Contribution of systemic factors on macular vessel density: a sex-specific population-based study.

PURPOSE: To evaluate the influence of systemic factors on macular vessel density in quantitative Optical Coherence Tomography Angiography (OCTA) by sex. STUDY DESIGN: A cross-sectional study. METHODS: A total of 2018 adults were recruited in this study. Participants were excluded (n=964) due to missing data, eye-related problems, or low OCTA scan quality. Macular vessel densities were measured with OCTA using split-spectrum amplitude decorrelation angiography algorithm. Only the data from the right eyes were selected for analysis. Multivariable linear regression analysis was performed to determine the associations between macular vessel density and obesity-related systemic factors in each gender group. RESULTS: The right eyes of 1054 participants (59.6% women) were enrolled. Men had significantly higher obesity parameters and associated risk factors. In multivariable linear regression analysis in men, older age and type 2 diabetes mellitus were independently associated with lower superficial retinal vessel density (ß = -0.37, p = 0.002; ß = -1.22, p = 0.03) and deep retinal vessel density, respectively (ß = -0.66, p < 0.001; ß = -1.76, p = 0.02); positive association was also observed between body mass index (BMI) and superficial retinal vessel density (ß = 0.56, p = 0.02). In women, only higher systolic blood pressure was independently associated with a lower deep retinal vessel density (ß = -0.50, p = 0.003). CONCLUSIONS: This large cross-sectional study shows that older age and type 2 diabetes mellitus are associated with lower superficial and deep retinal capillary vessel density in men. This may help clinicians better understand how systemic factors influence retinal vessel density in different genders and future studies can ascertain more potential sex differences.

Messenger RNA Coronavirus Disease 2019 (COVID-19) Vaccination With BNT162b2 Increased Risk of Bell's Palsy: A Nested Case-Control and Self-Controlled Case Series Study.

BACKGROUND: Observable symptoms of Bell's palsy following vaccinations arouse concern over the safety profiles of novel coronavirus disease 2019 (COVID-19) vaccines. However, there are only inconclusive findings on Bell's palsy following messenger (mRNA) COVID-19 vaccination. This study aims to update the previous analyses on the risk of Bell's palsy following mRNA (BNT162b2) COVID-19 vaccination. METHODS: This study included cases aged ≥16 years with a new diagnosis of Bell's palsy within 28 days after BNT162b2 vaccinations from the population-based electronic health records in Hong Kong. Nested case-control and self-controlled case series (SCCS) analyses were used, where the association between Bell's palsy and BNT162b2 was evaluated using conditional logistic and Poisson regression, respectively. RESULTS: Totally 54 individuals were newly diagnosed with Bell's palsy after BNT162b2 vaccinations. The incidence of Bell's palsy was 1.58 (95% confidence interval [CI], 1.19-2.07) per 100 000 doses administered. The nested case-control analysis showed significant association between BNT162b2 vaccinations and Bell's palsy (adjusted odds ratio [aOR], 1.543; 95% CI, 1.123-2.121), with up to 1.112 excess events per 100 000 people who received 2 doses of BNT162b2. An increased risk of Bell's palsy was observed during the first 14 days after the second dose of BNT162b2 in both nested case-control (aOR, 2.325; 95% CI, 1.414-3.821) and SCCS analysis (adjusted incidence rate ratio, 2.44; 95% CI, 1.32-4.50). CONCLUSIONS: There was an overall increased risk of Bell's palsy following BNT162b2 vaccination, particularly within the first 14 days after the second dose, but the absolute risk was very low.

mRNA (BNT162b2) and Inactivated (CoronaVac) COVID-19 Vaccination and Risk of Adverse Events and Acute Diabetic Complications in Patients with Type 2 Diabetes Mellitus: A Population-Based Study.

