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Purpose: Unloading of the diaphragm via mechanical ventilation for more than 5 days leads to weaning difficulties. Mechanical ventilation can induce production of inflammatory cytokines and extracellular matrix proteins. The mechanisms regulating interactions between mechanical ventilation and diaphragmatic injury are unclear. We hypothesized that high tidal volume mechanical stretch augmented diaphragmatic injury via serine/threonine kinase/protein kinase B (Akt) and c-Jun NH(2)-terminal kinase (JNK) pathways.Methods: Male C57BL/6, either wild type or Akt deficient, weighing between 20 and 25 g, were exposed to high tidal volume (30 ml/kg) or low tidal volume (6 ml/kg) mechanical ventilation with room air for 2-8 h.Results: High tidal volume mechanical ventilation induced Akt, JNK, and class O of forkhead box transcription factor 4 (Foxo4) activation in a time-dependent manner. Disruption and atrophy of muscle fibers in the diaphragm, positive staining of phospho-Akt in the myofiber membrane, and increased production of free radicals were also found. Mechanical ventilation of Akt-deficient mice resulted in attenuated diaphragmatic injury, Akt, JNK, and Foxo4 activation, and free radical production.Conclusions: Our data suggest that high tidal volume mechanical ventilation produces diaphragmatic muscle damage and free radical production through activation of the Akt and JNK pathways. [ABSTRACT FROM AUTHOR]

Rationale: Asthma is often work-related and can be classified as atopic or nonatopic on the basis of its pathogenesis. Few studies have reported an association between exposure to occupational asthmogens and asthma with and without atopy. Objectives: We investigated, in adults with asthma, whether occupational exposure to asthmogens influenced the risk of having atopic or nonatopic asthma, and their level of lung function. Methods: We recruited 504 hospital-based adults with current asthma, 504 community-based control subjects, and 504 hospital-based control subjects in southern Taiwan. Asthma with atopy was defined as having asthma in combination with an increase in total IgE (>=100 U/ml) or a positive Phadiatop test (>=0.35 Pharmacia arbitrary unit/L) (Pharmacia ImmunoCAP; Pharmacia, Uppsala, Sweden). Occupational exposure to asthmogens was assessed with an asthma-specific job exposure matrix. Measurements and Main Results: We found a significant association between atopic asthma and exposure to high molecular weight asthmogens (adjusted odds ratio [AOR], 4.0; 95% confidence interval [CI], 1.8-8.9). Nonatopic asthma was significantly associated with exposure to low molecular weight asthmogens (AOR, 2.6; 95% CI, 1.6-4.3), including industrial cleaning agents and metal sensitizers. Agriculture was associated with both atopic and nonatopic asthma (AOR, 7.8; 95% CI, 2.8-21.8; and AOR, 4.1; 95% CI, 1.3-13.0, respectively). The ratio of FEV(1) to FVC in the high-risk group was significantly lower than in the no-risk group (P = 0.026) in currently employed patients with asthma. Conclusions: In adults with asthma, occupational exposure to high and low molecular weight asthmogens appears to produce differential risks for atopic and nonatopic asthma. [ABSTRACT FROM AUTHOR]

The integrity of the cement-bone interface is vital to the long-term stability of cemented hip arthroplasty. Most of the previous studies investigating the interface have been confined to the continuum level, neglecting the effects of microstructure. Microscopic damage at the interface may eventually lead to macroscopic loosening of the implant. However, as the strength of the interface depends on the interlock of the cement with bone and because the properties of cancellous bone depend on its microstructure, the study of the behaviour of the interface at the microstructural level may help to gain an understanding of the factors governing initiation of loosening. In this study, two complementary non-destructive methods, acoustic emission (AE) and computed tomography (CT), have been implemented to study the initiation and progression of damage of an analogue cement-bone interface sample under four-point bending. Early failure was detected, localized, and characterized using AE. CT images of the sample before and after loading were used to visualize damage in three dimensions. Damage initiated at the interface and was found to be related to stress-raising microstructural features in the cement. These were caused by irregularities in the geometry of the bone analogue and recesses and notches formed by the flow of cement. [ABSTRACT FROM AUTHOR]

OBJECTIVES: We examined the effect of New York's HIV Reporting and Partner Notification law on HIV testing levels and on the HIV testing decisions of high-risk individuals. METHODS: In-person interviews were administered to 761 high-risk individuals to assess their knowledge, attitudes, and behaviors regarding HIV testing and reporting. Trends in HIV testing were also assessed in publicly funded HIV counseling and testing programs, Medicaid, and New York's Maternal Pediatric Newborn Prevention and Care Program. RESULTS: High-risk individuals had limited awareness of the reporting and notification law, and few cited concern about named reporting as a reason for avoiding or delaying HIV testing. HIV testing levels, posttest counseling rates, and anonymous-to-confidential conversion rates among those who tested HIV positive were not affected by the law. Medicaid-related HIV testing rates also remained stable. HIV testing during pregnancy continued to trend upward following implementation of the law. Findings held true within demographic and risk-related subgroups. CONCLUSIONS: HIV reporting has permitted improved monitoring of New York's HIV/AIDS epidemic. This benefit has not been offset by decreases in HIV testing behavior, including willingness to test among those at high risk of acquiring HIV. [ABSTRACT FROM AUTHOR]

Tetrahedral finite element meshes with smooth surfaces can be created from computed tomography scans of cancellous bone in order to evaluate its mechanical properties. Image processing before creation of the mesh can affect the accuracy of determined mechanical properties. For a cancellous bone analogue, threshold, mesh density and surface smoothing parameters used in mesh generation were varied and the mechanical properties predicted by the resulting meshes were compared to experimental results. This study has shown that threshold selection is vital for accurate determination of volume fraction and resulting mechanical properties. [ABSTRACT FROM AUTHOR]

Describes the identification of 18 cased of primary brain lymphoma (PBL) during a 16-year period among HIV negative patients in Queen Mary Hospital, Hong Kong. Presence of Epstein Barr virus in one case of post-transplantation lymphoproliferative disease; Incidence rate of PBL in immunocompetent patients.

