Associations of comorbid depression with cardiovascular-renal events and all-cause mortality accounting for patient reported outcomes in individuals with type 2 diabetes: a 6-year prospective analysis of the Hong Kong Diabetes Register.

Background: Psychosocial status and patient reported outcomes (PRO) [depression and health-related quality-of-life (HRQoL)] are major health determinants. We investigated the association between depression and clinical outcomes in Chinese patients with type 2 diabetes (T2D), adjusted for PRO. Methods: Using prospective data from Hong Kong Diabetes Register (2013-2019), we estimated the hazard-ratio (HR, 95%CI) of depression (validated Patient Health Questionnaire 9 (PHQ-9) score≥7) with incident cardiovascular disease (CVD), ischemic heart disease (IHD), chronic kidney disease (CKD: eGFR<60 ml/min/1.73m2) and all-cause mortality in 4525 Chinese patients with T2D adjusted for patient characteristics, renal function, medications, self-care and HRQoL domains (mobility, self-care, usual activities, pain/discomfort, anxiety/depression measured by EQ-5D-3L) in linear-regression models. Results: In this cohort without prior events [mean ± SD age:55.7 ± 10.6, 43.7% women, median (IQR) disease duration of 7.0 (2.0-13.0) years, HbA1c, 7.2% (6.6%-8.20%), 26.4% insulin-treated], 537(11.9%) patients had depressive symptoms and 1923 (42.5%) patients had some problems with HRQoL at baseline. After 5.6(IQR: 4.4-6.2) years, 141 patients (3.1%) died, 533(11.8%) developed CKD and 164(3.6%) developed CVD. In a fully-adjusted model (model 4) including self-care and HRQoL, the aHR of depression was 1.99 (95% confidence interval CI):1.25-3.18) for CVD, 2.29 (1.25-4.21) for IHD. Depression was associated with all-cause mortality in models 1-3 adjusted for demographics, clinical characteristics and self-care, but was attenuated after adjusting for HRQoL (model 4- 1.54; 95%CI: 0.91-2.60), though HR still indicated same direction with important magnitude. Patients who reported having regular exercise (3-4 times per week) had reduced aHR of CKD [0.61 (0.41-0.89)]. Item 4 of PHQ-9 (feeling tired, little energy) was independently associated with all-cause mortality with aHR of 1.66 (1.30-2.12). Conclusion: Depression exhibits significant association with CVD, IHD, and all-cause mortality in patients with diabetes, adjusting for their HRQoL and health behaviors. Despite the association between depression and all-cause mortality attenuated after adjusting for HRQoL, the effect size remains substantial. The feeling of tiredness or having little energy, as assessed by item Q4 of the PHQ-9 questionnaire, was found to be significantly associated with an increased risk of all-cause mortality after covariate adjustments. Our findings emphasize the importance of incorporating psychiatric evaluations into holistic diabetes management.

Natural history of infants with vitamin D deficiency in Hong Kong.

BACKGROUND AND OBJECTIVES: The usual recommended intake of vitamin D for healthy infants is 400 international unit (IU) daily. However, a high dose of vitamin D at 2000-3000 IU daily is needed for those with vitamin D deficiency (VDD). This study aimed to assess the natural history of a group of healthy infants with VDD and the associated factors for persistent VDD. METHODS AND STUDY DESIGN: Healthy infants detected to have VDD (25OHD <25 nmol/L) in a population study were followed, and their demographics and clinical data were collected. RESULTS: One hundred and thirty-one subjects (boys = 66%) were included. Their first serum 25OHD was taken at a median age of 87.5 days. None were treated with high-dose vitamin D supplements, but some have been given vitamin D at 400 IU daily. They were assessed again at the median age of 252.5 days when 15 remained to have VDD and 26 were in the insufficient range (25 - 49.9nmol/L). All persistent VDD children were on exclusive breastfeeding. Exclusive breastfeeding and no vitamin D supplementation were significant risk factors for persistent vitamin D insufficiency (<50nmol/L). CONCLUSIONS: Persistent VDD is common among infants exclusively breastfeeding and those who did not receive vitamin D supplementation.

Dissociative symptoms among community health service users in Hong Kong: a longitudinal study of clinical course and consequences.

