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Baricitinib – an anti-inflammatory treatment for rheumatoid arthritis– is being investigated in the RECOVERY trial, the world’s largest clinical trial of treatments for patients hospitalised with COVID-19, taking place in 177 hospital sites across the UK and with over 33,000 patients recruited so far. As an anti-inflammatory, baricitinib may block the signalling activity of cytokine molecules which contribute to the hyper-inflammatory state seen in severe COVID-19. It is thought that baricitinib may act also have some anti-viral activity. The other treatments currently being investigated in the RECOVERY trial are Regeneron’s antibody cocktail, Aspirin and Colchicine.
Application of machine learning in early childhood development research: a scoping review.
BackgroundEarly childhood development (ECD) lays the foundation for lifelong health, academic success and social well-being, yet over 250 million children in low- and middle-income countries are at risk of not reaching their developmental potential. Traditional measures fail to fully capture the risks associated with a child's development outcomes. Artificial intelligence techniques, particularly machine learning (ML), offer an innovative approach by analysing complex datasets to detect subtle developmental patterns.ObjectiveTo map the existing literature on the use of ML in ECD research, including its geographical distribution, to identify research gaps and inform future directions. The review focuses on applied ML techniques, data types, feature sets, outcomes, data splitting and validation strategies, model performance, model explainability, key themes, clinical relevance and reported limitations.DesignScoping review using the Arksey and O'Malley framework with enhancements by Levac et al. DATA SOURCES: A systematic search was conducted on 16 June 2024 across PubMed, Web of Science, IEEE Xplore and PsycINFO, supplemented by grey literature (OpenGrey) and reference hand-searching. No publication date limits were applied.Eligibility criteriaIncluded studies applied ML or its variants (eg, deep learning (DL), natural language processing) to developmental outcomes in children aged 0-8 years. Studies were in English and addressed cognitive, language, motor or social-emotional development. Excluded were studies focusing on robotics; neurodevelopmental disorders such as autism spectrum disorder, attention-deficit/hyperactivity disorder and communication disorders; disease or medical conditions; and review articles.Data extraction and chartingThree reviewers independently extracted data using a structured MS Excel template, covering study ML techniques, data types, feature sets, outcomes, outcome measures, data splitting and validation strategies, model performance, model explainability, key themes, clinical relevance and limitations. A narrative synthesis was conducted, supported by descriptive statistics and visualisations.ResultsOf the 759 articles retrieved, 27 met the inclusion criteria. Most studies (78%) originated from high-income countries, with none from sub-Saharan Africa. Supervised ML classifiers (40.7%) and DL techniques (22.2%) were the most used approaches. Cognitive development was the most frequently targeted outcome (33.3%), often measured using the Bayley Scales of Infant and Toddler Development-III (33.3%). Data types varied, with image, video and sensor-based data being most prevalent. Key predictive features were grouped into six categories: brain features; anthropometric and clinical/biological markers; socio-demographic and environmental factors; medical history and nutritional indicators; linguistic and expressive features; and motor indicators. Most studies (74.1%) focused solely on prediction, with the majority conducting predictions at age 2 years and above. Only 41% of studies employed explainability methods, and validation strategies varied widely. Few studies (7.4%) conducted external validation, and only one had progressed to a clinical trial. Common limitations included small sample sizes, lack of external validation and imbalanced datasets.ConclusionThere is growing interest in using ML for ECD research, but current research lacks geographical diversity, external validation, explainability and practical implementation. Future work should focus on developing inclusive, interpretable and externally validated models that are integrated into real-world implementation.
