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£18.5m will be invested in training the next generation of bioscience leaders at Oxford University to tackle global challenges such as food security and animal health.
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.
Engineering of extracellular vesicles for efficient intracellular delivery of multimodal therapeutics including genome editors.
Intracellular delivery of protein and RNA therapeutics represents a major challenge. Here, we develop highly potent engineered extracellular vesicles (EVs) by incorporating bio-inspired attributes required for effective delivery. These comprise an engineered mini-intein protein with self-cleavage activity for active cargo loading and release, and fusogenic VSV-G protein for endosomal escape. Combining these components allows high efficiency recombination and genome editing in vitro following EV-mediated delivery of Cre recombinase and Cas9/sgRNA RNP cargoes, respectively. In vivo, infusion of a single dose Cre loaded EVs into the lateral ventricle in brain of Cre-LoxP R26-LSL-tdTomato reporter mice results in greater than 40% and 30% recombined cells in hippocampus and cortex respectively. In addition, we demonstrate therapeutic potential of this platform by showing inhibition of LPS-induced systemic inflammation via delivery of a super-repressor of NF-ĸB activity. Our data establish these engineered EVs as a platform for effective delivery of multimodal therapeutic cargoes, including for efficient genome editing.
Inborn errors of thymic stromal cell development and function.
As the primary site for T cell development, the thymus is responsible for the production and selection of a functional, yet self-tolerant T cell repertoire. This critically depends on thymic stromal cells, derived from the pharyngeal apparatus during embryogenesis. Thymic epithelial cells, mesenchymal and vascular elements together form the unique and highly specialised microenvironment required to support all aspects of thymopoiesis and T cell central tolerance induction. Although rare, inborn errors of thymic stromal cells constitute a clinically important group of conditions because their immunological consequences, which include autoimmune disease and T cell immunodeficiency, can be life-threatening if unrecognised and untreated. In this review, we describe the molecular and environmental aetiologies of the thymic stromal cell defects known to cause disease in humans, placing particular emphasis on those with a propensity to cause thymic hypoplasia or aplasia and consequently severe congenital immunodeficiency. We discuss the principles underpinning their diagnosis and management, including the use of novel tools to aid in their identification and strategies for curative treatment, principally transplantation of allogeneic thymus tissue.
A phase 1/2a clinical trial to assess safety and immunogenicity of an adenoviral-vectored capsular group B meningococcal vaccine
Capsular group B meningococcus (MenB) remains an important cause of disease globally, and additional vaccines against MenB would aid in reducing the incidence of infection. Previous work has demonstrated that a MenB adenoviral-vectored vaccine, ChAdOx1 MenB.1, elicited high serum bactericidal responses in preclinical models after a single dose, supporting further clinical development of this vaccine. Here, we report the results of a trial designed to assess the safety and immunogenicity of ChAdOx1 MenB.1 in healthy adults aged 18 to 50. In this phase 1/2a, single-center trial, participants received one or two doses of ChAdOx1 MenB.1 at days 0 and 180. One dose of ChAdOx1 MenB.1 was also given at day 180 to some individuals primed with one dose of 4CMenB at day 0. Participants recorded their symptoms in an electronic diary after vaccination, and safety blood readouts were monitored. Serum bactericidal antibody (SBA) assays were performed against a panel of MenB target strains. ChAdOx1 MenB.1 was well tolerated with no safety concerns and elicited protective SBA titers against a MenB strain expressing a homologous factor H–binding protein (fHbp) variant in 100% of participants after two doses. However, cross-reactivity analysis indicated a low SBA response to strains expressing heterologous fHbp, suggesting that a multivalent vaccine may be needed. In sum, ChAdOx1 MenB.1 is immunogenic in humans, and addition of another fHbp variant or of another antigen in this platform could provide an approach to extend protection against endemic MenB disease.
Consultation report - considerations for a regulatory pathway for bivalent Salmonella Typhi/Paratyphi A vaccines for use in endemic countries.