Background: Previous studies have demonstrated the high prevalence of dissociative symptoms and their association with considerable healthcare costs. However, there is a lack of studies that describe whether dissociative symptoms persist and lead to other clinical outcomes over time in the community.Objectives: This study investigated the persistence, predictors, and consequences of dissociative symptoms in the community.Methods: We analyzed longitudinal data in a sample of community health service users in Hong Kong (N = 173).Results: A relatively high proportion (63.6%) of participants with baseline dissociative symptoms continued to exhibit dissociative symptoms after approximately 9 months. Baseline non-betrayal trauma predicted subsequent dissociative symptoms (ß = .141, p = .024). Participants with baseline dissociative symptoms were more likely to have received subsequent emergency mental health services (9.1% vs 0.7%, p = .005). Baseline dissociative symptoms significantly predicted subsequent post-traumatic symptoms (ß = .165 to .191, p < .05) and difficulty in social and occupational participation (ß = -.152 to -.182, p < .05) even after controlling for baseline scores, trauma exposure, and use of professional support. The predictive role of dissociative symptoms on subsequent disturbances in self-organization symptoms and social participation difficulty remained significant after applying the Bonferroni correction.Conclusions: This is one of the very few studies showing that dissociative symptoms are persistent to a certain degree and could predict other symptoms and subsequent impairments even in community settings. Factors that affect the trajectory of dissociative symptoms should be further investigated. Regular screening for dissociative symptoms is recommended. Considering its prevalence, persistence, and clinical and social consequences, dissociation should be given greater public health attention.

Dissociative symptoms have been linked to considerable healthcare costs.The persistence and consequences of dissociation in the community had not been previously reported.This study showed that dissociative symptoms persisted to a certain degree and predicted subsequent impairments after approximately 9 months.Dissociation should be given greater public health attention.

Prevalence and sociocultural correlates of post-traumatic stress disorder and complex PTSD among Chinese community health service users in Hong Kong.

OBJECTIVES: Complex post-traumatic stress disorder (CPTSD) is a newly recognized trauma disorder in ICD-11. Little is known about the prevalence and correlates of CPTSD in primary care settings. Its cultural aspects also remained minimally explored. This study investigated the prevalence and sociocultural correlates of PTSD and complex PTSD among Chinese community health service users in Hong Kong. METHODS: This study investigated ICD-11 PTSD and CPTSD in a sample of adults (N = 376) who had recently received services from Registered Chinese Medicine Practitioners in Hong Kong. Traditional Chinese medicine service is part of primary care services in Chinese societies. Participants completed self-report measures of CPTSD, trauma exposure, perceived family support, perceived caregiver's Chinese traditionality/modernity, participation (social activities and occupational productivity), depression and pain. RESULTS: The past-month prevalence of ICD-11 PTSD and CPTSD was 5.6% and 18.4%, respectively, in our sample. Chi-square tests and one-way ANOVAs revealed that participants with CPTSD were younger and reported more trauma, lower family support, lower levels of social participation and productivity, more depressive symptoms and pain, and more social welfare and mental health service usages than those without PTSD. We found that perceived caregiver's Chinese modernity (e.g. egalitarianism) was negatively correlated with CPTSD symptoms. Apart from age, non-betrayal trauma had the strongest association with classical PTSD symptoms, while betrayal trauma and perceived family support had the strongest association with disturbances in self-organization symptoms. CONCLUSION: This study provides the first data regarding the prevalence and correlates of ICD-11 PTSD and CPTSD among community health service users in Hong Kong. PTSD and CPTSD are common but often unrecognized mental health problems which are associated with more impairments and more service needs.

Brief mindful coloring for stress reduction in nurses working in a Hong Kong hospital during COVID-19 pandemic: A randomized controlled trial.