Background Although many literatures demonstrated heavy rainfall was associated with an increased risk of acute gastroenteritis via contaminated food and water, we hypothesized there is no association between rainfall and paediatric acute gastroenteritis in a setting with high-standard food and water hygiene. Methods Intestinal infection-related hospital admissions data during 1998-2018 for children under 5 years of age in Hong Kong were collected. Meteorological data were collected from the Hong Kong Observatory. A distributed lag nonlinear model was employed to examine the associations between meteorological factors and the risk of hospital admissions due to acute gastroenteritis. Results Rainfall did not exhibit a statistically significant association with the risk of paediatric admission due to acute gastroenteritis but low temperature, low and high relative humidity did. The risk was 6.3% higher (95% confidence interval: 0.3% to 12.6%) when temperature was at 15.1oC (i.e. the 5th percentile). The adjusted relative risk was statistically significantly higher when relative humidity was ≤73.0% or ≥ 84.0%. Conclusions Text: We suggest rainfall playing a minor role in disease transmission via contaminated food and water in affluent societies like Hong Kong. Instead, we speculate low temperature and humidity extremes have greater impact on transmission through increased stability and infectivity of enteric viruses. Key messages Weather plays a minor role in food and water contamination in affluent societies. Low temperature and humidity extremes might improve survival of enteric viruses. [ABSTRACT FROM AUTHOR]

Background: Gastric intestinal metaplasia (IM) is a precancerous stage spanning a morphological spectrum that is poorly represented by human cell line models., Objective: We aim to establish and characterise human IM cell models to better understand IM progression along the cancer spectrum., Design: A large human gastric IM organoid (IMO) cohort (n=28), their clonal derivatives and normal gastric organoids (n=42) for comparison were established. Comprehensive multi-omics profiling and functional characterisation were performed., Results: Single-cell transcriptomes revealed IMO cells spanning a spectrum from hybrid gastric/intestinal to advanced intestinal differentiation. Their lineage trajectories connected different cycling and quiescent stem and progenitors, highlighting differences in gastric to IM transition and the potential origin of IM from STMN1 cycling isthmus stem cells. Hybrid IMOs showed impaired differentiation potential, high lineage plasticity beyond gastric or intestinal fates and reactivation of a fetal gene programme.Cell populations in gastric IM and cancer tissues were highly similar to those derived from IMOs and exhibited a fetal signature. Genomically, IMOs showed elevated mutation burden, frequent chromosome 20 gain and epigenetic deregulation of many intestinal and gastric genes. Functionally, IMOs were FGF10 independent and showed downregulated FGFR2. Several IMOs exhibited a cell-matrix adhesion independent subpopulation that displayed chromosome 20 gain but lacked key cancer driver mutations, potentially representing the earliest neoplastic precursor of IM-induced gastric cancer., Conclusions: Overall, our IMO biobank captured the heterogeneous nature of IM, revealing mechanistic insights on IM pathogenesis and progression, offering an ideal platform for studying early gastric neoplastic transformation and chemoprevention., Competing Interests: Competing interests: SYL and STY have received research sponsorships from Pfizer, Merck, Servier. HC is an inventor on multiple patents related to organoid technology and one patent on a Matrigel replacement. He is also currently head of Roche’s R&D in Basel, as a member of the executive board. His full disclosures can be found on the following website: www.uu.nl/staff/JCClevers/Additional functions. The other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Uterine leiomyosarcoma (LMS) is an aggressive sarcoma and a subset of which exhibits DNA repair defects. Polo-like kinase 4 (PLK4) precisely modulates mitosis, and its inhibition causes chromosome missegregation and increased DNA damage. We hypothesize that PLK4 inhibition is an effective LMS treatment., Experimental Design: Genomic profiling of clinical uterine LMS samples was performed, and homologous recombination (HR) deficiency scores were calculated. A PLK4 inhibitor (CFI-400945) with and without an ataxia telangiectasia mutated (ATM) inhibitor (AZD0156) was tested in vitro on gynecologic sarcoma cell lines SK-UT-1, SKN, and SK-LMS-1. Findings were validated in vivo using the SK-UT-1 xenograft model in the Balb/c nude mouse model. The effects of CFI-400945 were also evaluated in a BRCA2-knockout SK-UT-1 cell line. The mechanisms of DNA repair were analyzed using a DNA damage reporter assay., Results: Uterine LMS had a high HR deficiency score, overexpressed PLK4 mRNA, and displayed mutations in genes responsible for DNA repair. CFI-400945 demonstrated effective antitumor activity in vitro and in vivo. The addition of AZD0156 resulted in drug synergism, largely due to a preference for nonhomologous end-joining DNA repair. Compared with wild-type cells, BRCA2 knockouts were more sensitive to PLK4 inhibition when both HR and nonhomologous end-joining repairs were impaired., Conclusions: Uterine LMS with DNA repair defects is sensitive to PLK4 inhibition because of the effects of chromosome missegregation and increased DNA damage. Loss-of-function BRCA2 alterations or pharmacologic inhibition of ATM enhanced the efficacy of the PLK4 inhibitor. Genomic profiling of an advanced-stage or recurrent uterine LMS may guide therapy., (©2024 The Authors; Published by the American Association for Cancer Research.)