INTRODUCTION: In Hong Kong, CoronaVac and BNT162b2 have been approved for emergency use owing to the coronavirus disease 2019 (COVID-19) pandemic. Reactions towards the vaccine and the risk of post-vaccination adverse events may be different between recipients with and without type 2 diabetes mellitus (T2DM). OBJECTIVE: The aim of this study was to evaluate the risk of adverse events of special interest (AESI) and acute diabetic complications in the T2DM population after COVID-19 vaccination in Hong Kong. RESEARCH DESIGN AND METHODS: Self-controlled case-series analysis was conducted. Patients with T2DM who received at least one dose of BNT162b2 or CoronaVac between 23 February 2021 and 31 January 2022 from electronic health records in Hong Kong were included. The incidence rates of 29 AESIs and acute diabetic complications (any of severe hypoglycemia, diabetic ketoacidosis or hyperosmolar hyperglycemic syndrome) requiring hospitalization within 21 days after the first or second dose of vaccination were reported. The risks of these outcomes were evaluated using conditional Poisson regression. RESULTS: Among 141,224 BNT162b2 recipients and 209,739 CoronaVac recipients with T2DM, the incidence per 100,000 doses and incidence per 100,000 person-years of individual AESIs and acute diabetic complications ranged from 0 to 24.4 and 0 to 438.6 in BNT162b2 group, and 0 to 19.5 and 0 to 351.6 in CoronaVac group. We did not observe any significantly increased risk of individual AESIs or acute diabetic complications after first or second doses of BNT162b2 or CoronaVac vaccine. Subgroup analysis based on HbA1c < 7% and ≥ 7% also did not show significantly excess risk after vaccination. CONCLUSIONS: Patients with T2DM do not appear to have higher risks of AESI and acute diabetic complications after BNT162b2 or CoronaVac vaccination. Moreover, given the low incidence of AESIs and acute diabetic complications after vaccination, the absolute risk increment was likely minimal.

Effect of puerarin supplementation on cardiovascular disease risk factors: A randomized, double-blind, placebo-controlled, 2-way crossover trial.

BACKGROUND: Cell culture and animal studies suggest puerarin could prevent cardiovascular disease (CVD). However, trials in human are scare, not primarily designed for prevention, and inadequately powered. We assessed the effect of puerarin supplementation on CVD risk factors in men using a crossover trial. METHODS: In total, 217 Chinese men aged 18-50 years without a history of CVD were recruited. They were randomized to take a puerarin supplement (90.2 mg daily) or a placebo, followed by a 4-week wash-out period, and then crossed over to the other intervention. An intention-to-treat analysis was used. Differences in primary outcomes (lipid profile such as low-density lipoprotein (LDL) cholesterol) and secondary outcomes (other CVD risk factors such as blood pressure and fasting glucose, and some potential mediating pathways such as testosterone) between supplementation and placebo within participants were compared using a paired t-test, or a crossover (CROS)-based analysis where a period effect existed. RESULTS: Lipid profile was similar after the puerarin supplementation or placebo (e.g., mean difference in LDL cholesterol: -0.02 mmol/L, 95% confidence interval (CI) -0.09 to -0.06). Conversely, fasting glucose was reduced after the puerarin supplementation (-0.13 mmol/L, 95% CI -0.25 to -0.008). There were no differences in blood pressure, testosterone, high-sensitive C-reactive protein, prothrombin time, liver or renal function. CONCLUSION: In young-to-middle-aged Chinese men, short-term puerarin supplementation did not improve the primary outcome of lipid profile, but an exploratory analysis suggested that puerarin could be beneficial for one of the secondary outcomes, i.e., fasting glucose.

Effectiveness of BNT162b2 and CoronaVac vaccinations against mortality and severe complications after SARS-CoV-2 Omicron BA.2 infection: a case-control study.