BACKGROUND: Effective interventions to promote well-being at work are required to reduce the prevalence and consequences of stress and burnout especially during the COVID-19 pandemic. This study determined the effects of mindful coloring on perceived stress levels, mental well-being, burnout, and state and trait mindfulness levels for nurses during COVID-19. METHODS: This was a single-center, two-armed, parallel, superiority, blinded randomized controlled trial. Seventy-seven participants were randomly allocated (by computer-generated sequence) to either mindful coloring (n = 39) or waitlist control groups (n = 38). Twenty-seven nurses in the mindful coloring group and 32 in the control group were included in the full compliance per protocol analysis. The mindful coloring intervention included participants viewing a 3-minutes instructional video and coloring mandalas for at least 5 working days or 100 minutes in total during a 10-day period. Participants in both groups completed the Perceived Stress Scale (total score 0-40), short Warwick-Edinburgh Mental Well-being Scale (total score 7-35), Maslach Burnout Inventory-Human Services Survey for Medical Personnel (3 subscales), Five Facets Mindfulness Questionnaire-Short Form (total score 24-120) and Mindful Attention Awareness Scale-State version (total score 0-30) instruments. The primary outcome was the perceived stress level. RESULTS: Baseline prevalence of moderate to high perceived stress level was high (79.2%). There was a large mindful coloring effect on reducing mean perceived stress levels (Mean difference [MD] in change between groups -3.0, 95% CI: -5.0 to -1.00; Cohen's d = 0.80). Mindful coloring may lead to a small improvement in mental well-being level (P = .08), with an improvement found in the intervention group (MD 0.9, 95% CI 0.0-1.8, P = .04) through enhanced state mindfulness (P < .001). There were no effects on changing burnout subscales or trait mindfulness levels. No adverse reactions were reported. CONCLUSION: Coloring mandalas may be an effective low-cost brief intervention to reduce perceived stress levels through enhancing state mindfulness and it may promote mental well-being. Hospitals may promote or provide mindful coloring as a self-care and stress-relief practice for nurses during their off hours or work breaks.

Mental Health, Support System, and Perceived Usefulness of Support in University Students in Hong Kong Amidst COVID-19 Pandemic: A Mixed-Method Survey.

BACKGROUND: This study explored the association of students' mental health with their support system, identified the preferred ways and sources of support, investigated the perceived usefulness of available university support, and recommended actionable strategies to enhance students' mental health. METHOD: An online questionnaire survey and semi-structured focus group interviews were conducted in 2021. RESULTS: Among 1121 university students, 39.4% reported anxiety symptoms, which were less common in Chinese students and those pursuing medical and health programmes. Overall, 32.6% reported depression symptoms, which were more common in undergraduates. Both anxiety and depression symptoms were less common in students with higher resilience and support system and more common in students with family distress. Students with higher resilience had a better support system and less family distress. Perceived support from universities was lower than from peers and families. Peer support and phone contacts were the most preferred sources and ways of support. The most useful available university support was updated university guidelines, and the least useful was the emotional hotline service from universities The qualitative findings corroborated the quantitative results. CONCLUSION: We suggested that a holistic care approach and more proactive student-oriented university support would help students face adversity and enhance mental health.

Prevalence of Serious Pathology Among Adults with Low Back Pain Presenting for Chiropractic Care: A Retrospective Chart Review of Integrated Clinics in Hong Kong.

BACKGROUND There is a limited understanding of the frequency at which chiropractors encounter patients with serious pathology such as malignancy, fracture, and infection. This retrospective study aimed to estimate the prevalence and types of serious pathology among adults with new low back pain presenting to chiropractors in an integrated healthcare organization in Hong Kong, with the hypothesis that such pathology would be found in less than 5% of patients. MATERIAL AND METHODS We identified adults presenting to a chiropractor with new low back pain across 30 clinics with 38 chiropractors, and a subset with previously undiagnosed serious pathology from January 2020 through July 2022. Data were extracted from the electronic medical records, including messaging alerts for serious pathology, notes, radiology reports, and specialist follow-up. Descriptive statistics were utilized to analyze results. RESULTS Among the 7221 identified patients with new-onset low back pain (mean age 61.6±14.3), 35 presented with serious pathology. After excluding 54 cases not meeting inclusion criteria, the prevalence of serious pathology (95% CI) was 35/7221 (0.48%; 0.35-0.67%). Individual condition prevalence included metastasis (0.25%; 0.16-0.39%), fracture (0.12%; 0.07-0.24%), infection (0.04%; 0.01-0.12%), vascular pathology (0.03%; 0.01-0.10%), primary tumor (0.03%; 0.01-0.10%), and gastrointestinal emergency (0.01%; 0.00-0.08%). CONCLUSIONS This study found that serious pathology was uncommon among adults with new low back pain presenting for chiropractic care in Hong Kong, findings which are most consistent with previous research describing the prevalence of serious pathology among low back pain patients in primary care settings.

Effects of a group-based lifestyle medicine for depression: A pilot randomized controlled trial.