Somatic copy number alterations (CNAs) are major mutations that contribute to the development and progression of various cancers. Despite a few computational methods proposed to detect CNAs from single-cell transcriptomic data, the technical sparsity of such data makes it challenging to identify allele-specific CNAs, particularly in complex clonal structures. In this study, we present a statistical method, XClone, that strengthens the signals of read depth and allelic imbalance by effective smoothing on cell neighborhood and gene coordinate graphs to detect haplotype-aware CNAs from scRNA-seq data. By applying XClone to multiple datasets with challenging compositions, we demonstrated its ability to robustly detect different types of allele-specific CNAs and potentially indicate whole genome duplication, therefore enabling the discovery of corresponding subclones and the dissection of their phenotypic impacts., (© 2024. The Author(s).)

Compared with analyzing omics data from a single platform, an integrative analysis of multi-omics data provides a more comprehensive understanding of the regulatory relationships among biological features associated with complex diseases. However, most existing frameworks for integrative analysis overlook two crucial aspects of multi-omics data. Firstly, they neglect the known dependencies among biological features that exist in highly credible biological databases. Secondly, most existing integrative frameworks just simply remove the subjects without full omics data to handle block missingness, resulting in decreasing statistical power. To overcome these issues, we propose a network-based integrative Bayesian framework for biomarker selection and disease outcome prediction based on multi-omics data. Our framework utilizes Dirac spike-and-slab variable selection prior to identifying a small subset of biomarkers. The incorporation of gene pathway information improves the interpretability of feature selection. Furthermore, with the strategy in the FBM (stand for "full Bayesian model with missingness") model where missing omics data are augmented via a mechanistic model, our framework handles block missingness in multi-omics data via a data augmentation approach. The real application illustrates that our approach, which incorporates existing gene pathway information and includes subjects without DNA methylation data, results in more interpretable feature selection results and more accurate predictions., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Many ethnic minorities in Hong Kong seek medical tourism after encountering inequalities in access to local healthcare because of language barriers and cultural-religious differences. The present study explored the ethnic minorities' lived experiences of medical tourism and issues arising from cross-border health-seeking relevant to this specific population., Methods: Qualitative in-depth interviews with 25 ethnic minority informants from five South Asian countries in 2019., Results: The 19 informants out of the 25 have sought assistance from their international networks for home remedies, medical advice and treatments of traditional/Western medicines, for they are more costly or unavailable in Hong Kong and for issues related to racial discrimination, language barriers, transnationalism engagement, cultural insensitivity, and dissatisfaction with healthcare services in Hong Kong., Discussion: Medical tourism can relieve the host country's caring responsibilities from healthcare services, so the government might no longer be hard-pressed to fix the failing healthcare system. Consequently, it could cause public health concerns, such as having patients bear the risks of exposure to new pathogens, the extra cost from postoperative complications, gaps in medical documentation and continuum of care, etc. It also triggers global inequities in health care, exacerbating unequal distribution of resources among the affordable and non-affordable groups., Conclusion: Ethnic minorities in Hong Kong sought cross-border healthcare because of structural and cultural-religious issues. The surge of medical tourism from rich and developed countries to poor and developing countries may infringe upon the rights of residents in destination countries. To mitigate such negative impacts, policymakers of host countries should improve hospital infrastructure, as well as train and recruit more culturally sensitive healthcare workers to promote universal health coverage. Healthcare professionals should also strive to enhance their cultural competence to foster effective intercultural communication for ethnic minority groups., (© 2024. The Author(s).)

Background: DEHP, a common plasticizer known for its hormone-disrupting properties, has been associated with asthma. However, a significant proportion of adult asthma cases are "non-atopic", lacking a clear etiology., Methods: In a case-control study conducted between 2011 and 2015, 365 individuals with current asthma and 235 healthy controls from Kaohsiung City were enrolled. The control group comprised individuals without asthma, Type 2 Diabetes Mellitus (T2DM), hypertension, or other respiratory/allergic conditions. The study leveraged asthma clusters (Clusters A to F) established in a prior investigation. Analysis involved the examination of urinary DEHP metabolites (MEHP and MEHHP), along with the assessment of oxidative stress, sphingolipid metabolites, and inflammatory biomarkers. Statistical analyses encompassed Spearman's rank correlation coefficients, multiple logistic regression, and multinomial logistic regression., Results: Asthma clusters (E, D, C, F, A) exhibited significantly higher ORs of MEHHP exposures compared to the control group. When considering asthma-related comorbidities (T2DM, hypertension, or both), patients without comorbidities demonstrated significantly higher ORs of the sum of primary and secondary metabolites (MEHP + MEHHP) and MEHHP compared to those with asthma comorbidities. A consistent positive correlation between urinary HEL and DEHP metabolites was observed, but a consistent negative correlation between DEHP metabolites and selected cytokines was identified., Conclusion: The current study reveals a heightened risk of MEHHP and MEHP + MEHHP exposure in specific asthma subgroups, emphasizing its complex relationship with asthma. The observed negative correlation with cytokines suggests a new avenue for research, warranting robust evidence from epidemiological and animal studies., (© 2024. The Author(s).)

Inflammatory bowel disease alters the gut microbiota, causes defects in mucosal barrier function, and leads to dysregulation of the immune response to microbial stimulation. This study investigated and compared the efficacy of a candidate probiotic strain, Bacillus coagulans BC198, and its heat-killed form in treating dextran sulfate sodium-induced colitis. Both live and heat-killed B. coagulans BC198 increased gut barrier-associated protein expression, reduced neutrophil and M1 macrophage infiltration of colon tissue, and corrected gut microbial dysbiosis induced by colitis. However, only live B. coagulans BC198 could alleviate the general symptoms of colitis, prevent colon shortening, and suppress inflammation and tissue damage. At the molecular level, live B. coagulans BC198 was able to inhibit Th17 cells while promoting Treg cells in mice with colitis, reduce pro-inflammatory MCP-1 production, and increase anti-inflammatory IL-10 expression in the colonic mucosa. The live form of B. coagulans BC198 functioned more effectively than the heat-killed form in ameliorating colitis by enhancing the anti-inflammatory response and promoting Treg cell accumulation in the colon., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