A subpopulation of high IL-21-producing CD4+ T cells in Peyer’s Patches is induced by the microbiota and regulates germinal centers
AbstractThe production of IL-21 by T follicular helper (Tfh) cells is vital in driving the germinal centre reaction and high affinity antibody formation. However, the degree of Tfh cell heterogeneity and function is not fully understood. We used a novel IL-21eGFP reporter mouse strain to analyze the diversity and role of Tfh cells. Through the analysis of GFP expression in lymphoid organs of IL-21eGFP mice, we identified a subpopulation of GFP+, high IL-21 producing Tfh cells present only in Peyer’s Patches. GFP+Tfh cells were found to be polyclonal and related to GFP−Tfh cells of Peyer’s Patches in TCR repertoire composition and overall gene expression. Studies on the mechanisms of induction of GFP+Tfh cells demonstrated that they required the intestinal microbiota and a diverse repertoire of CD4+ T cells and B cells. Importantly, ablation of GFP+ cells resulted in a reduced frequency of Peyer’s Patches IgG1 and germinal center B cells in addition to small but significant shifts in gut microbiome composition. Our work highlights the diversity among IL-21 producing CD4+ Tfh cells, and the interrelationship between the intestinal bacteria and Tfh cell responses in the gut.
Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine in children aged 6-17 years: Final results of a phase 2, single-blind, randomised controlled trial (COV006).
Paediatric COVID-19 vaccination programmes were initiated in response to the coronavirus pandemic declared by the World Health Organisation (WHO) in 2020. Ten COVID-19 vaccines received WHO Emergency Use Listing, however, only five were approved for use in children. ChAdOx1 nCoV-19 (AZD1222) was approved in adults in a two-dose regimen. We previously reported interim findings of a phase 2 study of ChAdOx1 nCoV-19 in children with immunogenicity, comparable with adults. Final results after 12 month follow-up are reported. Single-blind, randomised controlled trial across four UK centres, recruiting 261 children and adolescents (aged 6-17 years). Participants received either two doses of ChAdOx1 nCoV-19 or Bexsero vaccine (controls). The primary outcome was safety (adverse events for 28 days following vaccination and serious adverse events throughout), and secondary outcome was immunogenicity (measured by SARS-CoV-2 anti-spike enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunosorbent spot (ELISpot)). Five serious adverse events and four adverse events of special interest were reported. None were related to study vaccinations, and there were no deaths. Geometric mean titres (GMTs) from an anti-spike (Wuhan) ELISA in participants aged 6-11 years were 1 EU/ml (95% CI 1-2) at baseline versus 796 EU (95% CI 161-3948, n =4) at D364. In participants aged 12-17 years, GMTs were 1 EU/ml (95% CI 1-2, n=3) at baseline versus 1432 EU/ml (95% CI 2337-6083; n=6) at D364 (2 dose regimen at 112-day interval), compared to 3 EU/ml (95% CI 0-62) at baseline versus 392 EU/ml (95% CI 24, 6493; n=3) at D364 (2 dose regimen at a 28-day interval). A two-dose regimen of ChAdOx1 nCoV-19 was immunogenic and safe in the trial population. No vaccine-related serious adverse events were reported. Immune responses persisted to 12 months in participants who did not experience breakthrough infection, This trial was registered with ISRCTN, trial number 15638344. The study was funded by the Department of Health and Social Care, through the National Institute for Health Research, and AstraZeneca.
MAIT and other innate-like T cells integrate adaptive immune responses to modulate interval-dependent reactogenicity to mRNA vaccines
Adenoviral (Ad) vectors and mRNA vaccines exhibit distinct patterns of immune responses and reactogenicity, but underpinning mechanisms remain unclear. We longitudinally compared homologous ChAdOx1 nCoV-19 and BNT162b2 vaccination, focusing on cytokine-responsive innate-like lymphocytes—mucosal-associated invariant T (MAIT) cells and Vδ2 + γδ T cells—which sense and tune innate-adaptive cross-talk. Ad priming elicited robust type I interferon (IFN)–mediated innate-like T cell activation, augmenting T cell responses (innate-to-adaptive signaling), which was dampened at boost by antivector immunity. Conversely, mRNA boosting enhanced innate-like responses, driven by prime-induced spike-specific memory T cell–derived IFN-γ (adaptive-to-innate signaling). Extending the dosing interval dampened inflammation at boost because of waning T cell memory. In a separate vaccine trial, preboost spike-specific T cells predicted severe mRNA reactogenicity regardless of the priming platform or interval. Overall, bidirectional innate-like and adaptive cross-talk, and IFN-γ–licensed innate-like T cells, orchestrate interval-dependent early vaccine responses, suggesting modifiable targets for safer, more effective regimens.