Given the growing evidence that a range of lifestyle factors are involved in the etiology of depression, a 'lifestyle medicine' approach can be potentially safe and cost-effective to prevent or treat depression. To examine the effects and acceptability of a group-based, integrative lifestyle medicine intervention as a standalone treatment for managing depressive symptoms, a pilot randomized controlled trial (RCT) was conducted in a Chinese adult population in 2018. Participants (n = 31) with PHQ-9 score above the cut-off of ≥ 10, which was indicative of moderate to severe depression, were recruited from the general community in Hong Kong and randomly assigned to lifestyle medicine group (LM group) or care-as-usual group (CAU group) in a ratio of 1:1. Participants in the LM group received 2-hour group sessions once per week for six consecutive weeks, which covered diet, exercise, mindfulness, psychoeducation, and sleep management. Linear mixed-effects model analyses showed that the LM group had a significant reduction in PHQ-9 scores compared to the CAU group at immediate posttreatment and 12-week posttreatment follow-up (d = 0.69 and 0.73, respectively). Moreover, there were significantly greater improvements in anxiety, stress, and insomnia symptoms (measured by DASS-21 and ISI) at all time points in the LM group (d = 0.42-1.16). The results suggests that our 6-week group-based, integrative lifestyle intervention program is effective in lowering depressive, anxiety, stress, and insomnia symptoms in the Chinese population. Further studies in clinical populations with a larger sample size and longer follow-up are warranted.

A public survey of traditional, complementary and integrative medicine use during the COVID-19 outbreak in Hong Kong.

BACKGROUND: During COVID-19, the public actively sought non-pharmacological and self-management approaches to prevent infection. Little is known on the use of traditional, complementary and integrative medicine (TCIM) by the public as preventive measures. This study investigated the prevalence and patterns of TCIM use during the pandemic, and identified factors associated with its use among the general population in Hong Kong. METHODS: An online cross-sectional survey was conducted from November to December 2020. The survey solicited information on the respondents' sociodemographic characteristics, risk perception of the pandemic, and use of TCIM before and during the pandemic. Logistic regression analysis was conducted to determine predictors of TCIM use. RESULTS: In total, 632 responses (completion rate = 88.1%) were analyzed. TCIM was used by 44.0% of respondents during the pandemic. The most popular forms of TCIM were vitamins or other dietary supplements (n = 160, 25.3%) and Chinese herbal medicine (n = 122, 19.3%) during the pandemic. The most frequently reported indication was strengthening the immune system, especially for vitamins or other dietary supplements (n = 142/160, 88.8%). Respondents who reported using TCIM were more likely to be female (adjusted odds ratio [aOR] = 1.82, 95% confidence interval [CI] = 1.29-2.59), had higher education attainment (aOR = 2.21, 95% CI = 1.39-3.59), and older-aged (age >55 years: aOR = 1.77, 95% CI = 1.04-3.02). Respondents who resided in districts with moderate to high number of confirmed COVID-19 cases (aOR = 1.60, 95% CI = 1.07-2.42) and had a higher level of risk perception (aOR = 1.04, 95% CI = 1.01-1.07) were also more likely to use TCIM. CONCLUSION: TCIM was used commonly in Hong Kong during the COVID-19 pandemic. While vaccination and social distancing remain the mainstay of controlling the pandemic, professional bodies should proactively consider public preferences and provide information regarding the effectiveness and safety of TCIM for COVID-19 prevention and treatment.

An Assessment of Risk Factors for Insufficient Levels of Vitamin D during Early Infancy.

Recent evidence suggests that breastfeeding may increase the risk of vitamin D deficiency in offspring. However, it is unclear whether increased risk results from breastfeeding alone, or whether it is associated together with other risk factors. This study surveyed 208 infant-mother dyads recruited by stratified random sampling in different districts of Hong Kong. Mothers were asked to complete a questionnaire on their demographics, history of risk behavior, and feeding practices. Peripheral blood samples were collected from infants to determine their vitamin D status. Among all infant participants, 70 were vitamin D insufficient or deficient. Being breastfed, being a girl, having a multiparous mother, and the use of sun cream were found to be the strongest risk factors for vitamin D insufficiency during infancy (all p < 0.05), after mutual adjustment. The cumulative risk model displayed a dose-response pattern between the number of risk factors and the risk of vitamin D insufficiency during this period. Our findings indicate the risk profile of infants with insufficient vitamin D. Guidelines and recommendations on healthy diet and lifestyle should be provided to mothers during the early stage of pregnancy to increase the likelihood of adequate levels of vitamin D in their offspring.

Treatment with direct oral anticoagulants or warfarin and the risk for incident diabetes among patients with atrial fibrillation: a population-based cohort study.