The three-dimensional (3D) tumor microenvironment (TME) comprises multiple interacting cell types that critically impact tumor pathology and therapeutic response. Efficient 3D imaging assays and analysis tools could facilitate profiling and quantifying distinctive cell-cell interaction dynamics in the TMEs of a wide spectrum of human cancers. Here, we developed a 3D live-cell imaging assay using confocal microscopy of patient-derived tumor organoids and a software tool, SiQ-3D (single-cell image quantifier for 3D), that optimizes deep learning (DL)-based 3D image segmentation, single-cell phenotype classification, and tracking to automatically acquire multidimensional dynamic data for different interacting cell types in the TME. An organoid model of tumor cells interacting with natural killer cells was used to demonstrate the effectiveness of the 3D imaging assay to reveal immuno-oncology dynamics as well as the accuracy and efficiency of SiQ-3D to extract quantitative data from large 3D image datasets. SiQ-3D is Python-based, publicly available, and customizable to analyze data from both in vitro and in vivo 3D imaging. The DL-based 3D imaging analysis pipeline can be employed to study not only tumor interaction dynamics with diverse cell types in the TME but also various cell-cell interactions involved in other tissue/organ physiology and pathology., Significance: A 3D single-cell imaging pipeline that quantifies cancer cell interaction dynamics with other TME cell types using primary patient-derived samples can elucidate how cell-cell interactions impact tumor behavior and treatment responses., (©2023 American Association for Cancer Research.)

Cholinergic nerves are involved in tumor progression and dissemination. In contrast to other visceral tissues, cholinergic innervation in the hepatic parenchyma is poorly detected. It remains unclear whether there is any form of cholinergic regulation of liver cancer. Here, we show that cholinergic T cells curtail the development of liver cancer by supporting antitumor immune responses. In a mouse multihit model of hepatocellular carcinoma (HCC), we observed activation of the adaptive immune response and induction of two populations of CD4 + T cells expressing choline acetyltransferase (ChAT), including regulatory T cells and dysfunctional PD-1 + T cells. Tumor antigens drove the clonal expansion of these cholinergic T cells in HCC. Genetic ablation of Chat in T cells led to an increased prevalence of preneoplastic cells and exacerbated liver cancer due to compromised antitumor immunity. Mechanistically, the cholinergic activity intrinsic in T cells constrained Ca 2+ -NFAT signaling induced by T cell antigen receptor engagement. Without this cholinergic modulation, hyperactivated CD25 + T regulatory cells and dysregulated PD-1 + T cells impaired HCC immunosurveillance. Our results unveil a previously unappreciated role for cholinergic T cells in liver cancer immunobiology., (© 2023. The Author(s).)

Organoids derived from adult stem cells (ASCs) and pluripotent stem cells (PSCs) are important preclinical models for studying cancer and developing therapies. Here, we review primary tissue-derived and PSC-derived cancer organoid models and detail how they have the potential to inform personalized medical approaches in different organ contexts and contribute to the understanding of early carcinogenic steps, cancer genomes, and biology. We also compare the differences between ASC- and PSC-based cancer organoid systems, discuss their limitations, and highlight recent improvements to organoid culture approaches that have helped to make them an even better representation of human tumors., Competing Interests: Declaration of interests S.Y.L. has received research sponsorships from Pfizer, Merck, and Servier. S.Y.L. is an advisory board member of Cell Stem Cell., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Sex differences in the pathogenesis of hypertension exist. While gut microbiota (GM) has been associated with hypertension, it is unclear whether there are sex-linked differences in the association between GM and hypertension., Methods: We conducted a cross-sectional study to investigate the sex differences in associations between GM characterized by shotgun sequencing, GM-derived short-chain fatty acids, and 24-hour ambulatory blood pressure in 241 Hong Kong Chinese (113 men and 128 women; mean age, 54±6 years)., Results: The hypertensive group was associated with GM alterations; however, significant differences in β-diversity and GM composition in hypertensive versus normotensive groups were only observed in women and not in men under various statistical models adjusting for the following covariates: age, sex, body mass index, sodium intake estimated by spot urine analysis, blood glucose, triglycerides, low- and high-density lipoprotein cholesterol, smoking, menopause, and fatty liver status. Specifically, Ruminococcus gnavus , Clostridium bolteae , and Bacteroides ovatus were significantly more abundant in the hypertensive women, whereas Dorea formicigenerans was more abundant in the normotensive women. No bacterial species were found to be significantly associated with hypertension in men. Furthermore, total plasma short-chain fatty acids and propionic acid were independent predictors of systolic and diastolic blood pressure in women but not men., Conclusions: GM dysregulation was strongly associated with 24-hour ambulatory blood pressure in women but not men, which may be mediated through propionic acid. Our work suggests that sex differences may be an important consideration while assessing the role of GM in the development and treatment of hypertension., Competing Interests: Disclosures K.K. Lau received grants from Research Fund Secretariat of the Food and Health Bureau, Innovation and Technology Bureau, Research Grants Council, Amgen, Boehringer Ingelheim, Eisai, and Pfizer and consultation fees from Amgen, Boehringer Ingelheim, Daiichi Sankyo, and Sanofi, all outside the submitted work. S.Y. Leung has received research sponsorship from Pfizer, Merck, Servier, and Curegenix. S.K. Chung received a faculty research grant (FRG-22-024-FMD) and Dr Neher’s Biophysics Laboratory for Innovative Drug Discovery from the Macao Science and Technology Development Fund (FDCT project code: 001/2020/ALC), all outside of the submitted work. The other authors report no conflicts.

