Kin Bong Hubert Lam

BackgroundThe blood eosinophil count (BEC) is a key biomarker of type-2 inflammation in established asthma and chronic obstructive pulmonary disease (COPD) with therapeutic and prognostic implications. Whether type-2 inflammation contributes to airway disease pathogenesis and is a risk factor for its development is uncertain. We investigated associations between BEC and incident asthma and COPD in individuals without pre-existing lung disease, and how long before diagnosis BEC may be associated with future disease.MethodsA prospective cohort analysis was conducted in UK Biobank using baseline BEC and spirometry. Incident cases were identified from linked primary and secondary care records using diagnostic code lists derived from published sources. Multivariable Cox regression estimated hazard ratios (HR) for asthma and COPD by BEC. Secondary analyses examined associations in participants with normal baseline spirometry, across increasing time intervals between BEC measurement and diagnosis, and in an internal validation cohort.FindingsAmong 128,404 participants followed for a median 7·9 years, 2,824 developed asthma and 1,394 developed COPD. Compared with BEC <150 cells/μL, BEC ≥300 cells/μL was associated with a two-fold higher risk of asthma (HR 2·04 [1·85–2·25]) and 56% higher risk of COPD (1·56 [1·35–1·79]) after adjustment. Associations were dose-dependent, unchanged in participants with normal baseline spirometry, and remained evident when BEC preceded diagnosis by ≥7 years. Findings were replicated in the validation cohort.InterpretationThese findings support a temporal relationship in which type-2 inflammation precedes clinically important airway disease even before spirometric abnormalities are apparent and may contribute to its pathogenesis. Funding:NDPH,Oxford,NIHR,EPSCR,ALUK

Background: Wealth-related inequalities affect cardiometabolic health worldwide, but their implications for cardiometabolic care and potentially preventable cardiovascular disease remain poorly understood. Methods: We analysed harmonised, nationally representative health examination surveys from 76 countries (109 surveys) in five WHO regions. Adults aged 18 years or older with data on age, sex, wealth, and at least one cardiometabolic outcome were eligible. Disease status was defined from measured biomarkers, self-reported diagnosis, or current medication; awareness and treatment were based on self-reported information, and control on measured biomarkers. Each indicator was expressed as the proportion of all individuals with the corresponding condition. Inequality was quantified by the wealthiest–poorest quintile difference and the slope index of inequality (SII). Predicted 10-year cardiovascular risk was estimated with Globorisk, and trial-derived relative risk reductions applied to estimate achievable absolute risk reduction. Findings: Among 315 403 participants (median age 40 years [IQR 30–52]; 185 209 [58·7%] women), inequalities widened progressively across the care cascade in all regions and were most pronounced for disease control. Pooled across regions, the SII for control increased from hypertension (0·04, 95% CI 0·02–0·06) to diabetes (0·05, 0·01–0·09) and hypercholesterolaemia (0·07, 0·04–0·09). However, regional patterns varied substantially. In the Americas, disease control consistently favoured wealthier individuals (hypertension SII 0·09, 0·01–0·18), whereas in Africa coverage was uniformly low, and the largest inequality was pro-poor, particularly for hypercholesterolaemia treatment (SII −0·38, −0·50 to −0·26). Baseline cardiovascular risk was higher among the poorest (13·6% vs 12·2%), but achievable risk reduction aligned more closely with baseline risk than with treatment coverage being greatest in Europe (3·9%) and lowest in Africa (2·5%). Across all regions, achievable risk reduction was greater in men than in women (EURO 4·6% vs 3·5%), reflecting sex-specific risk functions rather than differences in access to care. Interpretation: Populations with the largest treatment gaps are not necessarily those in which expanding treatment would prevent the greatest burden of cardiovascular disease. In settings where coverage is uniformly low, expanding the supply of care matters more than redistributing access to it. Moreover, because socioeconomic inequalities widen after diagnosis, screening alone is unlikely to reduce disparities unless accompanied by sustained access to treatment. Policy should therefore define whether its primary objective is to maximise equity or overall population health gains.

