknown, and analgesic therapy practices are highly variable. Therefore, we aimed to establish expert-based consensus recommendations on pain management for NEC. Experts of the European Society for Paediatric Research (ESPR) Special Interest Groups on Neonatal pain and NEC were invited to participate in two consensus meetings. Prior to the first hybrid consensus meeting, an online survey provided input for potential recommendations. During the consensus meetings, experts shared clinical expertise and voted on recommendations. An expert consensus statement, comprising nine recommendations on optimal pain assessment and pain treatment in infants with NEC, was developed. Expert recommendations included regular pain assessments with a neonatal pain scale with additional assessments on indication and pre-emptive administration of analgesic therapy (e.g., paracetamol and an opioid) in infants with NEC stage ≥ II. Conclusion: This expert consensus statement provides clinical recommendations essential for any healthcare professional caring for premature infants with NEC. The recommended guidance this statement provides on pain management strategies is key to preventing and reducing pain in this vulnerable population. What is Known: • Necrotizing enterocolitis (NEC) is a very painful disease, making effective pain management essential.• Current pain management practices for infants with NEC are highly variable. What is New: • This expert consensus statement provides recommendations on optimal pain assessment and pain treatment in infants with NEC.• These clinical recommendations may help better prevent pain in these vulnerable infants.
A real-world analysis of the impact of X-linked myotubular myopathy on caregivers in the United States.
BACKGROUND: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital myopathy with multisystem involvement, which often includes the need for invasive ventilator support, gastrostomy tube feeding, and wheelchair use in approximately 80% of patients. The direct and indirect financial impact of extensive supportive care, as reported by caregivers of individuals with XLMTM, and the health-related quality of life (HRQoL) of caregivers has not been previously described. Here, we use a survey co-designed by patient advocates to provide objective information on the physical and financial challenges of caregiving for individuals with XLMTM. METHODS: A real-world web-based survey was conducted in the United States between November 19, 2019, and January 23, 2020. The survey was developed in association with patient advocacy leaders from the XLMTM community, who were also caregivers of individuals with XLMTM. The survey included the EuroQol 5-dimension 5-level HRQoL instrument and visual analog scale, and a cost (direct and indirect medical costs) and healthcare resource questionnaire. The survey was shared among the XLMTM community by patient advocacy organizations. Caregivers who completed the survey and met the eligibility criteria were included. Descriptive statistics were conducted using Microsoft Excel. RESULTS: Twenty-two caregiver respondents agreed to participate. All respondents completed the cost and health resource survey. Productivity loss varied between participants over the prior 12 months. Durable medical equipment expenses comprised most of the direct medical out-of-pocket costs. Non-medical expenditures (e.g. home and vehicle modifications) were higher than direct medical out-of-pocket costs. Twelve of the 22 respondents completed the HRQoL survey. The HRQoL domains most impacted were usual activities, anxiety/depression, and pain/discomfort. CONCLUSIONS: Findings from this real-world survey of caregivers for individuals with XLMTM describe the caregiver experience, as well as the multifaceted impact of the disease on caregiver productivity loss, out-of-pocket expenses, and HRQoL. XLMTM comes with financial constraints and substantial impacts on caregivers' physical and mental health. Understanding these gaps is crucial to support the caregivers who provide care for this medically fragile population.
Newborn screening and rapid genomic diagnosis of neuromuscular diseases.
BackgroundIn recent years, treatments have been approved for certain neuromuscular diseases. In some cases, early pre-symptomatic treatment is necessary for optimal response, and thus newborn screening is critical.ObjectiveTo review the current status of newborn screening programs for neuromuscular diseases and early diagnosis through genetic testing.MethodsFollowing the PRISMA guidelines, a literature search was performed on PubMed for screening of neuromuscular diseases; the search was conducted on literature available as of 1 May 2024.ResultsIncluded were 77 articles on newborn screening for seven diseases: spinal muscular atrophy (19 studies), Duchenne muscular dystrophy (15), Pompe disease (20), X-linked adrenoleukodystrophy (14), Krabbe disease (6), metachromatic leukodystrophy (2), and myotonic dystrophy 1 (1). Ten articles on rapid genomic diagnosis were identified.ConclusionSince 2021, newborn screening programs for neuromuscular diseases have been established, notably in X-linked adrenoleukodystrophy, spinal muscular atrophy, Pompe disease, and Duchenne Muscular Dystrophy. Even in diseases where treatment is currently not life-changing, such as Krabbe disease, new newborn screening programs continue to be implemented, especially in the USA. The use of genetic diagnostic tests does not yet appear to be widespread or at least not widely reported. As new treatments become available, genomic newborn screening programs will need to be rapidly and broadly implemented.