Enteric fever caused by Salmonella enterica serovars Typhi and Paratyphi A and, to a lesser extent, S. Paratyphi B and C, remains a significant cause of mortality and morbidity in resource-constrained settings. Typhoid conjugate vaccines (TCVs) protect against S. Typhi but no vaccine to date protects against paratyphoid fever. There are several bivalent S. Typhi/Paratyphi A products in development; however, the low incidence of paratyphoid fever in many settings limits the feasibility of phase 3 efficacy studies. Two bivalent vaccines adding the S. Paratyphi A-specific O:2 lipopolysaccharide conjugated to a protein carrier to TCV constructs have successfully completed phase 1 studies and will progress rapidly in their development. The WHO's Product Development for Vaccines Advisory Committee (PDVAC) endorsed a regulatory pathway for a bivalent S. Typhi/Paratyphi A vaccine that contemplates demonstrating protective efficacy against S. Paratyphi A infection in a controlled human infection model (CHIM). Since the use of CHIM data in lieu of phase 3 efficacy studies and to identify markers of immune protection is not yet widely accepted by regulatory bodies, the WHO organized a consultation with vaccine developers, manufacturers, and regulators. The purpose of the meeting was to discuss the feasibility and considerations for the licensure of a bivalent S. Typhi/Paratyphi A vaccine. The aim of the consultation was to gain alignment among key stakeholders and facilitate the pathway to licensure in endemic countries.
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.
Prevalence, clinical management, and outcomes of adults hospitalised with endemic arbovirus illness in southeast Europe (MERMAIDS-ARBO): a prospective observational study.
BACKGROUND: Arboviruses have expanded into new regions in Europe, yet data indicate gaps in disease notifications and a risk of further spread. We aimed to report on prevalence, clinical management, and outcomes of endemic arbovirus infections in southeast Europe. METHODS: In this prospective observational study (MERMAIDS-ARBO), we enrolled adults (age ≥18 years) hospitalised with an arbovirus-compatible disease syndrome within 21 days of symptom onset across 21 hospitals in seven countries in southeast Europe over four arbovirus seasons (May 1-Oct 31, during 2016-19). We obtained data from case report forms completed by site investigators on admission and discharge. Participants were excluded if they had non-infectious CNS disorders, symptoms of another confirmed cause, an identified focal source of infection, or symptoms caused by recurrence of a pre-existing condition. The primary outcome was the proportion of participants with confirmed or probable acute infections with West Nile virus (WNV), tick-borne encephalitis virus (TBEV), Crimean-Congo haemorrhagic fever virus (CCHFV), or Toscana virus (TOSV), per reference laboratory criteria. Secondary outcomes were the proportions of patients treated with antivirals, antibiotics, or corticosteroids; the proportion of patients requiring intensive care; hospital length of stay; and mortality. FINDINGS: Of 2896 adults screened for eligibility, 929 were recruited and 913 met protocol-defined eligibility criteria (median age 43·1 years [IQR 29·5-59·7]; 550 [60%] men, 361 [40%] women, and two [<1%] with missing data). 530 (58%) participants presented with suspected meningitis, encephalitis, or both, and 318 (35%) with fever plus myalgia, fever plus arthralgia, or both. 820 (90%) reported no international travel within 21 days before symptom onset. 727 (80%) were administered antibiotics, 379 (42%) corticosteroids, and 222 (24%) antivirals. The median length of hospital stay was 9 days (IQR 6-14), and 113 (12%) required intensive care. Of 847 participants with a reference laboratory sample who met full eligibility criteria for analysis, 110 (13%) were diagnosed with 114 confirmed or probable acute arbovirus infections (four had coinfections or cross-reactivity): one (<1%) with CCHFV, 16 (2%) with TBEV, 44 (5%) with TOSV, and 53 (6%) with WNV. There was one death (<1%) of an individual with WNV. Of the 110 participants, 49 (45%) had a local clinician-attributed arbovirus discharge diagnosis. INTERPRETATION: Our data highlight the need to strengthen arbovirus surveillance systems for the early detection of emerging and re-emerging outbreaks, including investments to increase awareness of arbovirus infections among clinicians, to improve access to specialist diagnostics, and to develop effective and accessible vaccines and treatments to protect populations and health systems in southeast Europe. FUNDING: European Commission and Versatile Emerging infectious disease Observatory. TRANSLATIONS: For the Greek, Albanian, Romanian, Bosnian, Serbian, and Croatian translation of the summary see Supplementary Materials section.