BACKGROUND: Diabetes mellitus is a common comorbidity of atrial fibrillation (AF), which can complicate the management of AF. The pharmacology of oral anticoagulants (OACs) have been implicated in pathogenesis of diabetes, but the relationship between different OACs and risk of diabetes remains unexamined. This study aimed to evaluate the risk of diabetes with use of different OACs in AF patients. METHODS: Population-based retrospective cohort study using an electronic healthcare database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with AF from 2014 through 2018 and prescribed OACs were included and followed till December 31, 2019. Inverse probability of treatment weighting based on the propensity score (PS) is used to address potential bias due to nonrandomized allocation of treatment. The risks ofdiabetes were compared between different new OAC users using propensity score-weighted cumulative incidence differences (CID). RESULTS: There were 13,688 new users of OACs (warfarin: n = 3454; apixaban: n = 3335; dabigatran: n = 4210; rivaroxaban: n = 2689). The mean age was 75.0 (SD, 11.2), and 6,550 (47.9%) were women. After a median follow-up of 0.93 years (interquartile range, 0.21-1.92 years), 698 incident diabetes cases were observed. In Cox-regression analysis, dabigatran use was significantly associated with reduced risk of diabetes when compared with warfarin use [HR 0.69 (95% CI 0.56-0.86; P < 0.001)], with statistically insignificant associations observed for use of apixaban and rivaroxaban. The corresponding adjusted CIDs at 2 years after treatment with apixaban, dabigatran, and rivaroxaban users when compared with warfarin were - 2.06% (95% CI - 4.08 to 0.16%); - 3.06% (95% CI - 4.79 to - 1.15%); and - 1.8% (- 3.62 to 0.23%). In head-to-head comparisons between women DOAC users, dabigatran was also associated with a lower risk of diabetes when compared with apixaban and rivaroxaban. CONCLUSIONS: Among adults with AF receiving OACs, the use of dabigatran had the lowest risk of diabetes when compared with warfarin use.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal and appendiceal peritoneal metastases - The Hong Kong experience and literature review.

INTRODUCTION: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is increasingly used to treat peritoneal metastases from appendiceal or colorectal origin. We evaluate our institution's experience and survival outcomes with this procedure, and its efficacy in symptom relief. METHODS: This is a single-centre retrospective observational study on patients with peritoneal metastases (PM) from appendiceal neoplasm or colorectal cancer who underwent CRS/HIPEC in Queen Mary Hospital. Our primary endpoints were overall survival (OS) and morbidity and mortality of this procedure; secondary endpoints included disease-free survival (DFS) and symptom-free survival. RESULTS: Between 2006 and 2018, thirty CRS/HIPEC procedures were performed for 28 patients - 17 (60.7%) had appendiceal PM while 11 (39.9%) had colorectal PM. The median peritoneal cancer index was 20; complete cytoreduction was achieved in 83.3% patients. High-grade morbidity occurred in 13.3% cases. There was no 30-day mortality. Two-year OS were 71.6% and 50% for low-grade appendiceal PM and colorectal PM patients (p = 0.20). Complete cytoreduction improved OS (2-year OS 75.4% vs 20%, p = 0.04). Median DFS was 11.8 months. Median symptom-free duration was 36.8 months; patients with complete cytoreduction were more likely to remain asymptomatic (82.9% at 1 year, vs 60% in incomplete cytoreduction group, p < 0.01). 91.7% low-grade appendiceal PM patients and 58.4% colorectal PM patients remained asymptomatic at post-operative one year (p = 0.31). CONCLUSION: CRS/HIPEC is beneficial to appendiceal PM and selected colorectal PM patients - improving survival and offering prolonged symptom relief, with reasonable morbidity and mortality. Complete cytoreduction is key to realising this benefit.

Neighbourhood environment and depressive symptoms among the elderly in Hong Kong and Singapore.