Introduction The Nepal Family Cohort study uses a life course epidemiological approach to collect comprehensive data on children’s and their parents’ environmental, behavioural and metabolic risk factors. These factors can affect the overall development of children to adulthood and the onset of specific diseases. Among the many risk factors, exposure to air pollution and lifestyle factors during childhood may impact lung development and function, leading to the early onset of respiratory diseases. The global incidence and prevalence of respiratory diseases are rapidly increasing, with the rate of increase in Nepal being the highest. Although the cohort will primarily focus on respiratory health, other health outcomes such as cardiovascular, metabolic and mental health will be assessed to provide a comprehensive overall health assessment. All other health outcomes are self-reported following doctor diagnosis. Some of these health outcomes will be quality controlled during the follow-up by measuring disease specific markers. Our cohort study will likely provide evidence of risk factors and policy recommendations. Methods and analysis Using a life-course epidemiology approach, we established a longitudinal study to address the determinants of lung health and other health outcomes from childhood to adulthood. The baseline data collection (personal data anonymised) was completed in April 2024, and 16 826 participants (9225 children and 7601 parents) from 5829 families were recruited in different geographical and climate areas (hills and plains) of Nepal. We plan to follow up all the participants every 2–3 years. Descriptive analysis will be used to report demographic characteristics and compare rural and semi-urban regions. A linear regression model will assess the association between air pollution, particularly household air pollution (HAP) exposure, and other lifestyle factors, with lung function adjusted for potential confounders. A two-stage linear regression model will help to evaluate lung development based on exposure to HAP. Ethics Ethical approval was obtained from the Nepal Health Research Council, Kathmandu, Nepal, and McMaster University, Hamilton, Canada. Permissions were obtained from two municipalities where the study sites are located. Parents provided signed informed consent and children their assent. Dissemination Findings will be disseminated through traditional academic pathways, including peer-reviewed publications and conference presentations. We will also engage the study population and local media (ie, research blogs and dissemination events) and prepare research and policy briefings for stakeholders and leaders at the local, provincial and national levels.

The reliance of outdoor exposure data in epidemiological studies on temperature entails important uncertainties from personal exposure misclassification. We analysed ~88,000 concurrent person-hours of measured personal, household (kitchen and living room), and outdoor temperatures collected in the summer (MAY-SEP 2017) and winter (NOV 2017-JAN 2018) in rural and urban China. The temperatures across microenvironments were strongly correlated (Spearman’s ρ: 0.86-0.92) in summer. In winter, personal temperature was strongly related to household temperatures (ρ: 0.74-0.79) but poorly related to outdoor temperature (ρ: 0.30). Random forest (RF) algorithm identified household and outdoor temperatures and study date as top predictors of personal temperature exposure for both seasons, and heating-related factors were important in winter. Multivariable linear regression and RF models incorporating questionnaire and device data performed satisfactorily in predicting personal exposure in both seasons (R2summer: 0.92; R2winter: 0.68-0.70). Using generalised additive mixed effect models, we found consistent U-shaped associations between measured and predicted personal temperature exposures and heart rate (lowest at ~14.5ºC), but a weak positive linear association with outdoor temperature. Personal and outdoor temperatures differ substantially in winter, but prediction models incorporating household and outdoor temperatures and questionnaire data performed satisfactorily. Exposure misclassification from using outdoor temperature may produce inappropriate epidemiological findings.

Background: Existing evidence on long-term ambient air pollution (AAP) exposure and risk of cardio-respiratory diseases in China is mainly on mortality, and based on area average concentrations from fixed-site monitors for individual exposures. Substantial uncertainty persists, therefore, about the shape and strength of the relationship when assessed using more personalised individual exposure data. We aimed to examine the relationships between AAP exposure and risk of cardio-respiratory diseases using predicted local levels of AAP. Methods: A prospective study included 50,407 participants aged 30–79 years from Suzhou, China, with concentrations of nitrogen dioxide (NO₂), sulphur dioxide (SO₂), fine (PM_2.5), and inhalable (PM₁₀) particulate matter, ozone (O₃) and carbon monoxide (CO) and incident cases of cardiovascular disease (CVD) (n = 2,563) and respiratory disease (n = 1,764) recorded during 2013–2015. Cox regression models with time-dependent covariates were used to estimate adjusted hazard ratios (HRs) for diseases associated with local-level concentrations of AAP exposure, estimated using Bayesian spatio–temporal modelling. Results: The study period of 2013–2015 included a total of 135,199 person-years of follow-up for CVD. There was a positive association of AAP, particularly SO₂ and O₃, with risk of major cardiovascular and respiratory diseases. Each 10 µg/m³ increase in SO₂ was associated with adjusted hazard ratios (HRs) of 1.07 (95% CI: 1.02, 1.12) for CVD, 1.25 (1.08, 1.44) for COPD and 1.12 (1.02, 1.23) for pneumonia. Similarly, each 10 µg/m³ increase in O₃ was associated with adjusted HR of 1.02 (1.01, 1.03) for CVD, 1.03 (1.02, 1.05) for all stroke, and 1.04 (1.02, 1.06) for pneumonia. Conclusions: Among adults in urban China, long-term exposure to ambient air pollution is associated with a higher risk of cardio-respiratory disease.