Targetable drivers governing 5-fluorouracil and cisplatin (5FU + CDDP) resistance remain elusive due to the paucity of physiologically and therapeutically relevant models. Here, we establish 5FU + CDDP resistant intestinal subtype GC patient-derived organoid lines. JAK/STAT signaling and its downstream, adenosine deaminases acting on RNA 1 (ADAR1), are shown to be concomitantly upregulated in the resistant lines. ADAR1 confers chemoresistance and self-renewal in an RNA editing-dependent manner. WES coupled with RNA-seq identify enrichment of hyper-edited lipid metabolism genes in the resistant lines. Mechanistically, ADAR1-mediated A-to-I editing on 3'UTR of stearoyl-CoA desaturase (SCD1) increases binding of KH domain-containing, RNA-binding, signal transduction-associated 1 (KHDRBS1), thereby augmenting SCD1 mRNA stability. Consequently, SCD1 facilitates lipid droplet formation to alleviate chemotherapy-induced ER stress and enhances self-renewal through increasing β-catenin expression. Pharmacological inhibition of SCD1 abrogates chemoresistance and tumor-initiating cell frequency. Clinically, high proteomic level of ADAR1 and SCD1, or high SCD1 editing/ADAR1 mRNA signature score predicts a worse prognosis. Together, we unveil a potential target to circumvent chemoresistance., (© 2023. The Author(s).)

Background: While coronavirus 2019 (COVID-19) deaths were generally underestimated in many countries, Hong Kong may show a different trend of excess mortality due to stringent measures, especially for deaths related to respiratory diseases. Nevertheless, the Omicron outbreak in Hong Kong evolved into a territory-wide transmission, similar to other settings such as Singapore, South Korea, and recently, mainland China. We hypothesized that the excess mortality would differ substantially before and after the Omicron outbreak., Methods: We conducted a time-series analysis of daily deaths stratified by age, reported causes, and epidemic wave. We determined the excess mortality from the difference between observed and expected mortality from 23 January 2020 to 1 June 2022 by fitting mortality data from 2013 to 2019., Results: During the early phase of the pandemic, the estimated excess mortality was -19.92 (95% confidence interval (CI) = -29.09, -10.75) and -115.57 (95% CI = -161.34, -69.79) per 100 000 population overall and for the elderly, respectively. However, the overall excess mortality rate was 234.08 (95% CI = 224.66, 243.50) per 100 000 population overall and as high as 928.09 (95% CI = 885.14, 971.04) per 100 000 population for the elderly during the Omicron epidemic. We generally observed negative excess mortality rates of non-COVID-19 respiratory diseases before and after the Omicron outbreak. In contrast, increases in excess mortality were generally reported in non-respiratory diseases after the Omicron outbreak., Conclusions: Our results highlighted the averted mortality before 2022 among the elderly and patients with non-COVID-19 respiratory diseases, due to indirect benefits from stringent non-pharmaceutical interventions. The high excess mortality during the Omicron epidemic demonstrated a significant impact from the surge of COVID-19 infections in a SARS-CoV-2 infection-naive population, particularly evident in the elderly group., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests., (Copyright © 2023 by the Journal of Global Health. All rights reserved.)

Transient gut microbiota alterations have been reported after antibiotic therapy for Helicobacter pylori. However, alteration in the gut virome after H. pylori eradication remains uncertain. Here, we apply metagenomic sequencing to fecal samples of 44 H. pylori-infected patients at baseline, 6-week (N = 44), and 6-month (N = 33) after treatment. Following H. pylori eradication, we discover contraction of the gut virome diversity, separation of virome community with increased community difference, and shifting towards a higher proportion of core virus. While the gut microbiota is altered at 6-week and restored at 6-month, the virome community shows contraction till 6-month after the treatment with enhanced phage-bacteria interactions at 6-week. Multiple courses of antibiotic treatments further lead to lower virus community diversity when compared with treatment naive patients. Our results demonstrate that H. pylori eradication therapies not only result in transient alteration in gut microbiota but also significantly alter the previously less known gut virome community., (© 2023. The Author(s).)

Investigations of simple and accurate meteorology classification systems for influenza epidemics, particularly in subtropical regions, are limited. To assist in preparing for potential upsurges in the demand on healthcare facilities during influenza seasons, our study aims to develop a set of meteorologically-favorable zones for epidemics of influenza A and B, defined as the intervals of meteorological variables with prediction performance optimized. We collected weekly detection rates of laboratory-confirmed influenza cases from four local major hospitals in Hong Kong between 2004 and 2019. Meteorological and air quality records for hospitals were collected from their closest monitoring stations. We employed classification and regression trees to identify zones that optimize the prediction performance of meteorological data in influenza epidemics, defined as a weekly rate > 50 th percentile over a year. According to the results, a combination of temperature > 25.1℃ and relative humidity > 79% was favorable to epidemics in hot seasons, whereas either temperature < 16.4℃ or a combination of < 20.4℃ and relative humidity > 76% was favorable to epidemics in cold seasons. The area under the receiver operating characteristic curve (AUC) in model training achieved 0.80 (95% confidence interval [CI], 0.76-0.83) and was kept at 0.71 (95%CI, 0.65-0.77) in validation. The meteorologically-favorable zones for predicting influenza A or A and B epidemics together were similar, but the AUC for predicting influenza B epidemics was comparatively lower. In conclusion, we established meteorologically-favorable zones for influenza A and B epidemics with a satisfactory prediction performance, even though the influenza seasonality in this subtropical setting was weak and type-specific., (© 2023. The Author(s) under exclusive licence to International Society of Biometeorology.)