BACKGROUND: Geriatric depression is a growing public health issue worldwide. This study aims at identifying the relevant neighbourhood attributes, separate from the individual-level characteristics, that are related to the onset of depressive disorders among the geriatric population. METHODS: This study adopts a structural equation modelling (SEM) approach to understand the effect of the neighbourhood environment on geriatric depression, as identified by data collected from community-dwelling elderly living in Hong Kong and Singapore. Using network buffers as the unit of analysis, different features of the neighbourhood environment are captured and analysed. SEM also examines the strength and direction of the relationships using different parameters at both the individual and neighbourhood levels, as well as the prevalence of depressive symptoms among the elderly. RESULTS: The total sample size is 347, with 173 and 174 elderly people in Hong Kong and Singapore respectively. The results show that in addition to one's physical health status, both objective and subjective neighbourhood factors including the size of parks, land use mix, walkability, and connectivity are all statistically significant influential factors in geriatric depression. In particular, enhancing walkability and providing more parks at the neighbourhood level can bring mental health benefits. CONCLUSIONS: Public health policy initiatives aimed at tackling geriatric depression can be achieved by adopting a holistic and integrative approach to better prepare the neighbourhood environment in an ageing society.

Association of technologically assisted integrated care with clinical outcomes in type 2 diabetes in Hong Kong using the prospective JADE Program: A retrospective cohort analysis.

BACKGROUND: Diabetes outcomes are influenced by host factors, settings, and care processes. We examined the association of data-driven integrated care assisted by information and communications technology (ICT) with clinical outcomes in type 2 diabetes in public and private healthcare settings. METHODS AND FINDINGS: The web-based Joint Asia Diabetes Evaluation (JADE) platform provides a protocol to guide data collection for issuing a personalized JADE report including risk categories (1-4, low-high), 5-year probabilities of cardiovascular-renal events, and trends and targets of 4 risk factors with tailored decision support. The JADE program is a prospective cohort study implemented in a naturalistic environment where patients underwent nurse-led structured evaluation (blood/urine/eye/feet) in public and private outpatient clinics and diabetes centers in Hong Kong. We retrospectively analyzed the data of 16,624 Han Chinese patients with type 2 diabetes who were enrolled in 2007-2015. In the public setting, the non-JADE group (n = 3,587) underwent structured evaluation for risk factors and complications only, while the JADE (n = 9,601) group received a JADE report with group empowerment by nurses. In a community-based, nurse-led, university-affiliated diabetes center (UDC), the JADE-Personalized (JADE-P) group (n = 3,436) received a JADE report, personalized empowerment, and annual telephone reminder for reevaluation and engagement. The primary composite outcome was time to the first occurrence of cardiovascular-renal diseases, all-site cancer, and/or death, based on hospitalization data censored on 30 June 2017. During 94,311 person-years of follow-up in 2007-2017, 7,779 primary events occurred. Compared with the JADE group (136.22 cases per 1,000 patient-years [95% CI 132.35-140.18]), the non-JADE group had higher (145.32 [95% CI 138.68-152.20]; P = 0.020) while the JADE-P group had lower event rates (70.94 [95% CI 67.12-74.91]; P < 0.001). The adjusted hazard ratios (aHRs) for the primary composite outcome were 1.22 (95% CI 1.15-1.30) and 0.70 (95% CI 0.66-0.75), respectively, independent of risk profiles, education levels, drug usage, self-care, and comorbidities at baseline. We reported consistent results in propensity-score-matched analyses and after accounting for loss to follow-up. Potential limitations include its nonrandomized design that precludes causal inference, residual confounding, and participation bias. CONCLUSIONS: ICT-assisted integrated care was associated with a reduction in clinical events, including death in type 2 diabetes in public and private healthcare settings.

In Colorectal Cancer Cells With Mutant KRAS, SLC25A22-Mediated Glutaminolysis Reduces DNA Demethylation to Increase WNT Signaling, Stemness, and Drug Resistance.