Making MALDI-TOF MS for entomological parameters accessible: A practical guide for in-house library creation
Matrix-assisted laser desorption-ionisation time of flight mass spectrometry (MALDI-TOF MS) is a powerful analytical method that has been used extensively to identify sample ions of complex mixtures, and biological samples such as proteins, tissues and microorganisms. MALDI-TOF MS has revolutionised clinical microbiology with accurate, rapid, and inexpensive species-level identification of microbes. MALDI-TOF MS technology generates spectral signatures and matches them to a library of similar organisms using bioinformatics pattern matching. The use of MALDI-TOF MS for entomological samples has been explored by multiple groups with proven efficacy at differentiating between closely related species, as well as detecting pathogens in different vectors. The low cost per sample processing, rapid turnaround and robustness are attractive for surveillance of vector control programs. Libraries are built in-house for institutional usage, although a multi-user platform with sharing of spectra and data would be attractive. Only a few studies have strived to make their libraries publicly available. Here, we outline a stepwise approach for creating an in-house MALDI-TOF MS library and subsequent query, using malaria vector species identification as a case study for entomological samples. A protocol and video of the methodology are also shared. Moreover, the libraries related to this publication have been deposited in public repository (https://doi.org/10.7910/DVN/VYQFNO37) for anyone with MALDI-TOF MS equipment to adapt.
International Consensus on Global Surgery Learning Objectives and Competencies.
ObjectiveThis project aimed to achieve international consensus on core learning objectives for global surgery education.BackgroundAs global surgery emerges as an academic field, there is a growing need for consensus-driven learning objectives to guide education and training. Existing curricula vary widely and lack multidisciplinary input.MethodsA modified Delphi consensus was conducted with an international panel of global surgery experts. A scoping review informed an initial list of learning objectives, categorized into 14 domains based on the Consortium of Universities for Global Health framework. Panelists rated objectives over three iterative survey rounds, with consensus defined as ≥80% agreement within ±1 Likert point of the median.ResultsSixty-one experts from 26 countries across all World Health Organization (WHO) regions participated, representing surgery (40.1%), anesthesia (14.8%), obstetrics and gynecology (14.8%), general practitioners with and without enhanced surgical skills (16.4%), and allied health fields (6.6%). The majority (57.4%) had over 10 years of experience in global surgery. Across three Delphi rounds, 120 learning objectives reached consensus, covering key domains such as the global burden of surgical disease, surgical system strengthening, ethics and equity, health policy, and sustainable development. A total of 25 (20.8%) objectives were designated for introductory learners, 55 (45.8%) for advanced learners, and 40 (33.3%) for both levels.ConclusionThis Delphi consensus provides a structured, globally relevant framework for global surgery education, supporting curriculum development and competency-based training. These findings underscore the importance of aligning global surgery education with evolving healthcare priorities while ensuring adaptability across diverse surgical contexts.