Candidate adoptive T cell therapies (ACT), such as tumor infiltrating lymphocyte (TIL) treatments, have resulted in unprecedented and durable efficacy in clinical trials. Despite this, the manufacturing requires viable tumor resection, and TIL expansion conditions have the potential to promote T cell exhaustion. Moreover, a large proportion of patients do not respond to treatment, possibly due to exhaustion or to bystander T cells that are not tumor-specific present in the product candidates. In addition, we have shown that naturally occurring pro-tumor T cell responses to tumor-specific antigens we term Inhibigens™ are generated in nearly every subject with cancer; these T cells may be inadvertently expanded in the non-specific TIL manufacturing process. In animal models, Inhibigen-specific responses drive tumor hyperprogression. To avoid these pro-tumor T cells and improve upon ACT limitations, we are developing GEN-011, a neoantigen-targeted, peripheral T cell (NPT) therapy. GEN-011 is designed to contain primarily tumor-specific T cells with broad specificity and limited exhaustion, starting from easily accessible peripheral blood. Putatively beneficial neoantigen targets and deleterious pro-tumor Inhibigen targets are identified through measurement of cytokines in the assay supernatants of an in vitro ATLAS™ screen, in which each mutation identified in a patient's tumor is screened with the patient's own peripheral CD4⁺ and CD8⁺ T cells in a recall (overnight) assay, without algorithm prioritization. Next, the patient's peripheral T cells and monocyte-derived dendritic cells are incorporated into the PLANET™ manufacturing process where they are specifically stimulated with up to 30 ATLAS-verified neoantigens, avoiding Inhibigens, in a scalable, closed system. Development and engineering runs performed at scale show that the NPTs are up to 96% tumor-specific, with responses maintained for up to 89% of the intended neoantigen targets. They are non-exhausted effector and central memory T cells that express both proliferative and tissue homing markers. In addition to being highly polyfunctional, secreting multiple combinations of IFNγ, Granzyme B, TNFα, and MIP1α in response to specific neoantigens, they are also cytolytic in vitro and express memory-progenitor stem-like cell markers. The TITAN™ clinical trial evaluating GEN-011 NPTs is ongoing (NCT04596033). TiTAN is an open-label, multi-center Phase1/2a trial evaluating safety, tolerability, T cell persistence and proliferation, and clinical efficacy. The TiTAN clinical trial is testing two dosing regimens, a repeated lower dose regimen of GEN-011 without lymphodepletion and a single high dose administration of GEN-011 NPTs after lymphodepletion. Both groups will receive interleukin-2 after GEN-011 NPT dosing. By enriching healthy, broadly-specific neoantigen-targeted T cells and avoiding Inhibigens, the GEN-011 NPTs may represent an accessible and promising ACT for treating solid tumors. Citation Format: James Perry, Pranay D. Khare, Mercay Reuter, Daniel B. DeOliveira, Manish Jain, Colleen Winstead, Hubert Lam, Thomas Davis, Ray Stapleton, Jessica B. Flechtner. GEN-011: A neoantigen-targeted peripheral blood-derived T cell therapy that has broad neoantigen specificity and high T cell purity while avoiding pro-tumor T cells [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P005.

In network theory depression is conceptualized as a complex network of individual symptoms that influence each other, and central symptoms in the network have the greatest impact on other symptoms. Clinical features of depression are largely determined by sociocultural context. No previous study examined the network structure of depressive symptoms in Hong Kong residents. The aim of this study was to characterize the depressive symptom network structure in a community adult sample in Hong Kong during the COVID-19 pandemic. A total of 11,072 participants were recruited between 24 March and 20 April 2020. Depressive symptoms were measured using the Patient Health Questionnaire-9. The network structure of depressive symptoms was characterized, and indices of “strength”, “betweenness”, and “closeness” were used to identify symptoms central to the network. Network stability was examined using a case-dropping bootstrap procedure. Guilt, Sad Mood, and Energy symptoms had the highest centrality values. In contrast, Concentration, Suicide, and Sleep had lower centrality values. There were no significant differences in network global strength (p = 0.259), distribution of edge weights (p = 0.73) and individual edge weights (all p values > 0.05 after Holm–Bonferroni corrections) between males and females. Guilt, Sad Mood, and Energy symptoms were central in the depressive symptom network. These central symptoms may be targets for focused treatments and future psychological and neurobiological research to gain novel insight into depression.

