Potential asthma risk factors do not account for global asthma symptom prevalence patterns and time trends in children and adolescents.

Background: The International Study of Asthma and Allergies in Childhood (ISAAC) and the Global Asthma Network (GAN) conducted a series of global asthma prevalence surveys, between 1990 and 2020, in adolescents aged 13-14 and children aged 6-7 years. We used them to assess whether potential asthma risk factors explain global asthma symptom prevalence trends over this period. Method: We fitted mixed-effects linear regression models to estimate associations between centre-level risk factor prevalence and both the mid-point asthma symptom prevalence and the change per decade. We also estimated the 2019 asthma symptom prevalence across all included centres. Results: For adolescents, across 50 centres in 26 countries there was weak evidence that decreasing asthma prevalence over time was associated with regular fast-food consumption and frequent television viewing. However, frequent television viewing, along with heavy truck traffic, were associated with higher prevalence of asthma symptoms at the study mid-point. For children, across 41 centres in 21 countries, no risk factors were associated with time trends in asthma symptom prevalence, but truck traffic and paracetamol in the first year of life were associated with higher mid-point prevalence.We estimated the 2019 asthma symptom prevalence, across a total of 124 centres, to be 12.8% (11.4%, 14.2%) with little evidence of a difference by age. Low-income countries had lower prevalence (children 5.2% [2.5%, 7.8%], adolescents 5.3% [2.8%, 7.8%]), than lower-middle-, upper-middle- and high-income countries (all approximately 14-15%). Including risk factors in the models did not change the estimates. Conclusion: Potential asthma risk factors do not seem to explain the global prevalence patterns or time trends. Country income accounts for some of the differences, but the unexplained variation is very high.

Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes.

BACKGROUND: Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank. RESULTS: Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation. CONCLUSION: We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single "optimal" pubertal growth pattern.

Time course from cochlear implant surgery to non-use for congenitally deaf recipients implanted as children over ten years ago.

Objective: To determine the time-course from first cochlear implantation to non-use, to characterise non-users' receptive and expressive communication, and document known risk factors for inconsistent use, for congenitally deaf non-users of cochlear implants implanted as children at least ten years ago. Methods: Retrospective service evaluation. All congenitally deaf patients who received a first cochlear implant as children at least ten years ago at a regional service, and were currently non-users, were identified. They were characterised in terms of ages at implantation and non-use, known risk factors for inconsistent CI use or CI non-use, and outcome measures were the Meaningful Auditory Integration Scale (MAIS) and Meaningful Use of Speech Scale (MUSS) scores. Results: Seventeen patients met the inclusion criteria. They were implanted from 1990 to 2006. Median age at implantation was 4 years (range: 2-11), median age at non-use was 17 years (range: 9-31), and median duration of use was 8.5 years (range: 4-25). All used sign or gesture as their primary expressive and receptive communication modes. In addition, each child had at least one other known risk factor for inconsistent CI use. At 3 years post-implantation, mean Parent-rated MAIS scores were 76.5% (N = 14), and mean MUSS scores were 43.1% (N = 9). Discussion: This cohort included cases where CI use was rejected following longer periods of time than previously reported, highlighting a need for long-term support, particularly around the ages of life transitions. Studies conducted when the earliest cohort of paediatric CI users were younger, and studies reliant on parent or patient reports, may under-estimate long-term non-use rates. No non-users were identified among congenitally-deaf children implanted 10-15 years ago. Further research is warranted to explore relationships between risk factors, including communication mode, and non-use to inform expectation setting and candidacy selection.

PTEN deficiency exposes a requirement for an ARF GTPase module for integrin-dependent invasion in ovarian cancer.

Dysregulation of the PI3K/AKT pathway is a common occurrence in high-grade serous ovarian carcinoma (HGSOC), with the loss of the tumour suppressor PTEN in HGSOC being associated with poor prognosis. The cellular mechanisms of how PTEN loss contributes to HGSOC are largely unknown. We here utilise time-lapse imaging of HGSOC spheroids coupled to a machine learning approach to classify the phenotype of PTEN loss. PTEN deficiency induces PI(3,4,5)P3 -rich and -dependent membrane protrusions into the extracellular matrix (ECM), resulting in a collective invasion phenotype. We identify the small GTPase ARF6 as a crucial vulnerability of HGSOC cells upon PTEN loss. Through a functional proteomic CRISPR screen of ARF6 interactors, we identify the ARF GTPase-activating protein (GAP) AGAP1 and the ECM receptor ß1-integrin (ITGB1) as key ARF6 interactors in HGSOC regulating PTEN loss-associated invasion. ARF6 functions to promote invasion by controlling the recycling of internalised, active ß1-integrin to maintain invasive activity into the ECM. The expression of the CYTH2-ARF6-AGAP1 complex in HGSOC patients is inversely associated with outcome, allowing the identification of patient groups with improved versus poor outcome. ARF6 may represent a therapeutic vulnerability in PTEN-depleted HGSOC.