BACKGROUND & AIMS: Mutant KRAS promotes glutaminolysis, a process that uses steps from the tricarboxylic cycle to convert glutamine to α-ketoglutarate and other molecules via glutaminase and SLC25A22. This results in inhibition of demethylases and epigenetic alterations in cells that increase proliferation and stem cell features. We investigated whether mutant KRAS-mediated glutaminolysis affects the epigenomes and activities of colorectal cancer (CRC) cells. METHODS: We created ApcminKrasG12D mice with intestine-specific knockout of SLC25A22 (ApcminKrasG12DSLC25A22fl/fl mice). Intestine tissues were collected and analyzed by histology, immunohistochemistry, and DNA methylation assays; organoids were derived and studied for stem cell features, along with organoids derived from 2 human colorectal tumor specimens. Colon epithelial cells (1CT) and CRC cells (DLD1, DKS8, HKE3, and HCT116) that expressed mutant KRAS, with or without knockdown of SLC25A22 or other proteins, were deprived of glutamine or glucose and assayed for proliferation, colony formation, glucose or glutamine consumption, and apoptosis; gene expression patterns were analyzed by RNA sequencing, proteins by immunoblots, and metabolites by liquid chromatography-mass spectrometry, with [U-13C5]-glutamine as a tracer. Cells and organoids with knocked down, knocked out, or overexpressed proteins were analyzed for DNA methylation at CpG sites using arrays. We performed immunohistochemical analyses of colorectal tumor samples from 130 patients in Hong Kong (57 with KRAS mutations) and Kaplan-Meier analyses of survival. We analyzed gene expression levels of colorectal tumor samples in The Cancer Genome Atlas. RESULTS: CRC cells that express activated KRAS required glutamine for survival, and rapidly incorporated it into the tricarboxylic cycle (glutaminolysis); this process required SLC25A22. Cells incubated with succinate and non-essential amino acids could proliferate under glutamine-free conditions. Mutant KRAS cells maintained a low ratio of α-ketoglutarate to succinate, resulting in reduced 5-hydroxymethylcytosine-a marker of DNA demethylation, and hypermethylation at CpG sites. Many of the hypermethylated genes were in the WNT signaling pathway and at the protocadherin gene cluster on chromosome 5q31. CRC cells without mutant KRAS, or with mutant KRAS and knockout of SLC25A22, expressed protocadherin genes (PCDHAC2, PCDHB7, PCDHB15, PCDHGA1, and PCDHGA6)-DNA was not methylated at these loci. Expression of the protocadherin genes reduced WNT signaling to ß-catenin and expression of the stem cell marker LGR5. ApcminKrasG12DSLC25A22fl/fl mice developed fewer colon tumors than ApcminKrasG12D mice (P < .01). Organoids from ApcminKrasG12DSLC25A22fl/fl mice had reduced expression of LGR5 and other markers of stemness compared with organoids derived from ApcminKrasG12D mice. Knockdown of SLC25A22 in human colorectal tumor organoids reduced clonogenicity. Knockdown of lysine demethylases, or succinate supplementation, restored expression of LGR5 to SLC25A22-knockout CRC cells. Knockout of SLC25A22 in CRC cells that express mutant KRAS increased their sensitivity to 5-fluorouacil. Level of SLC25A22 correlated with levels of LGR5, nuclear ß-catenin, and a stem cell-associated gene expression pattern in human colorectal tumors with mutations in KRAS and reduced survival times of patients. CONCLUSIONS: In CRC cells that express activated KRAS, SLC25A22 promotes accumulation of succinate, resulting in increased DNA methylation, activation of WNT signaling to ß-catenin, increased expression of LGR5, proliferation, stem cell features, and resistance to 5-fluorouacil. Strategies to disrupt this pathway might be developed for treatment of CRC.

Tea drinking and the risk of esophageal cancer: focus on tea type and drinking temperature.

The association between tea drinking and esophageal cancer is still contradictory. This study is to determine the association between tea drinking and esophageal squamous cell carcinoma focusing on drinking temperature and tea types. A population-based case-control study was conducted in a high esophageal squamous cell carcinoma risk area in China. A total of 942 incident esophageal squamous cell carcinoma cases with historical confirmation and 942 age- and sex- individually matched community controls were recruited from the study area. Trained interviewers using a structured questionnaire collected detailed information on tea drinking, diet, smoking and alcohol drinking habits. Habitual tea drinking temperature was measured with a thermometer during interviews. We analyzed the association between tea consumption, drinking temperature and esophageal squamous cell carcinoma, stratified by tea type, while adjusting for other potentially confounding factors. Drinking very hot tea (>65°C) was significantly associated with the increased risk of esophageal squamous cell carcinoma (odds ratio = 1.67, 95% confidential interval 1.25-2.24) relative to non-drinkers. Consumption of black tea, irrespective of the frequency, intensity and tea leaf amount, was significantly associated with a higher risk (P for trend <0.01). Compared to those who consumed <300 g/month tea leaves at ≤65°C, those who consumed more than 300 g/month tea leave at >65°C had a more than 1.8-fold higher risk of esophageal squamous cell carcinoma for both green tea and black tea. Our results provide more evidence that drinking very hot tea (above 65°C) are significantly associated with an increased risk of esophageal squamous cell carcinoma.