Influence of context on engagement with COVID-19 testing: a scoping review of barriers and facilitators to testing for healthcare workers, care homes and schools in the UK.
OBJECTIVE: The UK government's response to the COVID-19 pandemic included a 'test, trace and isolate' strategy. Testing services for healthcare workers, care homes and schools accounted for the greatest spend and volume of tests. We reviewed relevant literature to identify common and unique barriers and facilitators to engaging with each of these testing services. DESIGN: Scoping review. SEARCH STRATEGY: PubMed, Scopus and the WHO COVID-19 Research Database were searched for evidence published between 1 January 2020 and 7 November 2022. This was supplemented by evidence identified via free-text searches on Google Scholar and provided by the UK Health Security Agency (UKHSA). DATA EXTRACTION AND SYNTHESIS: Data were extracted by a team of reviewers and synthesised thematically under the broad headings of perceptions, experiences, barriers and facilitators to engaging with the COVID-19 testing programme. RESULTS: This study included 40 sources, including 17 from projects that informed UKHSA's decisions during the pandemic. Eight themes emerged and were used to categorise barriers and facilitators to engaging with the testing services for healthcare workers, care homes and schools: (1) perceived value, (2) trust in the tests and public bodies, (3) importance of infrastructure, (4) impact of media and social networks, (5) physical burden of the test, (6) perceived capability to undertake testing, (7) importance of relevant information and 8) consequences of testing. CONCLUSIONS: Universal barriers and facilitators to engagement with the testing programme related to the core elements of each testing service, such as uncomfortable specimen collection and the influence of media and peers; these could be mitigated or leveraged to increase engagement across settings. However, the individuals involved, perceptions of value and available resources differed across services, leading to unique experiences between settings. Thus, consideration of context is crucial when designing and implementing a testing programme in response to a pandemic.
A multifaceted intervention to improve diagnosis and early management of hospitalised patients with suspected acute brain infections in Brazil, India, and Malawi: an international multicentre intervention study.
BACKGROUND: Brain infections pose substantial challenges in diagnosis and management and carry high mortality and morbidity, especially in low-income and middle-income countries. We aimed to improve the diagnosis and early management of patients admitted to hospital (adults aged 16 years and older and children aged >28 days) with suspected acute brain infections at 13 hospitals in Brazil, India, and Malawi. METHODS: With hospital stakeholders, policy makers, and patient and public representatives, we co-designed a multifaceted clinical and laboratory intervention, informed by an evaluation of routine practice. The intervention, tailored for each setting, included a diagnostic and management algorithm, a lumbar puncture pack, a testing panel, and staff training. We used multivariable logistic regression and interrupted time series analysis to compare the coprimary outcomes-the percentage of patients achieving a syndromic diagnosis and the percentage achieving a microbiological diagnosis before and after the intervention. The study was registered at ClinicalTrials.gov (NCT04190303) and is complete. FINDINGS: Between Jan 5, 2021, and Nov 30, 2022, we screened 10 462 patients and enrolled a total of 2233 patients at 13 hospital sites connected to the four study centres in Brazil, India, and Malawi. 1376 (62%) were recruited before the intervention and 857 (38%) were recruited after the intervention. 2154 patients (96%) had assessment of the primary outcome (1330 [62%] patients recruited pre-intervention and 824 [38%] recruited post-intervention). The median age across centres was 23 years (IQR 6-44), with 1276 (59%) being adults aged 16 years or older and 888 (41%) children aged between 29 days and 15 years; 1264 (59%) patients were male and 890 (41%) were female. Data on race and ethnicity were not recorded. 1020 (77%) of 1320 patients received a syndromic diagnosis before the intervention, rising to 701 (86%) of 813 after the intervention (adjusted odds ratio [aOR] 1·81 [95% CI 1·40-2·34]; p<0·0001). A microbiological diagnosis was made in 294 (22%) of 1330 patients pre-intervention, increasing to 250 (30%) of 824 patients post-intervention (aOR 1·46 [95% CI 1·18-1·79]; p=0·00040). Interrupted time series analysis confirmed that these increases exceeded a modest underlying trend of improvement over time. The percentage receiving a lumbar puncture, time to appropriate therapy, and functional outcome also improved. INTERPRETATION: Diagnosis and management of patients with suspected acute brain infections improved following introduction of a simple intervention package across a diverse range of hospitals on three continents. The intervention is now being implemented in other settings as part of the WHO Meningitis Roadmap and encephalitis control initiatives. FUNDING: UK National Institute for Health and Care Research.