Aim: To investigate the determinants of exercise capacity in postcardiac rehabilitation patients with coronary heart disease (CHD)., Design: A cross-sectional design was used., Methods: This study analysed the cross-sectional data from the baseline assessment of 130 CHD patients who participated in a longitudinal randomized controlled trial of music-paced physical activity intervention for CHD patients (ChiCTR-IOR-17011015) (September 2017 to February 2019). Exercise capacity was measured by using the 10-metre incremental shuttle-walk test. The amount of physical activity, exercise self-determination and exercise self-efficacy were measured by validated instruments. Participants' anthropometric parameters (body mass index, body fat mass percentage and waist circumference) were measured. Hierarchical regression analyses were used to identify the factors influencing exercise capacity., Results: The mean incremental shuttle-walk test distance was 493.00 ± 180.04 m. The factors significantly associated with exercise capacity were age (β = -.42), female (β = -.35), body mass index (β = -.25) and exercise self-efficacy (β = -.20). These factors accounted for 56.5% of the total variance of exercise capacity., (© 2022 The Authors. Nursing Open published by John Wiley & Sons Ltd.)

Hypertension (HT) continues to be a leading cause of cardiovascular death and an enormous burden on the healthcare system. Although telemedicine may provide improved blood pressure (BP) monitoring and control, it remains unclear whether it could replace face-to-face consultations in patients with optimal BP control. We hypothesized that an automatic drug refill coupled with a telemedicine system tailored to patients with optimal BP would lead to non-inferior BP control. In this pilot, multicenter, randomized control trial (RCT), participants receiving anti-HT medications were randomly assigned (1:1) to either the telemedicine or usual care group. Patients in the telemedicine group measured and transmitted their home BP readings to the clinic. The medications were refilled without consultation when optimal control (BP < 135/85 mmHg) was confirmed. The primary outcome of this trial was the feasibility of using the telemedicine app. Office and ambulatory BP readings were compared between the two groups at the study endpoint. Acceptability was assessed through interviews with the telemedicine study participants. Overall, 49 participants were recruited in 6 months and retention rate was 98%. Participants from both groups had similar BP control (daytime systolic BP: 128.2 versus 126.9 mmHg [telemedicine vs. usual care], p = 0.41) and no adverse events. Participants in the telemedicine group had fewer general outpatient clinic attendances (0.8 vs. 2, p < 0.001). Interviewees reported that the system was convenient, timesaving, cost saving, and educational. The system could be safely used. However, the results must be verified in an adequately powered RCT. Trial registration: NCT04542564., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Adult asthma is phenotypically heterogeneous with unclear aetiology. We aimed to evaluate the potential contribution of environmental exposure and its ensuing response to asthma and its heterogeneity., Methods: Environmental risk was evaluated by assessing the records of National Health Insurance Research Database (NHIRD) and residence-based air pollution (particulate matter with diameter less than 2.5 micrometers (PM 2.5 ) and PM 2.5 -bound polycyclic aromatic hydrocarbons (PAHs)), integrating biomonitoring analysis of environmental pollutants, inflammatory markers and sphingolipid metabolites in case-control populations with mass spectrometry and ELISA. Phenotypic clustering was evaluated by t-distributed stochastic neighbor embedding (t-SNE) integrating 18 clinical and demographic variables., Findings: In the NHIRD dataset, modest increase in the relative risk with time-lag effect for emergency (N=209 837) and outpatient visits (N=638 538) was observed with increasing levels of PM 2.5 and PAHs. Biomonitoring analysis revealed a panel of metals and organic pollutants, particularly metal Ni and PAH, posing a significant risk for current asthma (ORs=1.28-3.48) and its severity, correlating with the level of oxidative stress markers, notably Nε-(hexanoyl)-lysine (r=0.108-0.311, p<0.05), but not with the accumulated levels of PM 2.5 exposure. Further, levels of circulating sphingosine-1-phosphate and ceramide-1-phosphate were found to discriminate asthma (p<0.001 and p<0.05, respectively), correlating with the levels of PAH (r=0.196, p<0.01) and metal exposure (r=0.202-0.323, p<0.05), respectively, and both correlating with circulating inflammatory markers (r=0.186-0.427, p<0.01). Analysis of six phenotypic clusters and those cases with comorbid type 2 diabetes mellitus (T2DM) revealed cluster-selective environmental risks and biosignatures., Interpretation: These results suggest the potential contribution of environmental factors from multiple sources, their ensuing oxidative stress and sphingolipid remodeling to adult asthma and its phenotypic heterogeneity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Cell-cell (CC) and cell-matrix (CM) adhesions are essential for epithelial cell survival, yet dissociation-induced apoptosis is frequently circumvented in malignant cells., Design: We explored CC and CM dependence in 58 gastric cancer (GC) organoids by withdrawing either ROCK inhibitor, matrix or both to evaluate their tumorigenic potential in terms of apoptosis resistance, correlation with oncogenic driver mutations and clinical behaviour. We performed mechanistic studies to determine the role of diffuse-type GC drivers: ARHGAP fusions, RHOA and CDH1, in modulating CC (CCi) or CM (CMi) adhesion independence., Results: 97% of the tumour organoids were CMi, 66% were CCi and 52% were resistant to double withdrawal (CCi/CMi), while normal organoids were neither CMi nor CCi. Clinically, the CCi/CMi phenotype was associated with an infiltrative tumour edge and advanced tumour stage. Moreover, the CCi/CMi transcriptome signature was associated with poor patient survival when applied to three public GC datasets. CCi/CMi and CCi phenotypes were enriched in diffuse-type GC organoids, especially in those with oncogenic driver perturbation of RHO signalling via RHOA mutation or ARHGAP fusions. Inducible knockout of ARHGAP fusions in CCi/CMi tumour organoids led to resensitisation to CC/CM dissociation-induced apoptosis, upregulation of focal adhesion and tight junction genes, partial reversion to a more normal cystic phenotype and inhibited