Background: Over 3.5 billion individuals worldwide are exposed to household air pollution from solid fuel use. There is limited evidence from cohort studies on associations of solid fuel use with risks of major eye diseases, which cause substantial disease and economic burden globally. Methods and findings: The China Kadoorie Biobank recruited 512,715 adults aged 30 to 79 years from 10 areas across China during 2004 to 2008. Cooking frequency and primary fuel types in the 3 most recent residences were assessed by a questionnaire. During median (IQR) 10.1 (9.2 to 11.1) years of follow-up, electronic linkages to national health insurance databases identified 4,877 incident conjunctiva disorders, 13,408 cataracts, 1,583 disorders of sclera, cornea, iris, and ciliary body (DSCIC), and 1,534 cases of glaucoma. Logistic regression yielded odds ratios (ORs) for each disease associated with long-term use of solid fuels (i.e., coal or wood) compared to clean fuels (i.e., gas or electricity) for cooking, with adjustment for age at baseline, birth cohort, sex, study area, education, occupation, alcohol intake, smoking, environmental tobacco smoke, cookstove ventilation, heating fuel exposure, body mass index, prevalent diabetes, self-reported general health, and length of recall period. After excluding participants with missing or unreliable exposure data, 486,532 participants (mean baseline age 52.0 [SD 10.7] years; 59.1% women) were analysed. Overall, 71% of participants cooked regularly throughout the recall period, of whom 48% used solid fuels consistently. Compared with clean fuel users, solid fuel users had adjusted ORs of 1.32 (1.07 to 1.37, p < 0.001) for conjunctiva disorders, 1.17 (1.08 to 1.26, p < 0.001) for cataracts, 1.35 (1.10 to 1.66, p = 0.0046) for DSCIC, and 0.95 (0.76 to 1.18, p = 0.62) for glaucoma. Switching from solid to clean fuels was associated with smaller elevated risks (over long-term clean fuel users) than nonswitching, with adjusted ORs of 1.21 (1.07 to 1.37, p < 0.001), 1.05 (0.98 to 1.12, p = 0.17), and 1.21 (0.97 to 1.50, p = 0.088) for conjunctiva disorders, cataracts, and DSCIC, respectively. The adjusted ORs for the eye diseases were broadly similar in solid fuel users regardless of ventilation status. The main limitations of this study include the lack of baseline eye disease assessment, the use of self-reported cooking frequency and fuel types for exposure assessment, the risk of bias from delayed diagnosis (particularly for cataracts), and potential residual confounding from unmeasured factors (e.g., sunlight exposure). Conclusions: Among Chinese adults, long-term solid fuel use for cooking was associated with higher risks of not only conjunctiva disorders but also cataracts and other more severe eye diseases. Switching to clean fuels appeared to mitigate the risks, underscoring the global health importance of promoting universal access to clean fuels.

Background: Associations between adiposity and atrial fibrillation (AF) might differ between sexes. We aimed to determine precise estimates of the risk of AF by body mass index (BMI) and waist circumference (WC) in men and women. Methods and Results: Between 2008 and 2013, over 3.2 million adults attended commercial screening clinics. Participants completed health questionnaires and underwent physical examination along with cardiovascular investigations, including an ECG. We excluded those with cardiovascular and cardiac disease. We used multivariable logistic regression and determined joint associations of BMI and WC and the risk of AF in men and women by comparing likelihood ratio χ ² statistics. Among 2.1 million included participants 12 067 (0.6%) had AF. A positive association between BMI per 5 kg/m ² increment and AF was observed, with an odds ratio of 1.65 (95% CI, 1.57–1.73) for men and 1.36 (95% CI, 1.30–1.42) for women among those with a BMI above 20 kg/m ² . We found a positive association between AF and WC per 10 cm increment, with an odds ratio of 1.47 (95% CI, 1.36–1.60) for men and 1.37 (95% CI, 1.26–1.49) for women. Improvement of likelihood ratio χ ² was equal after adding BMI and WC to models with all participants. In men, WC showed stronger improvement of likelihood ratio χ ² than BMI (30% versus 23%). In women, BMI showed stronger improvement of likelihood ratio χ ² than WC (23% versus 12%). Conclusions: We found a positive association between BMI (above 20 kg/m2) and AF and between WC and AF in both men and women. BMI seems a more informative measure about risk of AF in women and WC seems more informative in men.