Aetiologies, neuroradiological features, and risk factors for mortality and long-term neurosequelae of febrile coma in Malawian children: a prospective cohort study
Background: Children in febrile coma in Africa are frequently hospitalised, with poorer outcomes than those in high-income settings. Cerebral malaria is historically the most common cause of febrile coma. Due to limited diagnostic and radiological resources and a decrease in malaria prevalence, there might be under-recognition of non-malarial coma. However, prospective data are scarce. We aimed to determine causes, neuroradiological features, risk factors for mortality, and neurosequelae of children in febrile coma in Malawi. Methods: In this prospective cohort study, we enrolled children in a coma (Blantyre Coma Scale score ≤2) who were aged between 3 months and 15 years at Queen Elizabeth Central Hospital, Blantyre, Malawi. We used pathogen-specific PCR analysis of blood and cerebrospinal fluid for 15 pathogens including Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Salmonella spp, non-typhoidal Salmonella, Salmonella enterica serotype Typhi (S Typhi), Klebsiella spp, Escherichia coli, Mycobacterium tuberculosis (also using GeneXpert), Streptococcus agalactiae, herpes simplex virus (types 1 and 2), varicella zoster virus, cytomegalovirus, enteroviruses, and SARS-CoV-2; microscopy for malaria; admission brain MRI to enhance the diagnosis of cause and identify brain injury, swelling, and any other complications; and electroencephalography tracings were used identify subclinical seizures or non-convulsive status epilepticus. Assessment of malarial retinopathy was performed by a trained ophthalmologist. We used regression models to estimate risk factors for (and the difference in) 30-day mortality and 180-day neurosequelae (outcome assessed in-person) between children with non-malarial coma and cerebral malaria. Findings: Between Jan 31, 2018, and June 30, 2021, we recruited 352 children with febrile coma. Cerebral malaria was the most common cause (in 231 [66%] of 352 children). Pathogenic diagnosis was possible in 289 (82%) of 352 children. Co-infection was identified in 63 (27%) of 231 children with cerebral malaria, of which 49 (78%) were bacterial. The most common non-malarial causes of coma were meningitis (48 [14%] of 352 children) and encephalitis (24 [7%] of 352); 32 (9%) cases had an unknown cause. Compared with standard cultures, PCR significantly increased pathogen diagnosis (p<0·0001), with the highest yield in patients with meningitis (seven [15%] of 48 vs 30 [63%] of 48). S pneumoniae (n=44) and non-typhoidal salmonella or S Typhi (n=24) were the most frequently detected bacterial pathogens. Brain parenchymal abnormalities were identified on MRI in most children with febrile coma (165 [92%] of 178), and were significantly more common in children with non-malarial coma (68 [100%] of 68]) than cerebral malaria (98 [89%] of 110; p<0·0001). Overall, at 30 days after discharge, death (69 [21%] of 323) or any neurological impairment (163 [50%] of 323) were common, but poorer long-term outcomes were more frequent following non-malarial coma than cerebral malaria (death at 30 days: 32 [28%] of 114 vs 37 [18%] of 209, p=0·029; severe neurological impairment at 180 days: 19 [17%] of 114 vs 15 [7%] of 209, p=0·0079). Children who had cerebral malaria with CNS co-infection had higher mortality (ten [37%] of 27) than those with cerebral malaria alone (19 [12%] of 154, p=0·0033). Interpretation: Despite malaria control efforts, cerebral malaria remains the most common cause of febrile coma in Malawi. However, non-malarial coma causes a greater disease burden (death and disability), and a higher case-fatality rate was observed in non-malarial coma and cerebral malaria with non-malarial co-infection than cerebral malaria alone. To adequately treat severe invasive bacterial infections, that are frequently not detected in routine clinical practice, commencing empirical antimicrobials in all children in febrile coma, including those with cerebral malaria, could and should be rapidly implemented across Africa and must be considered. The study highlights the value of molecular diagnostics and imaging to guide diagnosis. The frequent findings of brain abnormalities from imaging at admission emphasises the need for earlier escalation of children with febrile coma to specialist care. Further work is needed to develop feasible molecular and radiological diagnostics for their successful deployment across the continent. Implementation of these methods could improve diagnosis and outcomes for children with febrile coma in Africa. Funding: Wellcome Trust Translations: For the Chichewa, French and Portuguese translations of the abstract see Supplementary Materials section.
