Search results

Clinical significance of preleukemic somatic GATA1 mutations in children with Down syndrome.

Children with Down syndrome (DS) have a high risk of GATA1-associated myeloid leukemia (ML-DS) before age 4. Somatic N-terminal GATA1 mutations (GATA1s) are necessary, but not sufficient, for ML-DS, but their significance at birth for individual babies and whether mutations occur after birth is unclear. To address these questions, we performed a prospective study of DS newborns using next-generation sequencing-based GATA1 mutation analysis with detailed hematologic and clinical evaluation and follow-up for the window of ML-DS risk. Of 450 DS neonates, 113 (25%) had GATA1s mutations of which 20/113 (17.7%) were multiple and 59 (52%) were clinically silent. Variant allele frequency (VAF) varied from 0.3-89%. VAF positively correlated (p<0.0001) with % blasts, leukocytes, dyserythro- and dysmegakaryopoiesis scores and clinical disease and negatively with hemoglobin, although only 4/113 were anemic. GATA1s mutations were detected from 28 weeks(w) gestation; the highest frequency (45%) was at 34-35w while mutation frequency in early fetal samples (<20w) was only <4% (2/57). GATA1s clones (VAF, % blasts) fell rapidly post-natally becoming undetectable by 6 months (6m) except in neonates who developed ML-DS. 7/110 surviving neonates (6.4%) developed ML-DS at a median age of 17.5m. GATA1s clone size at birth was the only predictor of subsequent ML-DS. No neonates lacking GATA1s mutations acquired mutations after birth or developed ML-DS. Taken together, the fetal environment is essential for GATA1s mutation selection and expansion of GATA1s clones. Rates of leukemic transformation of GATA1s clones detected at birth are low but clones that persist beyond 6 months transformed.

The use of controlled human infection models to identify correlates of protection for invasive Salmonella vaccines.

Controlled human infection model (CHIM) studies, which involve deliberate exposure of healthy human volunteers to an infectious agent, are recognised as important tools to advance vaccine development. These studies not only facilitate estimates of vaccine efficacy, but also offer an experimental approach to study disease pathogenesis and profile vaccine immunogenicity in a controlled environment, allowing correlation with clinical outcomes. Consequently, the data from CHIMs can be used to identify immunological correlates of protection (CoP), which can help accelerate vaccine development. In the case of invasive Salmonella infections, vaccination offers a potential instrument to prevent disease. Invasive Salmonella disease, caused by the enteric fever pathogens Salmonella enterica serovar Typhi (S. Typhi) and S. Paratyphi A, B and C, and nontyphoidal Salmonella (iNTS), remains a significant cause of mortality and morbidity in low- and middle-income countries, resulting in over 200,000 deaths and the loss of 15 million DALYs annually. CHIM studies have contributed to the understanding of S. Typhi infection and provided invaluable insight into the development of vaccines and CoP following vaccination against S. Typhi. However, CoP are less well understood for S. Paratyphi A and iNTS. This brief review focuses on the contribution of vaccine-CHIM trials to our understanding of the immune mechanisms associated with protection following vaccines against invasive Salmonella pathogens, particularly in relation to CoP.

Acute Plasmodium yoelii 17XNL Infection During BCG Vaccination Limits T Cell Responses and Mycobacterial Growth Inhibition.

Tuberculosis and malaria overlap in many sub-Saharan African countries where Bacillus Calmette Guérin (BCG) vaccination is routinely administered. The aim of this study was to determine whether the timing of BCG vaccination in relation to a malaria infection has implications for BCG vaccine efficacy. Mice were intradermally vaccinated with BCG either 4 weeks before infection with blood-stage Plasmodium yoelii 17XNL, at 13 days post-infection (during an acute blood-stage malaria infection) or 21 days post-infection (after clearance of P. yoelii 17XNL infection). Ex vivo control of mycobacterial growth by splenocytes was used as a surrogate of protective efficacy, and PPD-specific T-cell responses were quantified by flow cytometry. No differences in mycobacterial growth control were detected between BCG vaccinated mice and groups receiving vaccination prior to or after clearance of P. yoelii 17XNL infection. Poorer control of mycobacterial growth was observed following BCG vaccination administered during an acute malarial infection compared to BCG vaccination only or BCG vaccination after blood-stage malaria infection, and mycobacterial growth negatively correlated with the magnitude of total cytokine production from PPD-specific CD4+ T cells (p 

The waning of maternal measles antibodies: a multi-country maternal-infant seroprevalence study.