xenograft formation. Normal gastric organoids engineered with CDH1 or RHOA mutations became CMi or CCi, respectively., Conclusions: The CCi/CMi phenotype has a critical role in malignant transformation and tumour progression, offering new mechanistic information on RHO-ROCK pathway inhibition that contributes to GC pathogenicity., Competing Interests: Competing interests: SYL and STY have received research sponsorships from Pfizer, Merck, Servier. The other authors declare no competing interests., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Early commencement of rehabilitation might counteract the loss of muscle strength due to a chronic obstructive pulmonary disease acute exacerbation (COPDAE). Blood flow restriction resistance exercise (BFR-RE) using a low intensity of training load has demonstrated muscle strength gain in varieties of clinical populations. This trial aimed at studying the efficacy and acceptability of BFR-RE in patients with post-COPDAE which was not reported before., Method: A prospective, assessor blinded, randomized controlled study with 2-week in-patient rehabilitation program with BFR-RE was compared to a matched program with resistance exercise without BFR in patients with post-COPDAE. The primary outcome was the change of muscle strength of knee extensor of dominant leg. The secondary outcomes included changes of hand grip strength (HGS), 6-minute walk test (6MWT) distance, short physical performance battery (SPPB) scores, COPD assessment test (CAT) scores; acceptability and feasibility of BFR-RE; and 1-month unplanned re-admission rate., Results: Forty-Five post-COPDAE patients (mean age = 76 ± 10, mean FEV1%=49% ± 24%) were analyzed. After training, BFR-RE group and control group demonstrated a statistically significant median muscle strength gain of 20 (Interquartile range (IQR) 3 to 38) Newton(N) and 12 (IQR -9 to 30) N respectively. BFR-RE group showed a significant change in SPPB scores, but not in 6MWT distance and HGS after training. Between groups did not have statistically significant different in all primary and secondary outcomes, though with similar acceptability. Drop-out rate due to training-related discomfort in BFR-RE group was 3.7%., Conclusion: BFR-RE is feasible and acceptable in patients with post-COPDAE. A 2-week inpatient pulmonary rehabilitation with BFR-RE improved muscle strength of knee extensors, but not a greater extent than the same rehabilitation program with resistance exercise without BFR. Further studies could be considered with a longer training duration and progression of resistance load. [ClinicalTrials.gov Identifier: NCT04448236]., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: RNA therapeutics is an emerging field that widens the range of treatable targets and would improve disease outcome through bypassing the antibiotic bactericidal targets to kill Mycobacterium tuberculosis (M.tb)., Methods: We screened for microRNA with immune-regulatory functions against M.tb by next generation sequencing of peripheral blood mononuclear cells, followed by validation in an independent cohort., Results: Twenty three differentially expressed microRNAs were identified between 12 active pulmonary TB patients and 4 healthy subjects, and 35 microRNAs before and after 6-month anti-TB therapy. Enriched predicted target pathways included proteoglycan, HIF-1 signaling, longevity-regulating, central carbon metabolism, and autophagy. We validated miR-431-3p down-regulation and miR-1303 up-regulation accompanied with corresponding changes in their predicted target genes in an independent validation cohort of 46 active TB patients, 30 latent TB infection subjects, and 24 non-infected healthy subjects. In vitro experiments of transfections with miR-431-3p mimic/miR-1303 short interfering RNA in THP-1 cells under ESAT-6 stimuli showed that miR-431-3p and miR-1303 were capable to augment and suppress autophagy/apoptosis/phagocytosis of macrophage via targeting MDR1/MMP16/RIPOR2 and ATG5, respectively., Conclusions: This study provides a proof of concept for microRNA-based host-directed immunotherapy for active TB disease. The combined miR-431-3p over-expression and miR-1303 knock-down revealed new vulnerabilities of treatment-refractory TB disease., Competing Interests: Declaration of competing interest This is not an industry-sponsored study. All the authors declare that they have no potential conflicts of interest or financial support in any for-profit business agency. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Ganciclovir (GCV) is widely used in solid organ and haematopoietic stem cell transplant patients for prophylaxis and treatment of cytomegalovirus. It has long been considered a mutagen and carcinogen. However, the contribution of GCV to cancer incidence and other factors that influence its mutagenicity remains unknown., Methods: This retrospective cohort study analysed genomics data for 121,771 patients who had undergone targeted sequencing compiled by the Genomics Evidence Neoplasia Information Exchange (GENIE) or Foundation Medicine (FM). A statistical approach was developed to identify patients with GCV-associated mutational signature (GCV sig ) from targeted sequenced data of tumour samples. Cell line exposure models were further used to quantify mutation burden and DNA damage caused by GCV and other antiviral and immunosuppressive drugs., Results: Mutational profiles from 22 of 121,771 patient samples in the GENIE and FM cohorts showed evidence of GCV sig . A diverse range of cancers was represented. All patients with detailed clinical history available had previously undergone solid organ transplantation and received GCV and mycophenolate treatment. RAS hotspot mutations associated with GCV sig were present in 9 of the 22 samples, with all samples harbouring multiple GCV-associated protein-altering mutations in cancer driver genes. In vitro testing in cell lines showed that elevated DNA damage response and GCV sig are uniquely associated with GCV but not acyclovir, a structurally similar antiviral. Combination treatment of GCV with the immunosuppressant, mycophenolate mofetil (MMF), increased the misincorporation of GCV in genomic DNA and mutations attributed to GCV sig in cell lines and organoids., Conclusions: In summary, GCV can cause a diverse range of cancers. Its mutagenicity may be potentiated by other therapies, such as mycophenolate, commonly co-prescribed with GCV for post-transplant patients. Further investigation of the optimal use of these drugs could help reduce GCV-associated mutagenesis in post-transplant patients., (© 2022. The Author(s).)