Management of the infected arterial pseudoaneurysm secondary to groin injecting drug use and outcomes: a systematic review protocol.

INTRODUCTION: People who inject drugs are at risk of a range of injecting-related infections and injuries, which can threaten life and limb. In parallel to escalating rates of drug-related deaths seen in Scotland and the UK, there has also been an increase in hospital admissions for skin and soft tissue infections related to injecting drug use. One such injecting complication is the infected arterial pseudoaneurysm, which risks rupture and life-threatening haemorrhage. Surgical management options for the infected arterial pseudoaneurysm secondary to groin injecting drug use remain contentious, with some advocates for ligation and debridement alone, whilst others promote acute arterial reconstruction (suture or patch repair, bypass or, more recently, endovascular stent-graft placement). Rates of major lower limb amputations related to surgical management for this pathology vary in the literature. This review aims to evaluate the outcomes of arterial ligation alone compared with arterial reconstruction, including open and endovascular options, for the infected arterial pseudoaneurysm secondary to groin injecting drug use. METHODS AND ANALYSIS: The methods will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Three electronic databases will be searched and the resultant papers screened according to the study inclusion and exclusion criteria (detailed in the Population, Intervention, Comparison, Outcomes and Study design statement). Grey literature will be excluded. All papers at each stage will be screened by two independent authors, with disagreements arbitrated by a third. Papers will be subject to appropriate standardised quality assessments. PRIMARY OUTCOME: Major lower limb amputation. SECONDARY OUTCOMES: Reintervention rate, rebleeding rate, development of chronic limb-threatening ischaemia 30-day mortality and claudication. ETHICS AND DISSEMINATION: This is a systematic review based on previously conducted studies, therefore, no ethical approval is required. The results of this work will be published in a peer-reviewed journal and presented at relevant conferences. PROSPERO REGISTRATION NUMBER: CRD42022358209.

Spatial regulation of the glycocalyx component podocalyxin is a switch for prometastatic function.

The glycocalyx component and sialomucin podocalyxin (PODXL) is required for normal tissue development by promoting apical membranes to form between cells, triggering lumen formation. Elevated PODXL expression is also associated with metastasis and poor clinical outcome in multiple tumor types. How PODXL presents this duality in effect remains unknown. We identify an unexpected function of PODXL as a decoy receptor for galectin-3 (GAL3), whereby the PODXL-GAL3 interaction releases GAL3 repression of integrin-based invasion. Differential cortical targeting of PODXL, regulated by ubiquitination, is the molecular mechanism controlling alternate fates. Both PODXL high and low surface levels occur in parallel subpopulations within cancer cells. Orthotopic intraprostatic xenograft of PODXL-manipulated cells or those with different surface levels of PODXL define that this axis controls metastasis in vivo. Clinically, interplay between PODXL-GAL3 stratifies prostate cancer patients with poor outcome. Our studies define the molecular mechanisms and context in which PODXL promotes invasion and metastasis.

GWAS on retinal vasculometry phenotypes.

The eye is the window through which light is transmitted and visual sensory signalling originates. It is also a window through which elements of the cardiovascular and nervous systems can be directly inspected, using ophthalmoscopy or retinal imaging. Measurements of ocular parameters may therefore offer important information on the physiology and homeostasis of these two important systems. Here we report the results of a genetic characterisation of retinal vasculature. Four genome-wide association studies performed on different aspects of retinal vasculometry phenotypes, such as arteriolar and venular tortuosity and width, found significant similarities between retinal vascular characteristics and cardiometabolic health. Our analyses identified 119 different regions of association with traits of retinal vasculature, including 89 loci associated arteriolar tortuosity, the strongest of which was rs35131825 (p = 2.00×10-108), 2 loci with arteriolar width (rs12969347, p = 3.30×10-09 and rs5442, p = 1.9E-15), 17 other loci associated with venular tortuosity and 11 novel associations with venular width. Our causal inference analyses also found that factors linked to arteriolar tortuosity cause elevated diastolic blood pressure and not vice versa.