OBJECTIVES: To assess geographical variation in maternal measles antibody levels from birth to nine months of age, to inform recommendations for the timing of first measles vaccine dose. METHODS: Stored infant serum samples from 11 countries taken at delivery and/or follow-up time points prior to measles vaccination (N=2,845) were tested for measles plaque reduction neutralisation (PRNT) and measles, mumps, and rubella immunoglobulin G at a central laboratory. Antibody decay in infants was modelled using linear mixed effects models with participant-level random intercepts and random slopes. Proportions of infants with antibody concentrations above the clinical protection threshold (0.12 IU/mL) were estimated at each age. RESULTS: At birth most (94%, 519/552) infants had PRNT ≥0.12 IU/mL, but geometric mean concentrations ranged 0.32 IU/mL (Guatemala) to 1.60 IU/mL (Pakistan). There was no geographical variation in decay rate of PRNT nor immunoglobulin G. Geometric mean PRNT fell below 0.12 IU/mL between ages 2.5 months (Guatemala) and 6.2 months (Pakistan). At age 6 months <50% of infants had PRNT ≥0.12 IU/mL in all countries except Pakistan. CONCLUSIONS: Reliance on maternal antibodies for protection until age 9 months or later leaves most infants with insufficient direct protection against measles infection between ages 6-9 months.

Silencing of SOD1 sensitises ATRX-deficient cells to camptothecin treatment through increased activity of the Alternative Lengthening of Telomeres pathway

Hereditary Factors in Carcinogenesis and the Key Cancer Syndromes

The emergence of Fanconi anaemia type S: a phenotypic spectrum of biallelic BRCA1 mutations.

BRCA1 is involved in the Fanconi anaemia (FA) pathway, which coordinates repair of DNA interstrand cross-links. FA is a rare genetic disorder characterised by bone marrow failure, cancer predisposition and congenital abnormalities, caused by biallelic mutations affecting proteins in the FA pathway. Germline monoallelic pathogenic BRCA1 mutations are known to be associated with hereditary breast/ovarian cancer, however biallelic mutations of BRCA1 were long predicted to be incompatible with embryonic viability, hence BRCA1 was not considered to be a canonical FA gene. Despite this, several patients with biallelic pathogenic BRCA1 mutations and FA-like phenotypes have been identified - defining a new FA type (FA-S) and designating BRCA1 as an FA gene. This report presents a scoping review of the cases of biallelic BRCA1 mutations identified to date, discusses the functional effects of the mutations identified, and proposes a phenotypic spectrum of BRCA1 mutations based upon available clinical and genetic data. We report that this FA-S cohort phenotype includes short stature, microcephaly, facial dysmorphisms, hypo/hyperpigmented lesions, intellectual disability, chromosomal sensitivity to crosslinking agents and predisposition to breast/ovarian cancer and/or childhood cancers, with some patients exhibiting sensitivity to chemotherapy. Unlike most other types of FA, FA-S patients lack bone marrow failure.

Clinical variants in Caenorhabditis elegans expressing human STXBP1 reveal a novel class of pathogenic variants and classify variants of uncertain significance

Purpose: Modeling disease variants in animals is useful for drug discovery, understanding disease pathology, and classifying variants of uncertain significance (VUS) as pathogenic or benign. Methods: Using Clustered Regularly Interspaced Short Palindromic Repeats, we performed a Whole-gene Humanized Animal Model procedure to replace the coding sequence of the animal model's unc-18 ortholog with the coding sequence for the human STXBP1 gene. Next, we used Clustered Regularly Interspaced Short Palindromic Repeats to introduce precise point variants in the Whole-gene Humanized Animal Model–humanized STXBP1 locus from 3 clinical categories (benign, pathogenic, and VUS). Twenty-six phenotypic features extracted from video recordings were used to train machine learning classifiers on 25 pathogenic and 32 benign variants. Results: Using multiple models, we were able to obtain a diagnostic sensitivity near 0.9. Twenty-three VUS were also interrogated and 8 of 23 (34.8%) were observed to be functionally abnormal. Interestingly, unsupervised clustering identified 2 distinct subsets of known pathogenic variants with distinct phenotypic features; both p.Tyr75Cys and p.Arg406Cys cluster away from other variants and show an increase in swim speed compared with hSTXBP1 worms. This leads to the hypothesis that the mechanism of disease for these 2 variants may differ from most STXBP1-mutated patients and may account for some of the clinical heterogeneity observed in the patient population. Conclusion: We have demonstrated that automated analysis of a small animal system is an effective, scalable, and fast way to understand functional consequences of variants in STXBP1 and identify variant-specific intensities of aberrant activity suggesting a genotype-to-phenotype correlation is likely to occur in human clinical variations of STXBP1.