Prothrombotic autoantibodies targeting platelet factor 4/polyanion are associated with pediatric cerebral malaria.
BACKGROUNDFeatures of consumptive coagulopathy and thromboinflammation are prominent in cerebral malaria (CM). We hypothesized that thrombogenic autoantibodies contribute to a procoagulant state in CM.METHODSPlasma from children with uncomplicated malaria (UM) (n = 124) and CM (n = 136) was analyzed by ELISA for a panel of 8 autoantibodies including anti-platelet factor 4/polyanion (anti-PF4/P), anti-phospholipid, anti-phosphatidylserine, anti-myeloperoxidase, anti-proteinase 3, anti-dsDNA, anti-β-2-glycoprotein I, and anti-cardiolipin. Plasma samples from individuals with nonmalarial coma (NMC) (n = 49) and healthy controls (HCs) (n = 56) were assayed for comparison. Associations with clinical and immune biomarkers were determined using univariate and logistic regression analyses.RESULTSMedian anti-PF4/P and anti-PS IgG levels were elevated in individuals with malaria infection relative to levels in HCs (P < 0.001) and patients with NMC (PF4/P: P < 0.001). Anti-PF4/P IgG levels were elevated in children with CM (median = 0.27, IQR: 0.19-0.41) compared with those with UM (median = 0.19, IQR: 0.14-0.22, P < 0.0001). Anti-PS IgG levels did not differ between patients with UM and those with CM (P = 0.39). When patients with CM were stratified by malaria retinopathy (Ret) status, the levels of anti-PF4/P IgG correlated negatively with the peripheral platelet count in patients with Ret+ CM (Spearman's rho [Rs] = 0.201, P = 0.04) and associated positively with mortality (OR = 15.2, 95% CI: 1.02-275, P = 0.048). Plasma from patients with CM induced greater platelet activation in an ex vivo assay relative to plasma from patients with UM (P = 0.02), and the observed platelet activation was associated with anti-PF4/P IgG levels (Rs= 0.293, P = 0.035).CONCLUSIONSThrombosis mediated by elevated anti-PF4/P autoantibodies may be one mechanism contributing to the clinical complications of CM.
Delandistrogene Moxeparvovec Gene Therapy in Individuals With Duchenne Muscular Dystrophy: Evidence in Focus: Report of the AAN Guidelines Subcommittee.