MALDI-TOF MS for identification of Afro-tropical secondary malaria vectors
Abstract Background Characterizing malaria epidemiology at the local level requires understanding the diverse malaria vector species driving transmission, including both primary and secondary vectors. Effective mosquito surveillance and accurate species identification are critical; however, due to the associated cost and complexity, most surveillance strategies mainly focus on the primary malaria vectors. There is a need for cost-effective methods that can reliably identify both primary and secondary vectors as their role in transmission becomes increasingly important while reaching towards elimination. This study aimed to evaluate the use of MALDI-TOF MS as a sustainable tool for identifying secondary malaria vector. Methods Adult mosquitoes were collected in Kenya and Mozambique and morphologically identified. Secondary malaria vectors were considered as any Anopheline that did not pertain to Anopheles gambiae sensu lato (s.l.). or Anopheles funestus sensu lato (s.l.). At KEMRI Wellcome Trust Research Programme, MALDI TOF MS spectra were obtained from individual cephalothoraxes. Library creation and querying were guided by confirmatory species identification using Sanger sequencing of a subset of mosquitoes, targeting the Internal Transcribed Spacer 2 (ITS2) region of nuclear ribosomal DNA and the mitochondrial Cytochrome c Oxidase Subunit I (COI) gene. The libraries were then applied for the identification of other secondary malaria vectors. Results Species identification of secondary malaria vectors using MALDI-TOF MS showed high concordance with Sanger sequencing with an overall accuracy of 91% and a kappa value of 0.87. The technique demonstrated a sensitivity and specificity of 100% for most species, except for distinguishing between Anopheles cf. coustani 2 NFL-2015 and Anopheles ziemanni. In Kenya, the Anopheles species identified were Anopheles cf. coustani 2 NFL-2015 (19), Anopheles pretoriensis (6), Anopheles rufipes (8), Anopheles ziemanni (8), Anopheles coustani (2), and Anopheles pharoensis (1). In Mozambique, the identified species comprised: An. cf. coustani 2 NFL-2015 (10), An. pretoriensis (2), An. ziemanni (7), An. coustani (28), and An. pharoensis (4). Conclusion The results provide evidence that MALDI-TOF can identify secondary malaria vectors from Eastern and Southeastern African regions. This technique was as efficient as DNA sequencing in identifying mosquito species. Indeed, except for An. cf coustani 2NFL-2015 and An. ziemanni, an exact species identification was obtained for all individual mosquitoes. These findings highlight the potential of MALDI-TOF MS for monitoring malaria vectors.
IgG Antibodies to Pneumococcal Serotypes 1 and 5 in Relation to PCV13 Vaccination Status in Children Aged Under 5 Years in Lao PDR: A Cross-Sectional Survey
Background/Objectives: Pneumococcal serotypes 1 and 5 are associated with invasive pneumococcal disease (IPD). However, data on the circulation of these serotypes in Asia following the introduction of the pneumococcal conjugate vaccine (PCV) is limited. The Lao People’s Democratic Republic (Lao PDR) introduced PCV13 into its national immunisation programme in 2013. We undertook a serosurvey to assess the IgG responses to serotypes 1 and 5 from a convenience sample of children aged under 5 years in Vientiane, Lao PDR. Methods: This cross-sectional analysis used a convenience sample of the close contacts of children under five years old who had been hospitalised with acute respiratory infections between 2013 and 2016 in Vientiane, Lao PDR. Serotype-specific IgG concentrations to serotypes 1 and 5 were measured using a modified WHO ELISA method. Results: A total of 214 participants were included, 130 of whom were unvaccinated and 84 were vaccinated with PCV13. Compared to unvaccinated participants, a higher number of PCV-vaccinated participants met the IgG threshold for IPD (≥0.35 μg/mL) [41.5% (54/130) vs. 71.4% (60/84)] for serotype 1. In contrast, for serotype 5, a similar number of participants in the PCV-vaccinated and unvaccinated group met the IgG threshold for IPD (85.7% (72/84) vs. 82.3% (107/130). Among unvaccinated children, serotype 1 IgG levels peaked at 12 and 23 months at 0.49 µg/mL (95% CIs: 0.25–0.96), while serotype 5 IgG levels were similar across age groups, ranging from 0.55 to 0.79 µg/mL. Conclusions: Our findings indicate the considerable circulation of serotypes 1 and 5 within the community in Lao PDR. Ongoing surveillance is important for informing PCV vaccination strategies.