Data regarding protection against mortality and severe complications after Omicron BA.2 infection with CoronaVac and BNT162b2 vaccines remains limited. We conducted a case-control study to evaluate the risk of severe complications and mortality following 1-3 doses of CoronaVac and BNT162b2 using electronic health records database. Cases were adults with their first COVID-19-related mortality or severe complications between 1 January and 31 March 2022, matched with up-to 10 controls by age, sex, index date, and Charlson Comorbidity Index. Vaccine effectiveness against COVID-19-related mortality and severe complications by type and number of doses was estimated using conditional logistic regression adjusted for comorbidities and medications. Vaccine effectiveness (95% CI) against COVID-19-related mortality after two doses of BNT162b2 and CoronaVac were 90.7% (88.6-92.3) and 74.8% (72.5-76.9) in those aged ≥65, 87.6% (81.4-91.8) and 80.7% (72.8-86.3) in those aged 50-64, 86.6% (71.0-93.8) and 82.7% (56.5-93.1) in those aged 18-50. Vaccine effectiveness against severe complications after two doses of BNT162b2 and CoronaVac were 82.1% (74.6-87.3) and 58.9% (50.3-66.1) in those aged ≥65, 83.0% (69.6-90.5) and 67.1% (47.1-79.6) in those aged 50-64, 78.3% (60.8-88.0) and 77.8% (49.6-90.2) in those aged 18-50. Further risk reduction with the third dose was observed especially in those aged ≥65 years, with vaccine effectiveness of 98.0% (96.5-98.9) for BNT162b2 and 95.5% (93.7-96.8) for CoronaVac against mortality, 90.8% (83.4-94.9) and 88.0% (80.8-92.5) against severe complications. Both CoronaVac and BNT162b2 vaccination were effective against COVID-19-related mortality and severe complications amidst the Omicron BA.2 pandemic, and risks decreased further with the third dose.

Thromboembolic events and hemorrhagic stroke after mRNA (BNT162b2) and inactivated (CoronaVac) covid-19 vaccination: A self-controlled case series study.

Background: This study aims to evaluate the association between thromboembolic events and hemorrhagic stroke following BNT162b2 and CoronaVac vaccination. Methods: Patients with incident thromboembolic events or hemorrhagic stroke within 28 days of covid-19 vaccination or SARS-CoV-2 positive test during 23 February to 30 September 2021 were included. The incidence per 100,000 covid-19 vaccine doses administered and SARS-CoV-2 test positive cases were estimated. A modified self-controlled case series (SCCS) analysis using the data from the Hong Kong territory-wide electronic health and vaccination records. Seasonal effect was adjusted by month. Findings: A total of 5,526,547 doses of BNT162b2 and 3,146,741 doses of CoronaVac were administered. A total of 334 and 402 thromboembolic events, and 57 and 49 hemorrhagic stroke cases occurred within 28 days after BNT162b2 and CoronaVac vaccination, respectively. The crude incidence of thromboembolic events and hemorrhagic stroke per 100,000 doses administered for both covid-19 vaccines were smaller than that per 100,000 SARS-CoV-2 test positive cases. The modified SCCS detected an increased risk of hemorrhagic stroke in BNT162b2 14-27 days after first dose with adjusted IRR of 2.53 (95% CI 1.48-4.34), and 0-13 days after second dose with adjusted IRR 2.69 (95% CI 1.54-4.69). No statistically significant risk was observed for thromboembolic events for both vaccines. Interpretation: We detected a possible safety signal for hemorrhagic stroke following BNT162b2 vaccination. The incidence of thromboembolic event or hemorrhagic stroke following vaccination is lower than that among SARS-CoV-2 test positive cases; therefore, vaccination against covid-19 remains an important public health intervention. Funding: This study was funded by a research grant from the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region (reference COVID19F01).

Herpes zoster related hospitalization after inactivated (CoronaVac) and mRNA (BNT162b2) SARS-CoV-2 vaccination: A self-controlled case series and nested case-control study.