miR-107 represses DMPK and is sequestered by CUG repeats triggering the MSI2/miR-7 pathogenesis axis in myotonic dystrophy

Myotonic dystrophy type 1 (DM1) is a multisystem genetic disorder characterized by muscle disease, including muscle atrophy partially originating from excessive autophagy. We have previously demonstrated that excessive Musashi-2 (MSI2) repressed the biogenesis of miR-7, which derepressed autophagy, ultimately contributing to muscle atrophy, but the root cause of MSI2 dysregulation is unknown. Herein, we investigate the intricate role of miR-107 in DM1 pathogenesis, focusing on its involvement in the MSI2>miR-7>autophagy axis as this microRNA (miRNA) directly regulates MSI2. We found that in DM1, miR-107 function is impaired because expanded CUG repeats sequester it, causing an increase in the expression of its targets, including MSI2. Through different experimental approaches, including luciferase reporter assays, differential scanning fluorimetry, and electrophoretic mobility shift assay (EMSA), we confirm that miR-107 directly binds to CUG repeats in mutant DMPK transcripts. DMPK posttranscriptional regulation by miR-107 was also demonstrated. Modulation of miR-107 in a DM1 cell model context significantly affects its downstream targets, MSI2 and miR-7, thus decreasing excessive autophagic markers and restoring pathological phenotypes such as ribonuclear foci and impaired fusion capacity. These findings underscore the critical role of miR-107 in regulating the MSI2>miR-7>autophagy axis and support this miRNA as a promising therapeutic target for correcting muscle dysfunction in DM1.

Respiratory viral detection in children hospitalized with pneumonia during periods of major population disruptions in Nepal, 2014-2018.

BACKGROUND: Respiratory viruses commonly cause pneumonia in children. We aimed to identify respiratory viral nucleic acids in the nasopharynx of children admitted with pneumonia from 2014 to 2018, a period including a major earthquake (April 2015), PCV10 introduction (August 2015), and a fuel shortage (October 2015 to March 2016). METHODS: Children 2 months to 14 years admitted to Patan Hospital between March 2014 and February 2018 with a clinical diagnosis of pneumonia had nasopharyngeal swabs collected and tested with a multiplex panel for the presence of genetic material from 23 respiratory pathogens. RESULTS: Of 1343 children with pneumonia, 974 (72.5%) had the nucleic acids of at least one respiratory virus in the nasopharynx. The median age of children with any viral genetic material detected was lower than those without (1.18, IQR: 0.59-2.39 years; versus 2.01 years, IQR: 0.81-4.34 years; p<0.001). Commonly detected viral nucleic acids included those of RSV (21.0%), rhino/enterovirus (30.8%), and parainfluenza (7.4%). The odds of detecting any respiratory viral genetic material in children with pneumonia increased by 1.88 (95% confidence interval: 1.15, 3.06) in the year after the earthquake, when there were several aftershocks and a fuel crisis, relative to other periods and accounting for other potential confounding factors. CONCLUSIONS: These findings highlight the importance of viral diagnostics in pediatric pneumonia and suggest that public health measures addressing environmental conditions during disasters might help reduce respiratory infections.

LISTEN: lived experiences of Long COVID: a social media analysis of mental health and supplement use