Detection of Mycoplasma pneumoniae in hospitalized children with pneumonia in Laos
Mycoplasma pneumoniae has been described worldwide as an important cause of community-acquired pneumonia. From December 2013 to December 2014, 461 children admitted to Mahosot Hospital, Vientiane, Laos, with acute respiratory infection were investigated for upper respiratory microorganisms using probe-based real-time polymerase chain reaction (PCR) (FTD33). M. pneumoniae was detected by FTD33 in the upper respiratory tract of three patients, two girls and one boy, 5.7 and 3.9 years old and 13.6 years old, respectively. They presented with clinical features compatible with M. pneumoniae infection. They improved without M. pneumoniae directed therapy. The two girls were also positive for other potential pathogens. The boy had abnormal pulmonary auscultation, and one of the girls had significant anaemia. These results suggest that enhancement of diagnostic systems for M. pneumoniae detection is needed to improve understanding of the epidemiology of M. pneumoniae infection in Laos.
Direct real-time RT-PCR for the detection of dengue virus from patient serum in Lao PDR
Introduction Dengue fever is a growing global concern with an estimated 100–400 million infections every year and rising mortality over the past decade. In 2017, 40,000 deaths were attributed to dengue. Real-time reverse transcription PCR (RT-qPCR) is the gold standard technique to detect dengue virus (DENV) during the acute phase of the infection. However, it requires prior RNA purification which is costly and time consuming. We evaluated direct RT-qPCR using Luna Universal Probe One-Step RT-qPCR kit (Luna RT-qPCR) for the detection of DENV in sera. Methods Luna RT-qPCR conditions were optimized using DENV2 isolates. The efficiency of direct Luna RT-qPCR was evaluated on a panel of 132 patient sera using RNA purification (EZ1&2 Virus Mini Kit) followed by RT-qPCR (SuperScript III Platinum One-Step qRT-PCR system) as reference standard. Results The sensitivity (95% CI) of direct Luna RT-qPCR using neat patient sera was 34% (25–45). By reducing PCR inhibitors through a 1/10 dilution of the sera, the sensitivity improved to 86% (95% CI: 77–92). Comparable results were obtained between direct Luna RT-qPCR and reference standard process for samples with Cq < 35. Conclusion The results obtained in this study are promising. Direct RT-qPCR for DENV detection in patient sera, could make PCR-based dengue detection and typing, and potentially other target detections, more affordable for reference laboratories in LMICs by reducing reagent cost by approximately two-thirds. Further studies are needed to evaluate DENV direct RT-qPCR on prospective samples in diagnosis context and to improve the sensitivity by minimizing the impact of inhibitors.
Case Report: Herpes simplex virus type 2 (HSV-2) meningo-encephalitis associated with traumatic brain injury – a case report from Lao PDR
Background Neurological symptoms following head trauma are common; however, the cause may not always be obvious. In the absence of open wounds, fractures, or surgical interventions, infectious causes may not be considered, and investigations may not be targeted to investigate this possibility. Case A 39-year-old male presented with a severe headache, reduced consciousness, and confusion. Two days earlier, he had been discharged from the hospital, where he had been treated for traumatic brain injury with subarachnoid hemorrhage following a road traffic accident. Herpes simplex virus type 2 (HSV-2) was detected in the cerebrospinal fluid, confirming the diagnosis of viral meningoencephalitis. He was treated with oral aciclovir for two weeks and achieved full neurological recovery. Conclusions This case highlights the risk of viral reactivation following trauma, particularly head injuries. Central nervous system infections should be considered in cases of delayed deterioration following trauma. The optimal treatment of herpes simplex virus (HSV) encephalitis may be challenging in resource-limited settings.