BACKGROUND: Stimulation of immunity by vaccination may elicit adverse events. There is currently inconclusive evidence on the relationship between herpes zoster related hospitalization and COVID-19 vaccination. This study aimed to evaluate the effect of inactivated virus (CoronaVac, Sinovac) and mRNA (BNT162b2, BioNTech/Fosun Pharma) COVID-19 vaccine on the risk of herpes zoster related hospitalization. METHODS: Self-controlled case series (SCCS) analysis was conducted using the data from the electronic health records in Hospital Authority and COVID-19 vaccination records in the Department of Health in Hong Kong. We conducted the SCCS analysis including patients with a first primary diagnosis of herpes zoster in the hospital inpatient setting between February 23 and July 31, 2021. A confirmatory analysis by nested case-control method was also conducted. Each herpes zoster case was randomly matched with ten controls according to sex, age, Charlson comorbidity index, and date of hospital admission. Conditional Poisson regression and logistic regression models were used to assess the potential excess rates of herpes zoster after vaccination. FINDINGS: From February 23 to July 31, 2021, a total of 16 and 27 patients were identified with a first primary hospital diagnosis of herpes zoster within 28 days after CoronaVac and BNT162b2 vaccinations. The incidence of herpes zoster was 7.9 (95% Confidence interval [CI]: 5.2-11.5) for CoronaVac and 7.1 (95% CI: 4.1-11.5) for BNT162b2 per 1,000,000 doses administered. In SCCS analysis, CoronaVac vaccination was associated with significantly higher risk of herpes zoster within 14 days after first dose (adjusted incidence rate ratio [aIRR]=2.67, 95% CI: 1.08-6.59) but not in other periods afterwards compared to the baseline period. Regarding BNT162b2 vaccination, a significantly increased risk of herpes zoster was observed after first dose up to 14 days after second dose (0-13 days after first dose: aIRR=5.23, 95% CI: 1.61-17.03; 14-27 days after first dose: aIRR=5.82, 95% CI: 1.62-20.91; 0-13 days after second dose: aIRR=5.14, 95% CI: 1.29-20.47). Using these relative rates, we estimated that there has been an excess of approximately 5 and 7 cases of hospitalization as a result of herpes zoster after every 1,000,000 doses of CoronaVac and BNT162b2 vaccination, respectively. The findings in the nested case control analysis showed similar results. INTERPRETATION: We identified an increased risk of herpes zoster related hospitalization after CoronaVac and BNT162b2 vaccinations. However, the absolute risks of such adverse event after CoronaVac and BNT162b2 vaccinations were very low. In locations where COVID-19 is prevalent, the protective effects on COVID-19 from vaccinations will greatly outweigh the potential side effects of vaccination. FUNDING: The project was funded by Research Grant from the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region (Ref. No.COVID19F01). FTTL (Francisco Tsz Tsun Lai) and ICKW (Ian Chi Kei Wong)'s posts were partly funded by D24H; hence this work was partly supported by AIR@InnoHK administered by Innovation and Technology Commission.

Bell's palsy following vaccination with mRNA (BNT162b2) and inactivated (CoronaVac) SARS-CoV-2 vaccines: a case series and nested case-control study.