IntroductionLong COVID, or Post-Acute Sequelae of SARS-CoV-2 infection (PASC), is a complex condition characterized by a wide range of persistent symptoms that can significantly impact an individual's quality of life and mental health. This study explores public perspectives on the mental health impact of Long COVID and the use of dietary supplements for recovery, drawing on social media content. It uniquely addresses how individuals with Long COVID discuss supplement use in the absence of public health recommendations.MethodsThe study employs the LISTEN method (“Collaborative and Digital Analysis of Big Qual Data in Time Sensitive Contexts”), an interdisciplinary approach that combines human insight and digital analysis software. Social media data related to Long COVID, mental health, and supplement use were collected using the Pulsar Platform. Data were analyzed using the free-text discourse analysis tool Infranodus and collaborative qualitative analysis methods.ResultsThe findings reveal key themes, including the impact of Long COVID on mental health, occupational health, and the use of food supplements. Analysis of attitudes toward supplement use highlights the prevalence of negative emotions and experiences among Long COVID patients. The study also identifies the need for evidence-based recommendations and patient education regarding supplement use.DiscussionThe findings contribute to a better understanding of the complex nature of Long COVID and inform the development of comprehensive, patient-centered care strategies addressing both physical and mental health needs.

What is the current evidence base for measles vaccination earlier than 9 months of age?: Report from an informal technical consultation of the World Health Organization.

Measles is one of the most contagious vaccine preventable diseases, causing severe complications and deaths globally. While vaccination with a measles-containing vaccine (MCV) has prevented millions of measles deaths, recent trends, especially from low- and middle-income countries, are discouraging. Measles cases have increased since 2021 as MCV coverage has decreased; and an estimated 107,500 measles deaths, mostly in children under-five years, occurred in 2023. Thus, a renewed focus on proven and innovative strategies to control measles is needed. The World Health Organization (WHO) recommends a first MCV dose administered at 9-15 months of age (routine MCV1), however MCV1 below 9 months of age (early MCV1) may increase vaccination coverage because uptake of all vaccines tends to be higher the younger the child, and this might protect vulnerable infants earlier in life. However, due to concerns about possible reduced vaccine performance, early MCV1 is not routinely recommended by WHO. WHO hosted an informal technical consultation on December 6-7, 2023, in Geneva, Switzerland to evaluate recent evidence on early MCV1 and identify evidence gaps for policy making. The recent evidence suggests a robust humoral immune response shortly after early MCV1 at 5-8 months of age. Immune blunting of a routine second MCV dose (e.g., MCV2) after early MCV1 was not demonstrated in the presented data. However, 3-7 years after MCV1, children receiving early MCV1 had lower measles antibodies than children receiving routine MCV1, suggesting faster waning of immunity. The totality of evidence on immune blunting remains inconsistent. Meeting participants thought more data are needed before revisiting WHO's current recommendation for a potential revision. Evidence gaps include: understanding measles disease burden and severity in infants; early MCV1 effectiveness and duration; vaccine-induced cellular immunogenicity; whether measles in infants is acquired from other infants or older children or adults; and blunting of routine MCV2. Addressing evidence gaps through targeted studies and measles outbreak investigations, as well as evaluations of country-level introductions of early MCV1 are warranted. Ensuring high MCV1 and MCV2 coverage remains the priority in measles control.

Leveraging paired serology to estimate the incidence of typhoidal Salmonella infection in the STRATAA study

Seroprevalence of Cytomegalovirus Among Pregnant Women at Kawempe National Referral Hospital, Uganda: A Cross-sectional Study.

BACKGROUND: Maternal primary cytomegalovirus (CMV) infection is associated with abortion and congenital anomalies. In Uganda, the burden of maternal CMV infection is not well studied. This study thus assessed the seroprevalence and factors associated with CMV infection among pregnant women at Kawempe National Referral Hospital in Kampala. This work forms a part of the PROGRESS study, an observational cohort study undertaken in Kampala, Uganda, between November 2018 and April 2021. METHODS: We conducted a cross-sectional study between September 2020 and January 2021 among the 639 pregnant women admitted to the labor ward at a government hospital. Sociodemographic, medical, obstetric, and socioeconomic data were collected. Blood samples from study participants were drawn and analyzed for the presence of CMV immunoglobulin G (IgG) and IgM using enzyme-linked immunosorbent assay-based quantitative assays. Further analysis of all IgM-positive samples was conducted using CMV IgG avidity assays. All infants had a nasal polymerase chain reaction (PCR) on the first day of life to investigate CMV positivity. Logistic regression was performed to determine the factors associated with CMV infection. RESULTS: Seroprevalence of CMV IgG among the 637 women was universal (100%), and that of CMV (IgM) was 5.8% (37/637). CMV (IgM) was associated with being low socioeconomic status (odds ratio, 3.44; 95% CI, 1.05-11.32; P = .04). Transmission risk was low, and no infant had a positive PCR for CMV at birth. CONCLUSIONS: Universally, by the time women in Kampala conceive, they will have been exposed to CMV. Women of lower socioeconomic status were more likely to have recent CMV infection than their more affluent counterparts, highlighting the need for screening guidelines in this setting.