Asthma management and control in children, adolescents, and adults in 25 countries: a Global Asthma Network Phase I cross-sectional study.

BACKGROUND: Asthma is one of the most common non-communicable diseases globally. This study aimed to assess asthma medicine use, management plan availability, and disease control in childhood, adolescence, and adulthood across different country settings. METHODS: We used data from the Global Asthma Network Phase I cross-sectional epidemiological study (2015-20). A validated, written questionnaire was distributed via schools to three age groups (children, 6-7 years; adolescents, 13-14 years; and adults, ≥19 years). Eligible adults were the parents or guardians of children and adolescents included in the surveys. In individuals with asthma diagnosed by a doctor, we collated responses on past-year asthma medicines use (type of inhaled or oral medicine, and frequency of use). Questions on asthma symptoms and health visits were used to define past-year symptom severity and extent of asthma control. Income categories for countries based on gross national income per capita followed the 2020 World Bank classification. Proportions (and 95% CI clustered by centre) were used to describe results. Generalised structural equation multilevel models were used to assess factors associated with receiving medicines and having poorly controlled asthma in each age group. FINDINGS: Overall, 453 473 individuals from 63 centres in 25 countries were included, comprising 101 777 children (6445 [6·3%] with asthma diagnosed by a doctor), 157 784 adolescents (12 532 [7·9%]), and 193 912 adults (6677 [3·4%]). Use of asthma medicines varied by symptom severity and country income category. The most used medicines in the previous year were inhaled short-acting ß2 agonists (SABA; range across age groups, 29·3-85·3% participants) and inhaled corticosteroids (12·6-51·9%). The proportion of individuals with severe asthma symptoms not taking inhaled corticosteroids (inhaled corticosteroids alone or with long-acting ß2 agonists) was high in all age groups (934 [44·8%] of 2085 children, 2011 [60·1%] of 3345 adolescents, and 1142 [55·5%] of 2058 adults), and was significantly higher in middle-to-low-income countries. Oral SABA and theophylline were used across age groups and country income categories, contrary to current guidelines. Asthma management plans were used by 4049 (62·8%) children, 6694 (53·4%) adolescents, and 3168 (47·4%) adults; and 2840 (44·1%) children, 6942 (55·4%) adolescents, and 4081 (61·1%) adults had well controlled asthma. Independently of country income and asthma severity, having an asthma management plan was significantly associated with the use of any type of inhaled medicine (adjusted odds ratio [OR] 2·75 [95% CI 2·40-3·15] for children; 2·45 [2·25-2·67] for adolescents; and 2·75 [2·38-3·16] for adults) or any type of oral medicine (1·86 [1·63-2·12] for children; 1·53 [1·40-1·68] for adolescents; and 1·78 [1·55-2·04] for adults). Poor asthma control was associated with low country income (lower-middle-income and low-income countries vs high-income countries, adjusted OR 2·33 [95% CI 1·32-4·14] for children; 3·46 [1·83-6·54] for adolescents; and 4·86 [2·55-9·26] for adults). INTERPRETATION: Asthma management and control is frequently inadequate, particularly in low-resource settings. Strategies should be implemented to improve adherence to asthma treatment guidelines worldwide, with emphasis on access to affordable and quality-assured essential asthma medicines especially in low-income and middle-income countries. FUNDING: International Union Against Tuberculosis and Lung Disease, Boehringer Ingelheim New Zealand, AstraZeneca, UK National Institute for Health Research, UK Medical Research Council, European Research Council, the Spanish Instituto de Salud Carlos III. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

The hygiene hypothesis for allergy - conception and evolution.

In 1989, a short paper entitled "Hay fever, hygiene and household size" observed that British children from larger families were less likely to develop hay fever and suggested that this could be because early exposure to infection prevents allergy. This sibship size association for hay fever, since replicated many times in Britain and other affluent countries and confirmed by objective measures of atopy, prompted what has come to be known as the "hygiene hypothesis for allergy", although that term was not specifically used in the 1989 paper. The present paper reviews the historical roots of the "hygiene hypothesis" and charts its development over more than 30 years. Initial scepticism among immunologists turned to enthusiasm in the mid-1990s as the Th1/Th2 paradigm for allergic sensitisation emerged from animal experiments and the concept of "immunological old friends" became popular from the early 2000s. From the late 1990s, observations of reduced allergy risk among children of anthroposophic families and those brought up on farms suggested that the sibship size effects formed part of a broader range of "hygiene-related" determinants of allergy. Children from large families with farming exposure have approximately sixfold reduction in prevalence of hay fever, indicating the potential strength and epidemiological importance of these environmental determinants. During the 21st century, a wide range of specific microbial, environmental and lifestyle factors have been investigated as possible underlying mechanisms, but sadly none have emerged as robust explanations for the family size and farming effects. Thus, while the "hygiene hypothesis" led to a fundamental reappraisal of our relationship with our microbial environment and to the concept that early exposure, rather than avoidance, is beneficial for developing a healthy immune system, the underlying mechanism for variations in allergy prevalence with family size remains, in Churchillian terms, "a riddle wrapped in a mystery inside an enigma".