BACKGROUND: Bell's palsy is a rare adverse event reported in clinical trials of COVID-19 vaccines. However, to our knowledge no population-based study has assessed the association between the inactivated SARS-CoV-2 vaccines and Bell's palsy. The aim of this study was to evaluate the risk of Bell's palsy after BNT162b2 and CoronaVac vaccination. METHODS: In this case series and nested case-control study done in Hong Kong, we assessed the risk of Bell's palsy within 42 days following vaccination with BNT162b2 (Fosun-BioNTech [equivalent to Pfizer-BioNTech]) or CoronaVac (from Sinovac Biotech, Hong Kong) using data from voluntary surveillance reporting with the Hospital Authority, the COVID-19 Vaccine Adverse Event Online Reporting system for all health-care professionals, and the Hospital Authority's territory-wide electronic health records from the Clinical Data Analysis and Reporting System. We described reported cases of Bell's palsy among vaccine recipients (aged 18-110 years for CoronaVac and aged 16-110 years for BNT162b2). We compared the estimated age-standardised incidence of clinically confirmed cases among individuals who had received the CoronaVac or BNT162b2 vaccination (up to 42 days before presentation) with the background incidence in the population. A nested case-control study was also done using conditional logistic regression to estimate the odds ratio (OR) for risk of Bell's palsy and vaccination. Cases and controls were matched (1:4) by age, sex, admission setting, and admission date. FINDINGS: Between February 23 and May 4, 2021, 451 939 individuals received the first dose of CoronaVac and 537 205 individuals received the first dose of BNT162b2. 28 clinically confirmed cases of Bell's palsy were reported following CoronaVac and 16 cases were reported following BNT162b2. The age-standardised incidence of clinically confirmed Bell's palsy was 66·9 cases per 100 000 person-years (95% CI 37·2 to 96·6) following CoronaVac vaccination and 42·8 per 100 000 person-years (19·4 to 66·1) for BNT162b2 vaccination. The age-standardised difference for the incidence compared with the background population was 41·5 (95% CI 11·7 to 71·4) for CoronaVac and 17·0 (-6·6 to 40·6) for BNT162b2, equivalent to an additional 4·8 cases per 100 000 people vaccinated for CoronaVac and 2·0 cases per 100 000 people vaccinated for BNT162b2. In the nested case-control analysis, 298 cases were matched to 1181 controls, and the adjusted ORs were 2·385 (95% CI 1·415 to 4·022) for CoronaVac and 1·755 (0·886 to 3·477) for BNT162b2. INTERPRETATION: Our findings suggest an overall increased risk of Bell's palsy after CoronaVac vaccination. However, the beneficial and protective effects of the inactivated COVID-19 vaccine far outweigh the risk of this generally self-limiting adverse event. Additional studies are needed in other regions to confirm our findings. FUNDING: The Food and Health Bureau of the Government of the Hong Kong Special Administrative Region, China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Demographic and Epidemiological Contributions to Recent Trends in Cancer Incidence in Hong Kong.

BACKGROUND: Hong Kong has an ageing Chinese population with high life expectancy and a rising number of cancer cases. While population ageing could lead to higher incidence, we aim to quantify the demographic and epidemiological contributions to this trend by disentangling the effect of these factors. METHODS: We analysed secular trends of cancer incidences of all cancer sites combined, including the five top cancers in men and women in Hong Kong in 1983-2017, by disentangling effects of demographics (ageing population and population growth) and cancer risk/rate change using the RiskDiff methodology. RESULTS: Overall, age-standardised incidences of all cancers combined in women and in men declined over the study period (-5.3% for women, -30.2% for men), but total incident cancer case counts increased dramatically (156.5% for women, 96% for men). This increase was primarily due to ageing and increasing population (95% age, 66.1% growth for women, and 119.4% age, 25.4% growth for men), while disease risk for all cancers combined has a decreasing trend (-4.5% for women and -48.8% for men). For the site-specific risk changes among the most five common cancer types, there were increases in risks of prostate and colorectal cancers in men, and breast, endometrial, and thyroid cancers in women. CONCLUSION: Demographic changes and ageing in our Chinese population resulted in a marked increase in the number of cancer diagnoses in Hong Kong in past decades. The surge in incident case counts overall is expected to stress the healthcare system in terms of the increased demand of healthcare professionals. Cancer surveillance should be enhanced in view of the growing demand from older patients and the cancer types with fast-increasing incidence rates in our population.

Integrating Social Determinants in Decision-Making Processes for Health: Insights from Conceptual Frameworks-the 3-D Commission.