The validity of test-negative design for assessment of typhoid conjugate vaccine protection: comparison of estimates by different study designs using data from a cluster-randomised controlled trial.

BACKGROUND: Typhoid fever remains a substantial public health challenge in low-income and middle-income countries. By 2023, typhoid conjugate vaccines (TCVs) had been introduced in six countries globally, with more than 50 million doses distributed. Now that TCVs are being deployed, there is a need for observational studies to assess vaccine effectiveness in the field. We aimed to evaluate the validity of different observational study designs in estimating vaccine protection. METHODS: We compared different observational and experimental study designs for assessing vaccine effectiveness by re-analysing data from the TyVAC Bangladesh trial, a participant-blinded and observer-blinded cluster-randomised controlled trial done in Mirpur, Dhaka, Bangladesh. 150 geographical clusters were randomly assigned (1:1) to receive either TCV or Japanese encephalitis vaccine. Eligible children aged 9 months to 15 years were offered a single dose of the vaccine randomly assigned to their cluster of residence, and baseline vaccination was done between April 15 and May 15, 2018. We compared estimates of vaccine effectiveness from the cluster-randomised controlled trial analysis-which assessed the risk of blood-culture-confirmed typhoid fever among recipients of TCV versus recipients of Japanese encephalitis vaccine-with estimates from cohort study and test-negative case-control study design (TND) analyses, which compared recipients of TCV with non-vaccinees in the 75 geographical clusters where TCV was administered. We further conducted negative-control exposure (NCE) and negative-control outcome (NCO) analyses as bias indicators. FINDINGS: 41 344 (67%) of 62 025 age-eligible children in the study area received the TCV or Japanese encephalitis vaccine during the baseline vaccination campaign. Among the 62 025 age-eligible children, 5582 blood-culture specimens were collected by passive surveillance, including 2546 (46%) specimens from the 75 TCV clusters. The estimated vaccine efficacy was 89% (95% CI 81-93) in the cluster-randomised controlled trial analysis, 79% (70-86) by the cohort design, 88% (79-93) by the TND when pan-negatives were used as test-negative controls, and 90% (75-96) by the TND when specimens positive for pathogens other than Salmonella enterica serotype Typhi were used as test-negative controls. Using NCE analysis, Japanese encephalitis vaccination was associated with an increased risk of typhoid fever compared with non-vaccinees in the 75 Japanese encephalitis clusters in the cohort design (incidence rate ratio 1·98 [95% CI 1·56-2·52]), but no significant association between Japanese encephalitis vaccination and typhoid fever was found with the TND. Similarly, an increased risk of non-typhoid infections was observed in the cohort NCO analyses when comparing vaccinees with non-vaccinees in both Japanese encephalitis vaccine clusters and TCV clusters, but not in the TND NCO analyses. INTERPRETATION: Our findings suggests that the TND provides reliable estimates of TCV effectiveness, whereas the cohort design can bias vaccine effectiveness estimates, possibly due to unmeasured confounding effects, such as health-care-seeking behaviours. NCE and NCO approaches are useful tools for identifying such biases. FUNDING: The Bill & Melinda Gates Foundation.

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.

The TyphiNET data visualisation dashboard: unlocking Salmonella Typhi genomics data to support public health.