Artificial intelligence-enabled retinal vasculometry for prediction of circulatory mortality, myocardial infarction and stroke.

AIMS: We examine whether inclusion of artificial intelligence (AI)-enabled retinal vasculometry (RV) improves existing risk algorithms for incident stroke, myocardial infarction (MI) and circulatory mortality. METHODS: AI-enabled retinal vessel image analysis processed images from 88 052 UK Biobank (UKB) participants (aged 40-69 years at image capture) and 7411 European Prospective Investigation into Cancer (EPIC)-Norfolk participants (aged 48-92). Retinal arteriolar and venular width, tortuosity and area were extracted. Prediction models were developed in UKB using multivariable Cox proportional hazards regression for circulatory mortality, incident stroke and MI, and externally validated in EPIC-Norfolk. Model performance was assessed using optimism adjusted calibration, C-statistics and R2 statistics. Performance of Framingham risk scores (FRS) for incident stroke and incident MI, with addition of RV to FRS, were compared with a simpler model based on RV, age, smoking status and medical history (antihypertensive/cholesterol lowering medication, diabetes, prevalent stroke/MI). RESULTS: UKB prognostic models were developed on 65 144 participants (mean age 56.8; median follow-up 7.7 years) and validated in 5862 EPIC-Norfolk participants (67.6, 9.1 years, respectively). Prediction models for circulatory mortality in men and women had optimism adjusted C-statistics and R2 statistics between 0.75-0.77 and 0.33-0.44, respectively. For incident stroke and MI, addition of RV to FRS did not improve model performance in either cohort. However, the simpler RV model performed equally or better than FRS. CONCLUSION: RV offers an alternative predictive biomarker to traditional risk-scores for vascular health, without the need for blood sampling or blood pressure measurement. Further work is needed to examine RV in population screening to triage individuals at high-risk.

Traject3d allows label-free identification of distinct co-occurring phenotypes within 3D culture by live imaging.

Single cell profiling by genetic, proteomic and imaging methods has expanded the ability to identify programmes regulating distinct cell states. The 3-dimensional (3D) culture of cells or tissue fragments provides a system to study how such states contribute to multicellular morphogenesis. Whether cells plated into 3D cultures give rise to a singular phenotype or whether multiple biologically distinct phenotypes arise in parallel is largely unknown due to a lack of tools to detect such heterogeneity. Here we develop Traject3d (Trajectory identification in 3D), a method for identifying heterogeneous states in 3D culture and how these give rise to distinct phenotypes over time, from label-free multi-day time-lapse imaging. We use this to characterise the temporal landscape of morphological states of cancer cell lines, varying in metastatic potential and drug resistance, and use this information to identify drug combinations that inhibit such heterogeneity. Traject3d is therefore an important companion to other single-cell technologies by facilitating real-time identification via live imaging of how distinct states can lead to alternate phenotypes that occur in parallel in 3D culture.

Retinal microvascular associations with cardiometabolic risk factors differ by diabetes status: results from the UK Biobank.