The inclusion of social determinants of health offers a more comprehensive lens to fully appreciate and effectively address health. However, decision-makers across sectors still struggle to appropriately recognise and act upon these determinants, as illustrated by the ongoing COVID-19 pandemic. Consequently, improving the health of populations remains challenging. This paper seeks to draw insights from the literature to better understand decision-making processes affecting health and the potential to integrate data on social determinants. We summarised commonly cited conceptual approaches across all stages of the policy process, from agenda-setting to evaluation. Nine conceptual approaches were identified, including two frameworks, two models and five theories. From across the selected literature, it became clear that the context, the actors and the type of the health issue are critical variables in decision-making for health, a process that by nature is a dynamic and adaptable one. The majority of these conceptual approaches implicitly suggest a possible role for data on social determinants of health in decision-making. We suggest two main avenues to make the link more explicit: the use of data in giving health problems the appropriate visibility and credibility they require and the use of social determinants of health as a broader framing to more effectively attract the attention of a diverse group of decision-makers with the power to allocate resources. Social determinants of health present opportunities for decision-making, which can target modifiable factors influencing health-i.e. interventions to improve or reduce risks to population health. Future work is needed to build on this review and propose an improved, people-centred and evidence-informed decision-making tool that strongly and explicitly integrates data on social determinants of health.

Improving Decision-Making for Population Health in Nonhealth Sectors in Urban Environments: the Example of the Transportation Sector in Three Megacities-the 3-D Commission.

Noncommunicable diseases (NCDs) represent a significant global public health burden. As more countries experience both epidemiologic transition and increasing urbanization, it is clear that we need approaches to mitigate the growing burden of NCDs. Large and growing urban environments play an important role in shaping risk factors that influence NCDs, pointing to the ineluctable need to engage sectors beyond the health sector in these settings if we are to improve health. By way of one example, the transportation sector plays a critical role in building and sustaining health outcomes in urban environments in general and in megacities in particular. We conducted a qualitative comparative case study design. We compared Bus Rapid Transit (BRT) policies in 3 megacities-Lagos (Africa), Bogotá (South America), and Beijing (Asia). We examined the extent to which data on the social determinants of health, equity considerations, and multisectoral approaches were incorporated into local politics and the decision-making processes surrounding BRT. We found that all three megacities paid inadequate attention to health in their agenda-setting, despite having considerable healthy transportation policies in principle. BRT system policies have the opportunity to improve lifestyle choices for NCDs through a focus on safe, affordable, and effective forms of transportation. There are opportunities to improve decision-making for health by involving more available data for health, building on existing infrastructures, building stronger political leadership and commitments, and establishing formal frameworks to improve multisectoral collaborations within megacities. Future research will benefit from addressing the political and bureaucratic processes of using health data when designing public transportation services, the political and social obstacles involved, and the cross-national lessons that can be learned from other megacities.

Association of Sugar-Sweetened Beverage Frequency with Adiposity: Evidence from the "Children of 1997" Birth Cohort.

BACKGROUND: Observationally, sugar-sweetened beverage (SSB) consumption is associated with adiposity in Western children but could be confounded. We examined the association of SSB frequency with adiposity in the non-Western setting of Hong Kong. METHODS: We examined the associations of SSB consumption frequency at 11 and 13 years assessed by using a food frequency questionnaire with subsequent body mass index (BMI) z-score and overweight/obesity up to 18 years using generalized estimating equations, and with waist circumference, waist-to-hip ratio, and body fat percentage at 16-19 years using linear regression in a population-representative Chinese birth cohort "Children of 1997" (n = 3628). RESULTS: At 11 and 13 years, 6.8% and 8.2% of children respectively consumed SSB daily. Neither SSB frequency at 11 nor at 13 years was associated with subsequent BMI z-score or overweight/obesity up to 18 years, or with waist circumference, waist-to-hip ratio, or body fat percentage at 16-19 years adjusted for age, sex, socioeconomic position, health status, physical activity and other food consumption, although bias to the null from under-reporting cannot be eliminated. CONCLUSION: Although we cannot definitively exclude a small association of SSB frequency with adiposity, lack of association of SSB frequency with adiposity in a non-Western setting with low SSB consumption suggests that the role of SSB in adiposity appears to be minor.

The effect of liver enzymes on body composition: A Mendelian randomization study.