BACKGROUND: Salmonella enterica subspecies enterica serovar Typhi (abbreviated as 'Typhi') is the bacterial agent of typhoid fever. Effective antimicrobial therapy reduces complications and mortality; however, antimicrobial resistance (AMR) is a major problem in many endemic countries. Prevention through vaccination is possible through recently-licensed typhoid conjugate vaccines (TCVs). National immunisation programs are currently being considered or deployed in several countries where AMR prevalence is known to be high, and the Gavi vaccine alliance has provided financial support for their introduction. Pathogen whole genome sequence data are a rich source of information on Typhi variants (genotypes or lineages), AMR prevalence, and mechanisms. However, this information is currently not readily accessible to non-genomics experts, including those driving vaccine implementation or empirical therapy guidance. RESULTS: We developed TyphiNET ( https://www.typhi.net ), an interactive online dashboard for exploring Typhi genotype and AMR distributions derived from publicly available pathogen genome sequences. TyphiNET allows users to explore country-level summaries such as the frequency of pathogen lineages, temporal trends in resistance to clinically relevant antimicrobials, and the specific variants and mechanisms underlying emergent AMR trends. User-driven plots and session reports can be downloaded for ease of sharing. Importantly, TyphiNET is populated by high-quality genome data curated by the Global Typhoid Pathogen Genomics Consortium, analysed using the Pathogenwatch platform, and identified as coming from non-targeted sampling frames that are suitable for estimating AMR prevalence amongst Typhi infections (no personal data is included in the platform). As of February 2024, data from a total of n = 11,836 genomes from 101 countries are available in TyphiNET. We outline case studies illustrating how the dashboard can be used to explore these data and gain insights of relevance to both researchers and public health policy-makers. CONCLUSIONS: The TyphiNET dashboard provides an interactive platform for accessing genome-derived data on pathogen variant frequencies to inform typhoid control and intervention strategies. The platform is extensible in terms of both data and features, and provides a model for making complex bacterial genome-derived data accessible to a wide audience.

Continuous Indexing of Fibrosis (CIF): improving the assessment and classification of MPN patients.

The grading of fibrosis in myeloproliferative neoplasms (MPN) is an important component of disease classification, prognostication and monitoring. However, current fibrosis grading systems are only semi-quantitative and fail to fully capture sample heterogeneity. To improve the quantitation of reticulin fibrosis, we developed a machine learning approach using bone marrow trephine (BMT) samples (n = 107) from patients diagnosed with MPN or a reactive marrow. The resulting Continuous Indexing of Fibrosis (CIF) enhances the detection and monitoring of fibrosis within BMTs, and aids MPN subtyping. When combined with megakaryocyte feature analysis, CIF discriminates between the frequently challenging differential diagnosis of essential thrombocythemia (ET) and pre-fibrotic myelofibrosis with high predictive accuracy [area under the curve = 0.94]. CIF also shows promise in the identification of MPN patients at risk of disease progression; analysis of samples from 35 patients diagnosed with ET and enrolled in the Primary Thrombocythemia-1 trial identified features predictive of post-ET myelofibrosis (area under the curve = 0.77). In addition to these clinical applications, automated analysis of fibrosis has clear potential to further refine disease classification boundaries and inform future studies of the micro-environmental factors driving disease initiation and progression in MPN and other stem cell disorders.

Apnoea suppresses brain activity in infants

Apnoea—the cessation of breathing—is commonly observed in premature infants. These events can reduce cerebral oxygenation and are associated with poorer neurodevelopmental outcomes. However, relatively little is known about how apnoea and shorter pauses in breathing impact brain function in infants, which will provide greater mechanistic understanding of how apnoea affects brain development. We analysed simultaneous recordings of respiration, electroencephalography (EEG), heart rate, and peripheral oxygen saturation in 124 recordings from 118 infants (post-menstrual age: 38.6 ± 2.7 weeks [mean ± standard deviation]) during apnoeas (pauses in breathing greater than 15 seconds) and shorter breathing pauses between 5 and 15 seconds. EEG amplitude significantly decreased during both apnoeas and short breathing pauses compared with normal breathing periods. Change in EEG amplitude was significantly associated with change in heart rate during apnoea and short breathing pauses and, during apnoeas only, with oxygen saturation change. No associations were found between EEG amplitude changes and apnoea/pause duration, post-menstrual age, or sleep state. As apnoeas often occur in premature infants, frequent disruption to brain activity may impact neural development and result in long-term neurodevelopmental consequences.

Hot, swollen or stiff joints in children and young people: British Society for Rheumatology guideline scope.

The objective of this guideline is to provide up-to-date, evidence-based recommendations for the management of children and young people (CYP) who present with one or more hot, swollen or stiff joints. It will incorporate assessment, diagnosis, monitoring, non-pharmacological and initial pharmacological management preceding definitive diagnosis. This is the first British Society for Rheumatology guideline for hot, swollen or stiff joints in CYP <18 years of age and will complement the hot, swollen joint guideline created for adults ≥18 years of age. The guideline will be developed using the methods and rigorous processes outlined in Creating Clinical Guidelines: British Society for Rheumatology Protocol version 5.4.