Background: Many foreign studies investigated glycemic control and fall risk. However, there was insufficient study on this topic in Hong Kong. This study aims to find out the association of glycemic control and fall risk in the diabetic elderly in a general outpatient clinic in the North District of Hong Kong. Their frequency of falls and other associated risk factors of fall were also studied., Methods: A cross-sectional questionnaire survey was conducted on 442 diabetic patients aged 65 years-old or above with regular follow-up in a general outpatient clinic. Main outcome measure was the number of falls in the past one year from the interview date. Recurrent falls was defined as two or more falls in the past one year from the interview date. Subjects were asked about experience of hypoglycemic symptoms. HbA1c level, chronic illness, retinopathy etc. were obtained through computerized medical record review. Chi square test and logistic regression were used to assess the association between outcomes and the explanatory variables., Results: In the past one year, 23.3% participants experienced at least one fall and 8.6% had recurrent falls. Hypoglycemic symptoms, and lower visual acuity < 0.6 were significantly associated with fall (OR 2.42, p = 0.007 and OR 1.75, p = 0.038 respectively). Age 75-79 years-old had a higher likelihood of fall than the 65-69 age group (OR 2.23, p = 0.044). Patients with HbA1c 7.0-7.4% had a lower risk of recurrent falls when compared to those with intensive control (OR 0.32, p = 0.044). Other risk factors that increased risk of recurrent falls were hypoglycemic symptoms (OR 6.64, p < 0.001) and history of cerebral vascular accident (OR 4.24, p = 0.003)., Conclusions: Hypoglycemic symptoms had a very strong association with falls. Less stringent HbA1c control reduced the risk of recurrent falls. Healthcare professionals need to take a more proactive approach in enquiring about hypoglycemia. There should be individualized diabetic treatment target for the diabetic elderly., (© 2022. The Author(s).)

Background: Hypertension is strongly associated with cardiovascular events. Studies have shown that electrocardiographic (ECG) abnormalities were associated with increased risks for cardiovascular events. However local data is limited. The objectives of this study were: (1) to determine the prevalence of major electrocardiographic abnormalities in patients with hypertension in primary care in Hong Kong, and (2) to determine the association of major electrocardiographic abnormalities with patients' socio-economical background, cardiovascular disease and cardiovascular risk factors., Methods: This was a cross-sectional study. Subjects were hypertensive patients aged between 18 and 80 who were enrolled in the Risk Assessment and Management Programme (RAMP) in a general outpatient clinic in Hong Kong. Outcome measures were prevalence of probable ischaemic heart disease (IHD), complete left bundle branch block (LBBB), left ventricular hypertrophy (LVH) and atrial fibrillation (AF) in patients with hypertension. The Pearson Chi-square test, independent t-test and Mantel-Haenszel test were used to measure the association between socioeconomic characteristics and cardiovascular risk factors, and ECG abnormalities., Results: 504 hypertensive patients aged 18-80 were recruited in a general outpatient clinic. 6.3% had probable IHD, 0.4% had complete LBBB, 4.0% had LVH and 1.0% had AF. Probable IHD was associated with smoking (P = 0.032), hypercholesterolaemia (P = 0.037) and higher 10-year CV risk (P = 0.04). Complete LBBB was associated with smoking (P = 0.021) and hypercholesterolaemia (P = 0.022). LVH was associated with male gender (P = 0.001) and longer duration of hypertension (P = 0.035). AF was not significantly associated with any of the clinical or sociodemographic parameters., Conclusions: This study showed that a significant proportion of patients with hypertension at the primary care setting in Hong Kong had probable ischaemic heart disease, left ventricular hypertrophy and atrial fibrillation. This finding is consistent with both overseas data and historic data in Hong Kong. The detection of electrocardiographic abnormalities is helpful in hypertension management by improving risk stratification., (© 2022. The Author(s).)

Lynch Syndrome (LS) is an autosomal dominant disease conferring a high risk of colorectal cancer due to germline heterozygous mutations in a DNA mismatch repair (MMR) gene. Although cancers in LS patients show elevated somatic mutation burdens, information on mutation rates in normal tissues and understanding of the trajectory from normal to cancer cell is limited. Here we whole genome sequence 152 crypts from normal and neoplastic epithelial tissues from 10 LS patients. In normal tissues the repertoire of mutational processes and mutation rates is similar to that found in wild type individuals. A morphologically normal colonic crypt with an increased mutation burden and MMR deficiency-associated mutational signatures is identified, which may represent a very early stage of LS pathogenesis. Phylogenetic trees of tumour crypts indicate that the most recent ancestor cell of each tumour is already MMR deficient and has experienced multiple cycles of clonal evolution. This study demonstrates the genomic stability of epithelial cells with heterozygous germline MMR gene mutations and highlights important differences in the pathogenesis of LS from other colorectal cancer predisposition syndromes., (© 2022. The Author(s).)

Shotgun metagenomics has enabled the discovery of antibiotic resistance genes (ARGs). Although there have been numerous studies benchmarking the bioinformatics methods for shotgun metagenomic data analysis, there has not yet been a study that systematically evaluates the performance of different experimental protocols on metagenomic species profiling and ARG detection. In this study, we generated 35 whole genome shotgun metagenomic sequencing data sets for five samples (three human stool and two microbial standard) using seven experimental protocols (KAPA or Flex kits at 50ng, 10ng, or 5ng input amounts; XT kit at 1ng input amount). Using this comprehensive resource, we evaluated the seven protocols in terms of robust detection of ARGs and microbial abundance estimation at various sequencing depths. We found that the data generated by the seven protocols are largely similar. The inter-protocol variability is significantly smaller than the variability between samples or sequencing depths. We found that a sequencing depth of more than 30M is suitable for human stool samples. A higher input amount (50ng) is generally favorable for the KAPA and Flex kits. This systematic benchmarking study sheds light on the impact of sequencing depth, experimental protocol, and DNA input amount on ARG detection in human stool samples.