This Evidence in Focus reviews the current evidence on the efficacy and adverse effects of delandistrogene moxeparvovec in patients with Duchenne muscular dystrophy (DMD) and presents clinical considerations regarding use. The author panel systematically reviewed available clinical trial data on delandistrogene moxeparvovec in patients with DMD. The risk of bias was evaluated using the American Academy of Neurology's 2017 therapeutic classification of evidence scheme. Safety information, regulatory decisions, and clinical context were also reviewed. Six clinical trials were identified, of which 4 had peer-reviewed data available. From the 4 studies with available data (2 Class I and 2 Class III), exposure data are available on 134 boys, of which 128 are ambulatory and aged ≥4 to <8 years. Both Class I studies failed to meet the primary functional motor outcome as assessed by change in the North Star Ambulatory Assessment score. Several secondary functional motor outcomes demonstrated improvement in the treatment group with small effect sizes, not meeting statistical significance from hierarchical analysis. Corticosteroid dose exposure was higher in the treatment group in the first 12 weeks after infusion, potentially contributing to measured differences between groups. Safety outcomes were similar across studies with multiple treatment-related adverse events, including peri-infusion effects, immune myositis and myocarditis, thrombocytopenia, and liver toxicity. One death has been reported in an individual who was treated with delandistrogene moxeparvovec outside of a trial. Despite not demonstrating efficacy in its primary outcome, delandistrogene moxeparvovec has been approved by the US Food and Drug Administration (FDA) for use in boys with DMD. This decision was supported by the relative safety of the product and secondary outcome measures data in the phase 3 clinical trial. As the drug may now be actively prescribed in the United States and other countries after FDA approval, providers should be aware of the limitations of the treatment and the need to monitor for immune-related side effects including myocarditis, liver injury, and thrombocytopenia, which may require expanded clinical infrastructure. Additional clinical trials and careful collection of real-world evidence from treated patients will be essential to establish short-term and long-term effectiveness and inform understanding of benefits and risks of delandistrogene moxeparvovec across the lifespan.
Severe Parvovirus B19-Associated Myocarditis in Children in the Post-COVID-19 Era: A Multicenter Observational Cohort Study.
This study describes a cluster of severe parvovirus B19-associated myocarditis cases in children across England in the context of an increase in circulating virus. Cases were identified across 3 large children's centers. Eight cases presented from 1 January 2019 to 31 December 2023 as compared with 19 from 1 January 2024 to 31 August 2024. Almost all (n = 25, 93%) required intensive care, and 24 (88%) received inotropes and 4 (15%) extracorporeal membrane oxygenation. Myocarditis appears to be temporally associated and a late sequela of parvovirus B19, resulting in high rates of intensive care unit admission. Testing with serology and blood polymerase chain reaction should be part of a syndromic screen for all children with severe myocarditis.
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
The immune-epithelial-stromal interactions underpinning intestinal damage in celiac disease (CD) are incompletely understood. To address this, we performed single-cell transcriptomics (RNA sequencing; 86,442 immune, parenchymal and epithelial cells; 35 participants) and spatial transcriptomics (20 participants) on CD intestinal biopsy samples. Here we show that in CD, epithelial populations shifted toward a progenitor state, with interferon-driven transcriptional responses, and perturbation of secretory and enteroendocrine populations. Mucosal T cells showed numeric and functional changes in regulatory and follicular helper-like CD4+ T cells, intraepithelial lymphocytes, CD8+ and γδ T cell subsets, with skewed T cell antigen receptor repertoires. Mucosal changes remained detectable despite treatment, representing a persistent immune-epithelial 'scar'. Spatial transcriptomics defined transcriptional niches beyond those captured in conventional histological scores, including CD-specific lymphoid aggregates containing T cell-B cell interactions. Receptor-ligand spatial analyses integrated with disease susceptibility gene expression defined networks of altered chemokine and morphogen signaling, and provide potential therapeutic targets for CD prevention and treatment.
Oral Swab Testing With Xpert MTB/RIF Ultra for the Diagnosis of Tuberculosis in Children Aged <5 Years in Uganda: An Exploratory Interim Analysis of Diagnostic Accuracy in the NOD-pedFEND Cohort.
BACKGROUND: Obtaining respiratory samples to diagnose tuberculosis in young children is challenging. Oral swabs are alternative noninvasive specimens for microbiology. METHODS: We conducted an interim prospective diagnostic accuracy evaluation of Xpert MTB/RIF Ultra (Ultra) on oral swabs for pulmonary tuberculosis in children aged <5 years in Uganda. Most children had 2 consecutive swabs collected in a single cryovial (double swabs). Reference tests consisted of Ultra and culture on 2 nasopharyngeal aspirates and 1 gastric aspirate and Ultra on 1 stool. Children were classified as having confirmed tuberculosis, unconfirmed tuberculosis, or unlikely tuberculosis per the National Institutes of Health. Diagnostic accuracy was determined against a microbiological reference standard and a composite reference standard. RESULTS: From August 2021 to February 2024, 444 children were enrolled, of whom 399 had complete classifications: 33 had confirmed tuberculosis, 269 had unconfirmed tuberculosis, 70 had unlikely tuberculosis, and 27 were unclassifiable. The median age was 16 months and 17% had HIV. Most children (398/399) had oral swabs collected, all with conclusive Ultra results. The sensitivity of double swabs was 6.9% with a microbiological reference standard (95% CI, 1.9%-22.0%) and 1.8% with a composite reference standard (95% CI, .8%-4.1%). Specificity was at least 99%. Swabs detected tuberculosis in 4 children with negative reference test results, of whom 3 had unconfirmed tuberculosis. CONCLUSIONS: The low sensitivity of Ultra on double swabs precludes its role as a principal diagnostic approach in young children. However, detection of tuberculosis in children who were not otherwise microbiologically diagnosed suggests the utility of oral swabs as add-on samples to increase yield.