Distinct type I and II interferon responses direct cortical and medullary thymic epithelial cell development.
Advances in genomics have redefined our understanding of thymic epithelial heterogeneity and architecture, yet signals driving thymic epithelial differentiation remain incompletely understood. Here, we elucidated pathways instructing human thymic epithelial cell development in the context of other anterior foregut-derived organs. Activation of interferon response gene regulatory networks distinguished epithelial cells of the thymus from those of other anterior foregut-derived organs. Thymic cortex and medulla epithelia displayed distinctive interferon-responsive signatures defined by lineage-specific chromatin accessibility. We explored the effects of type I and II interferons on thymic epithelial progenitor differentiation from induced pluripotent stem cells. Type II interferon was essential for expressing proteasome and antigen-presenting molecules, whereas type I or II interferons were essential for inducing different cytokines in thymic epithelial progenitor cells. Our findings suggest that interferons are critical to cortical and medullary thymic epithelial cell differentiation.
Genome-wide association meta-analysis of age at onset of walking in over 70,000 infants of European ancestry.
Age at onset of walking is an important early childhood milestone which is used clinically and in public health screening. In this genome-wide association study meta-analysis of age at onset of walking (N = 70,560 European-ancestry infants), we identified 11 independent genome-wide significant loci. SNP-based heritability was 24.13% (95% confidence intervals = 21.86-26.40) with ~11,900 variants accounting for about 90% of it, suggesting high polygenicity. One of these loci, in gene RBL2, co-localized with an expression quantitative trait locus (eQTL) in the brain. Age at onset of walking (in months) was negatively genetically correlated with ADHD and body-mass index, and positively genetically correlated with brain gyrification in both infant and adult brains. The polygenic score showed out-of-sample prediction of 3-5.6%, confirmed as largely due to direct effects in sib-pair analyses, and was separately associated with volume of neonatal brain structures involved in motor control. This study offers biological insights into a key behavioural marker of neurodevelopment.
Multi-antigen serology and a diagnostic algorithm for the detection of arbovirus infections as novel tools for arbovirus preparedness in southeast Europe (MERMAIDS-ARBO): a prospective observational study.
BACKGROUND: Arboviruses are increasingly affecting Europe, partly due to the effects of climate change. This increase in range and impact emphasises the need to improve preparedness for emerging arboviral infections that often co-circulate and might have overlapping clinical syndromes. We aimed to strengthen surveillance networks for four clinically relevant arboviruses in southeast Europe. METHODS: This study reports an in-depth analysis of the MERMAIDS-ARBO prospective observational study in adults (ie, aged ≥18 years) hospitalised with an arbovirus-compatible disease syndrome in 21 hospitals in seven countries in southeast Europe over four arbovirus seasons (May 1-Oct 31, 2016-19) to obtain arbovirus prevalence outcomes. The main objectives of the MERMAIDS-ARBO study, describing the clinical management and outcomes of four arboviruses endemic to southeast Europe, including Crimean-Congo haemorrhagic fever virus (CCHFV), tick-borne encephalitis virus (TBEV), Toscana virus, and West Nile virus (WNV), are reported elsewhere. In this analysis, given the challenges associated with arbovirus diagnostics, we developed a diagnostic algorithm accounting for serology outcomes and sample timing to study arbovirus prevalence in southeast Europe. Serum samples were collected on days 0, 7, 28, and 60 after hospital admission and tested for anti-CCHFV IgG and IgM antibodies with ELISAs (confirmed with an indirect immunofluorescence test) and for IgG and IgM antibodies specific to TBEV, Toscana virus, and WNV with custom-printed protein microarrays (confirmed with virus neutralisation tests). All acute-phase samples were tested by PCR for all four viruses. Descriptive analyses were performed for virus-reactive cases by geography and year, and possible factors (eg, age, sex, and insect bites) associated with virus reactivity were assessed. FINDINGS: Of 2896 individuals screened, 913 were eligible for inclusion, of whom 863 (514 men, 332 women, and 17 unknown) had samples sent to the study reference laboratories and were included in molecular and serological analyses. Some individuals had insufficient clinical data to be included in the clinical analysis, but met the eligibility criteria for and were included here. Serum sampling was incomplete (eg, samples missing from one or more timepoints or no data on time since symptom onset) for 602 (70%) patients, and the timing of collection was often heterogeneous after symptom onset up to 40 days (average median delay of 5-6 days across all timepoints), affecting the ability to diagnose arbovirus infection by serology. By use of an interpretation table incorporating timing and completeness of sampling, one (<1%) participant had a confirmed recent infection with CCHFV, ten (1%) with TBEV, 40 (5%) with Toscana virus, and 52 (6%) with WNV. Most acute confirmed infections of Toscana virus were found in Albania (25 [63%] of 40), whereas WNV was primarily identified in Romania (36 [69%] of 52). Albania also had the highest overall Toscana virus seropositivity (168 [60%] of 282), mainly explained by patients confirmed to be exposed or previously exposed (104 [62%] of 168). Patients without antibodies to WNV or Toscana virus were significantly younger than patients with antibodies (mean difference -8·48 years [95% CI -12·31 to -4·64] for WNV, and -6·97 years [-9·59 to -4·35] for Toscana virus). We found higher odds of Toscana virus reactivity in men (odds ratio 1·56 [95% CI 1·15 to 2·11]; p=0·0055), WNV reactivity with mosquito bites versus no mosquito bites (2·47 [1·54 to 3·97]; p=0·0002), and TBEV reactivity with tick bites versus no tick bites (2·21 [1·19 to 4·11]; p=0·018). INTERPRETATION: This study shows that despite incomplete and heterogeneous data, differential diagnosis of suspected arbovirus infections is possible, and the diagnostic interpretation algorithm we propose could potentially be used to strengthen routine diagnostics in clinical settings in areas at risk for arboviral diseases. Our data highlight potential hotspots for arbovirus surveillance and risk factors associated with these particular arbovirus infections. FUNDING: European Commission and Versatile Emerging infectious disease Observatory. TRANSLATIONS: For the Greek, Albanian, Romanian, Bosnian, Serbian, and Croatian translation of the summary see Supplementary Materials section.
How to Peer Review a Systematic Review: A Peer-Reviewer's Guide to Reviewing Reviews
Systematic reviews hold significant academic weight, but poor execution can render them misleading and unreliable. To help improve the quality of systematic reviews, the peer review process plays a crucial role. Peer reviewing systematic reviews requires a distinct skill set compared to reviewing primary research studies. Systematic reviews differ in their methodology and reporting standards, necessitating a structured approach to evaluation. This commentary offers guidance on best practice when peer reviewing systematic reviews, with an emphasis on synthesis of quantitative data from clinical trials. In this article, nine key topics are covered, namely correct classification of review type, adherence to systematic methods, pre-registration, methodological and reporting quality, search strategy evaluation, risk of bias assessment, evidence synthesis methods, data and code availability, and use of standardized assessment tools. By helping to ensure best practice is followed for each of these topics, peer reviewers can play a crucial role in upholding the methodological integrity of systematic reviews, ensuring they contribute reliable and meaningful evidence to the scientific literature.
Changes in iPSC-astrocyte morphology reflect Alzheimer's disease patient clinical markers.
Human induced pluripotent stem cells (iPSCs) provide powerful cellular models of Alzheimer's disease (AD) and offer many advantages over non-human models, including the potential to reflect variation in individual-specific pathophysiology and clinical symptoms. Previous studies have demonstrated that iPSC-neurons from individuals with Alzheimer's disease (AD) reflect clinical markers, including β-amyloid (Aβ) levels and synaptic vulnerability. However, despite neuronal loss being a key hallmark of AD pathology, many risk genes are predominantly expressed in glia, highlighting them as potential therapeutic targets. In this work iPSC-derived astrocytes were generated from a cohort of individuals with high versus low levels of the inflammatory marker YKL-40, in their cerebrospinal fluid (CSF). iPSC-derived astrocytes were treated with exogenous Aβ oligomers and high content imaging demonstrated a correlation between astrocytes that underwent the greatest morphology change from patients with low levels of CSF-YKL-40 and more protective APOE genotypes. This finding was subsequently verified using similarity learning as an unbiased approach. This study shows that iPSC-derived astrocytes from AD patients reflect key aspects of the pathophysiological phenotype of those same patients, thereby offering a novel means of modelling AD, stratifying AD patients and conducting therapeutic screens.