Association Between Treatment With Apixaban, Dabigatran, Rivaroxaban, or Warfarin and Risk for Osteoporotic Fractures Among Patients With Atrial Fibrillation: A Population-Based Cohort Study.

BACKGROUND: It is unclear whether anticoagulant type is associated with the risk for osteoporotic fracture, a deleterious complication of anticoagulants among patients with atrial fibrillation (AF). OBJECTIVE: To compare the risk for osteoporotic fracture between anticoagulants. DESIGN: Population-based cohort study. SETTING: Territory-wide electronic health record database of the Hong Kong Hospital Authority. PARTICIPANTS: Patients newly diagnosed with AF between 2010 and 2017 who received a new prescription for warfarin or a direct oral anticoagulant (DOAC) (apixaban, dabigatran, or rivaroxaban). Follow-up ended on 31 December 2018. MEASUREMENTS: Osteoporotic hip and vertebral fractures in anticoagulant users were compared using propensity score-weighted cumulative incidence differences (CIDs). RESULTS: There were 23 515 patients identified (3241 apixaban users, 6867 dabigatran users, 3866 rivaroxaban users, and 9541 warfarin users). Overall mean age was 74.4 years (SD, 10.8), ranging from 73.1 years (warfarin) to 77.9 years (apixaban). Over a median follow-up of 423 days, 401 fractures were identified (crude event number [weighted rate per 100 patient-years]: apixaban, 53 [0.82]; dabigatran, 95 [0.76]; rivaroxaban, 57 [0.67]; and warfarin, 196 [1.11]). After 24-month follow-up, DOAC use was associated with a lower risk for fracture than warfarin use (apixaban CID, -0.88% [95% CI, -1.66% to -0.21%]; dabigatran CID, -0.81% [CI, -1.34% to -0.23%]; and rivaroxaban CID, -1.13% [CI, -1.67% to -0.53%]). No differences were seen in all head-to-head comparisons between DOACs at 24 months (apixaban vs. dabigatran CID, -0.06% [CI, -0.69% to 0.49%]; rivaroxaban vs. dabigatran CID, -0.32% [CI, -0.84% to 0.18%]; and rivaroxaban vs. apixaban CID, -0.25% [CI, -0.86% to 0.40%]). LIMITATION: Residual confounding is possible. CONCLUSION: Among patients with AF, DOAC use may result in a lower risk for osteoporotic fracture compared with warfarin use. Fracture risk does not seem to be altered by the choice of DOAC. These findings may help inform the benefit-risk assessment when choosing between anticoagulants. PRIMARY FUNDING SOURCE: The University of Hong Kong and University College London Strategic Partnership Fund.

The effect of physical activity on dose-relationship between serum 25-hydroxyvitamin D and cardiovascular health events in older adults.

BACKGROUND AND AIMS: Reverse J- or U-shaped associations between serum 25-hydroxyvitamin D (25[OH]D) concentrations and cardiovascular outcomes have been reported, which need clarifications in older adults. Physical activity, correlating with both serum 25[OH]D concentration and cardiovascular health, may have an effect on the dose-relationships. METHODS AND RESULTS: At baseline, 2790 participants aged 65 years and over, free of vitamin D supplementation use, had assays for serum 25[OH]D concentrations and health related characteristics and measurements, were followed up for cardiovascular events and death by up to 7 and 15 years, respectively. The dose-response associations of serum 25[OH]D concentrations with cardiovascular events and mortality risk were examined using Cox regression models. After adjusting for physical activity and other covariates, serum 25[OH]D concentration was non-linearly associated with cardiovascular mortality risk (U-shaped, P = 0.009). According to the Institute of Medicine categories, the HR(95% CI) of cardiovascular mortality risk separately in deficient (<25 nmol/L), inadequate (25 to < 50 nmol/L) and potentially harmful (≥125 nmol/L) level was 1.67 (0.23, 12.01), 1.66 (1.25, 2.20) and 2.21 (0.30, 16.37), respectively. The risk of 25[OH]D inadequacy for cardiovascular mortality was significantly attenuated by increased physical activity, especially leisure activity (P for trend = 0.008 and 0.021, respectively). No significant finding was observed for incident cardiovascular events. CONCLUSION: Both lower and higher serum 25[OH]D concentrations were associated with risk of cardiovascular mortality in Chinese community-dwelling older adults. Physical activity may attenuate the cardiovascular mortality risk of vitamin D inadequacy, but its role in individuals with higher 25[OH]D concentrations remains unclear.