The safety and immunogenicity of a bivalent conjugate vaccine against Salmonella enterica Typhi and Paratyphi A in healthy Indian adults: a phase 1, randomised, active-controlled, double-blind trial.
BACKGROUND: Enteric fever caused by Salmonella enterica Typhi and Salmonella Paratyphi A is an important public health problem, especially in low-income and middle-income countries with limited access to safe water and sanitation. We present results from, to our knowledge, the first ever human study of a bivalent paratyphoid A-typhoid conjugate vaccine (Sii-PTCV). METHODS: In this double-blind phase 1 study, 60 healthy Indian adults were randomly assigned (1:1) to receive a single intramuscular dose of either Sii-PTCV or typhoid conjugate vaccine (Typbar-TCV). Safety was assessed by observing solicited adverse events for 1 week, unsolicited events for 1 month, and serious adverse events (SAEs) over 6 months. Immunogenicity at 1 month and 6 months was assessed by measuring anti-capsular polysaccharide antigen Vi (anti-Vi) IgG and IgA against Salmonella Typhi and anti-lipopolysaccharide (LPS) IgG against Salmonella Paratyphi A by ELISA, and functional antibodies using serum bactericidal assay (SBA) against Salmonella Paratyphi A. This study is registered with Clinical Trial Registry-India (CTRI/2022/06/043608) and is completed. FINDINGS: 60 participants were enrolled. Of these 60 participants, 57 (95%) participants were male and three (5%) participants were female. Solicited adverse events were observed in 27 (90%) of 30 participants who received Sii-PTCV and 26 (87%) of 30 participants who received Typbar-TCV. The most common local solicited event was pain in 27 (90%) participants who received Sii-PTCV and in 23 (77%) participants who received Typbar-TCV. The most common solicited systemic event was myalgia in five (17%) participants who received Sii-PTCV, whereas four (13%) participants who received Typbar-TCV had myalgia and four (13%) had headache. No vaccine-related unsolicited adverse events or SAEs were reported. The seroconversion rates on day 29 were 96·7% (95% CI 82·8-99·9) with Sii-PTCV and 100·0% (88·4-100·0) with Typbar-TCV for anti-Vi IgG; 93·3% (77·9-99·2) with Sii-PTCV and 100·0% (88·4-100·0) with Typbar-TCV for anti-Vi IgA; 100·0% (88·4-100·0) with Sii-PTCV and 3·3% (0·1-17·2) with Typbar-TCV for anti-LPS (paratyphoid); and 93·3% (77·9-99·2) with Sii-PTCV and 0% (0·0-11·6) with Typbar-TCV for SBA titres (paratyphoid). Paratyphoid anti-LPS immune responses were sustained at day 181. INTERPRETATION: Sii-PTCV was safe and immunogenic for both typhoid and paratyphoid antigens indicating its potential for providing comprehensive protection against enteric fever. FUNDING: Serum Institute of India.
Development of methodology to support molecular endotype discovery from synovial fluid of individuals with knee osteoarthritis: The STEpUP OA consortium.