Dosing interval is a major factor determining the quality of T cells induced by SARS-CoV-2 mRNA and adenoviral vector vaccines
Functional T cell responses are crucial for protective immunity induced by COVID-19 vaccination, but factors influencing the quality of these responses are incompletely understood. We used an activation-induced marker (AIM) assay and single-cell transcriptomic sequencing to analyze SARS-CoV-2 spike-responsive T cells after mild SARS-CoV-2 infection or after one or two doses of mRNA–lipid nanoparticle (mRNA-LNP) or adenoviral-vectored COVID-19 vaccines. Our findings revealed broad functional and clonal heterogeneity in T cells generated by vaccination or infection, including multiple distinct effector populations. T cell function was largely conserved between COVID-19 vaccine platforms but was distinct compared with SARS-CoV-2 infection. Notably, the dosing interval greatly influenced the quality of T cells after two vaccine doses, particularly after mRNA-LNP vaccination, where a longer interval led to reduced inflammatory signaling and increased secondary proliferation. These insights enhance our understanding of SARS-CoV-2–specific T cells and inform the optimization of mRNA vaccination regimens.
The range and reach of qualitative research in neurosurgery: A scoping review.
Following calls for more qualitative research in neurosurgery, this scoping review aimed to describe the range and reach of qualitative studies relevant to the field of neurosurgery and the patients and families affected by neurosurgical conditions. A systematic search was conducted in September 2024 across six databases: Medline via Ebsco; Embase via OVID; PsycINFO via Ebsco; Scopus; Web of Science Core Collection; and Global Health via Ebsco. Eligibility criteria were based on Population, Concept, and Context. The search identified 18,809 hits for screening with 812 included in the final analysis. Seven themes were identified from a content analysis of study aims: 1 Perspectives of living with a neurosurgical condition; 2 Family perspectives; 3 Perceptions of neurosurgery; 4 Perceptions of general healthcare care; 5 Decision making; 6 Advancing neurosurgery; and, 7 Understanding neurosurgical conditions. Traumatology was identified as the most researched sub-specialty (43.2%) yet few studies were led explicitly by a neurosurgeon (1.6%) or those with a neurosurgical affiliation (10.5%). Lead authors were predominantly from high income countries (93.7%), as were most multi-author teams (86.6%). There was a trend towards increasing publication over time; however, only 8.4% of papers were published in neurosurgical specific journals. The data set had an average Field Weighted Citation Impact of 0.96 and Field Weighted Views Impact of 1.11, 18.9% were cited in policy documents in 15 countries. This scoping review provides a comprehensive picture of the current qualitative research base in neurosurgery and suggests ways to improve the conduct and reporting of such studies in the future. Addressing these challenges is crucial if qualitative research is to advance the neurosurgical evidence base in a rigorous way.
Consensus Statements on Airway Clearance Interventions in Intubated Critically Ill Patients-Protocol for a Delphi Study.
Intubated critically ill patients are susceptible to secretion accumulation because of compromised airway clearance. Various airway clearance interventions are employed to prevent complications arising from mucus retention. This Delphi study aims to collect global opinions in an international expert panel of ICU professionals on the usefulness of these various airway clearance interventions. A steering committee performed a literature search informing the formulation of statements. Statements are grouped into two distinct parts: (1) Humidification and Nebulization, and (2) Suctioning and Mucus mobilization techniques. For each part, a diverse panel of 30-40 experts will be selected, with concerted effort to involve experts from various medical specialties involved in airway clearance methods. Multiple choice questions (MCQs) or 7-point Likert-scale statements will be used in the iterative Delphi rounds to reach consensus on various airway clearance interventions. Rounds will continue until stability is achieved for all statements. Consensus will be deemed achieved when a choice in MCQs or a Likert-scale statement achieves ≥75% agreement or disagreement. Starting from the second round of the Delphi process, stability will be assessed using non-parametric χ2 tests or Kruskal-Wallis tests. Stability will be defined by a p-value of ≥0.05.