AIMS/HYPOTHESIS: The aim of the study was to examine the association of retinal vessel morphometry with BP, body composition and biochemistry, and to determine whether these associations differ by diabetes status. METHODS: The UK Biobank ocular assessment included 68,550 participants aged 40-70 years who underwent non-mydriatic retinal photography, BP and body composition measurements, and haematological analysis. A fully automated image analysis program provided measurements of retinal vessel diameter and tortuosity. The associations between retinal vessel morphology and cardiometabolic risk factors by diabetes status were examined using multilevel linear regression, to provide absolute differences in vessel diameter and percentage differences in tortuosity (allowing for within-person clustering). RESULTS: A total of 50,233 participants (a reduction from 68,550) were included in these analyses. Overall, those with diabetes had significantly more tortuous venules and wider arteriolar diameters compared with those without. Associations between venular tortuosity and cardiometabolic risk factors differed according to diabetes status (p interaction <0.01) for total fat mass index, HbA1c, C-reactive protein, white cell count and granulocyte count. For example, a unit rise in white cell count was associated with a 0.18% increase (95% CI 0.05, 0.32%) in venular tortuosity for those without diabetes and a 1.48% increase (95% CI 0.90, 2.07%) among those with diabetes. For arteriolar diameter, significant interactions were evident for systolic BP, diastolic BP, mean arterial pressure (MAP) and LDL-cholesterol. For example, a 10 mmHg rise in systolic BP was associated with a -0.92 µm difference (95% CI -0.96 to -0.88 µm) in arteriolar diameter for those without diabetes, and a -0.58 µm difference (95% CI -0.76 to -0.41 µm) among those with diabetes. No interactions were observed for arteriolar tortuosity or venular diameters. CONCLUSIONS/INTERPRETATION: We provide clear evidence of the modifying effect of diabetes on cardiometabolic risk factor associations with retinal microvascular architecture. These observations suggest the occurrence of preclinical disease processes, and may be a sign of impaired autoregulation due to hyperglycaemia, which has been suggested to play a pivotal role in the development of diabetes-related microvascular complications. DATA AVAILABILITY: The data supporting the results reported here are available through the UK Biobank ( https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access ).

The burden of asthma, hay fever and eczema in adults in 17 countries: GAN Phase I study.

AIMS: Asthma, hay fever and eczema are three common chronic conditions. There have been no recent multi-country data on the burden of these three conditions in adults; the aims of this study are to fill this evidence gap. METHODS: The Global Asthma Network Phase I is a multi-country cross-sectional population-based study using the same core methodology as the International Study of Asthma and Allergies in Childhood Phase III. It provides data on the burden of asthma, hay fever and eczema in children and adolescents, and, for the first time, in their parents/guardians. RESULTS: Data were available from 193 912 adults (104 061 female; mean±sd age 38±7.5 years) in 43 centres in 17 countries. The overall prevalence (range) of symptoms was 6.6% (0.9-32.7%) for current wheeze, 4.4% (0.9-29.0%) for asthma ever, 14.4% (2.8-45.7%) for hay fever ever and 9.9% (1.6-29.5%) for eczema ever. Centre prevalence varied considerably both between countries and within countries. There was a moderate correlation between hay fever ever and asthma ever, and between eczema ever and hay fever ever at the centre level. There were moderate to strong correlations between indicators of the burden of disease reported in adults and the two younger age groups. CONCLUSION: We found evidence for a substantial burden of asthma, hay fever ever and eczema ever in the countries examined, highlighting the major public health importance of these diseases. Prevention strategies and equitable access to effective and affordable treatments for these three conditions would help mitigate the avoidable morbidity they cause.

The burden of asthma, hay fever and eczema in children in 25 countries: GAN Phase I study.

AIMS: There have been no worldwide standardised surveys of prevalence and severity of asthma, rhinoconjunctivitis and eczema in school children for 15 years. The present study aims to provide this information. METHODS: Following the exact International Study of Asthma and Allergies in Childhood (ISAAC) methodology (cross-sectional questionnaire-based survey), Global Asthma Network (GAN) Phase I was carried out between 2015 and 2020 in many centres worldwide. RESULTS: The study included 157 784 adolescents (13-14 years of age) in 63 centres in 25 countries and 101 777 children (6-7 years of age) in 44 centres in 16 countries. The current prevalence of symptoms, respectively, was 11.0% and 9.1% for asthma, 13.3% and 7.7% for rhinoconjunctivitis and 6.4% and 5.9% for eczema. The prevalence of asthma ever was 10.5% and 7.6%, hay fever ever was 15.2% and 11.1% and eczema ever was 10.6% and 13.4%, respectively. Centres in low or lower middle gross national income countries (LICs or LMICs) had significantly lower prevalence of the three disease symptoms and diagnoses (except for hay fever). In children, the prevalence of asthma and rhinoconjunctivitis symptoms was higher in boys, while the reverse occurred among adolescents. For eczema, while the prevalence among female adolescents was double that of males, there was no sex difference among children. Centre accounted for non-negligible variability in all disease symptoms (10-20%). CONCLUSION: The burdens of asthma, rhinoconjunctivitis and eczema vary widely among the limited number of countries studied. Although symptom prevalence is lower in LICs and LMICs, it represents a considerable burden everywhere studied.