OBJECTIVES: To develop a protocol for largescale analysis of synovial fluid proteins, for the identification of biological networks associated with subtypes of osteoarthritis. METHODS: Synovial Fluid To detect molecular Endotypes by Unbiased Proteomics in Osteoarthritis (STEpUP OA) is an international consortium utilising clinical data (capturing pain, radiographic severity and demographic features) and knee synovial fluid from 17 participating cohorts. 1746 samples from 1650 individuals comprising OA, joint injury, healthy and inflammatory arthritis controls, divided into discovery (n = 1045) and replication (n = 701) datasets, were analysed by SomaScan Discovery Plex V4.1 (>7000 SOMAmers/proteins). An optimised approach to standardisation was developed. Technical confounders and batch-effects were identified and adjusted for. Poorly performing SOMAmers and samples were excluded. Variance in the data was determined by principal component (PC) analysis. RESULTS: A synovial fluid standardised protocol was optimised that had good reliability (<20% co-efficient of variation for >80% of SOMAmers in pooled samples) and overall good correlation with immunoassay. 1720 samples and >6290 SOMAmers met inclusion criteria. 48% of data variance (PC1) was strongly correlated with individual SOMAmer signal intensities, particularly with low abundance proteins (median correlation coefficient 0.70), and was enriched for nuclear and non-secreted proteins. We concluded that this component was predominantly intracellular proteins, and could be adjusted for using an 'intracellular protein score' (IPS). PC2 (7% variance) was attributable to processing batch and was batch-corrected by ComBat. Lesser effects were attributed to other technical confounders. Data visualisation revealed clustering of injury and OA cases in overlapping but distinguishable areas of high-dimensional proteomic space. CONCLUSIONS: We have developed a robust method for analysing synovial fluid protein, creating a molecular and clinical dataset of unprecedented scale to explore potential patient subtypes and the molecular pathogenesis of OA. Such methodology underpins the development of new approaches to tackle this disease which remains a huge societal challenge.
The Effect of Acute Knee Injuries and Related Knee Surgery on Serum Levels of Pro- and Anti-inflammatory Lipid Mediators and Their Associations With Knee Symptoms.
BACKGROUND: Despite an acute knee injury being a major risk factor for osteoarthritis, the factors that initiate and maintain this risk of longer-term knee symptoms are poorly understood. Bioactive lipids derived from omega-3 and -6 polyunsaturated fatty acids have key roles in the regulation of the inflammatory response and have been linked to joint damage and osteoarthritis pain in translational models. HYPOTHESIS: There would be associations between systemic levels of bioactive lipids and knee symptoms longitudinally after an acute knee injury and related knee surgery. STUDY DESIGN: Controlled laboratory study. METHODS: This study analyzed a subset of young, active adults who had sustained an acute knee injury (recruited via a surgical care pathway) and healthy age- and sex-matched controls. Surgery, if performed, was conducted after the baseline serum sample was taken and before the 3-month and 2-year visits. Liquid chromatography-tandem mass spectrometry of 41 bioactive lipids was carried out in sera of (1) 47 injured participants (median age, 28 years) collected at baseline (median, 24 days after injury), 3 months, and 2 years, along with the Knee injury and Osteoarthritis Outcome Score, and (2) age- and sex-matched controls. RESULTS: Levels of the omega-3 polyunsaturated fatty acids eicosapentaenoic acid (P≤ .0001) and docosahexaenoic acid (P≤ .0001) and the pro-resolving lipid mediators 17- and 14-hydroxydocosahexaenoic acid, and 18-hydroxyeicosapentaenoic acid were all significantly greater at baseline in injured participants compared with the later time points and also higher than in healthy controls (P = .0019 and P≤ .0001, respectively). Levels of pro-inflammatory prostaglandins E2 and D2, leukotriene B4, and thromboxane B2 were significantly lower at baseline compared with the later time points. Higher levels of 8,9-, 11,12-, and 14,15-dihydroxyeicosatrienoic acid (DHET) were cross-sectionally associated with more severe knee pain/symptoms according to the Knee injury and Osteoarthritis Outcome Score at 2 years (P = .0004, R2 = 0.251; P = .0002, R2 = 0.278; and P = .0012, R2 = 0.214, respectively). CONCLUSION: The profile of pro-resolving versus pro-inflammatory lipids at baseline suggests an initial activation of pro-resolution pathways, followed by the later activation of pro-inflammatory pathways. CLINICAL RELEVANCE: In this largely surgically managed cohort, the association of soluble epoxide hydrolase metabolites, the DHETs, with more severe knee symptoms at 2 years provides a rationale for further investigation into the role of this pathway in persisting knee symptoms in this population, including potential therapeutic strategies.