BACKGROUND: Higher alanine transaminase (ALT), indicating poor liver function, is positively associated with diabetes but inversely associated with body mass index (BMI) in Mendelian randomization (MR) studies, suggesting liver function affects muscle mass. To clarify, we assessed the associations of liver enzymes with muscle and fat mass observationally with two-sample MR as a validation. METHODS: In the population-representative "Children of 1997" birth cohort (n = 3,455), we used multivariable linear regression to assess the adjusted associations of ALT and alkaline phosphatase (ALP) at ~17.5 years with muscle mass and body fat percentage observationally. Genetic variants predicting ALT, ALP and gamma glutamyltransferase (GGT) were applied to fat-free and fat mass in the UK Biobank (n = ~331,000) to obtain unconfounded MR estimates. RESULTS: Observationally, ALT was positively associated with muscle mass (0.11 kg per IU/L, 95% confidence interval (CI) 0.10 to 0.12) and fat percentage (0.15% per IU/L, 95% CI 0.13 to 0.17). ALP was inversely associated with muscle mass (-0.03 kg per IU/L, 95% CI -0.04 to -0.02) and fat percentage (-0.02% per IU/L, 95% CI -0.03 to -0.01). Using MR, ALT was inversely associated with fat-free mass (-0.41 kg per 100% in concentration, 95% CI -0.64 to -0.19) and fat mass (-0.58 kg per 100% in concentration, 95% CI -0.85 to -0.30). ALP and GGT were unclearly associated with fat-free mass or fat mass. CONCLUSION: ALT reducing fat-free mass provides a possible pathway for the positive association of ALT with diabetes and suggests a potential target of intervention.

Age of puberty and Sleep duration: Observational and Mendelian randomization study.

Earlier age of puberty has detrimental consequences for many aspects of health. Here, for the first time, we assessed the association of earlier puberty with sleep duration observationally and with validation using Mendelian Randomization. In the "Children of 1997" birth cohort (n = 8,327), we used adjusted multivariable logistic regression to assess the associations of each clinically assessed marker of earlier puberty with self-report sleep duration in adolescence. Using two-sample MR, we assessed the effect of earlier puberty timing based on 203 single nucleotide polymorphisms applied to genome wide association studies of sleep duration in adults (n = 335,410). In "Children of 1997", cross-sectionally, older age of menarche was associated with longer (9+ hours) sleep duration [odds ratio (OR) 1.11, 95% confidence interval (CI) 1.01 to 1.21] at 13.5 years. The other earlier puberty markers were unrelated to sleep duration. Using inverse variance weighting, later of age at menarche increased adult sleep duration [0.020 per category, 95% CI 0.006 to 0.034]. This study demonstrated a causal effect of age at menarche on adult sleep duration, since age of menarche also affects obesity, our novel finding may be relevant to the observed relation of sleep duration with obesity and poor health.

The effect of sleep duration on hemoglobin and hematocrit: observational and Mendelian randomization study.

STUDY OBJECTIVE: Observationally sleep duration is positively associated with hemoglobin (Hgb), whether this association is causal and consistent by sex remains unclear. Here, we assessed the association of sleep duration with Hgb and hematocrit (Hct) observationally in late adolescence in a population-representative Chinese birth cohort "Children of 1997" with validation using Mendelian randomization (MR) in adults. METHODS: In the "Children of 1997" birth cohort (recruited = 8327, included = 3144), we used multivariable linear regression to assess the adjusted associations of sleep duration (measured as time in bed) with Hgb and Hct at 17.5 years and any sex differences. Using two-sample MR, we assessed the effect of sleep duration on Hgb and Hct, based on 61 single nucleotide polymorphisms (SNPs) applied to genome-wide association studies of Hgb and Hct in adults (n = 361 194). RESULTS: Observationally, self-reported sleep duration was positively associated with Hct (0.034 standard deviations [SDs] per hour, 95% confidence interval [CI] 0.019 to 0.049), but not with Hgb. Using MR longer sleep increased Hct (0.077 SD per hour, 95% CI 0.035 to 0.119) and Hgb (0.065 SD per hour, 95% CI 0.020 to 0.109) using Mendelian randomization pleiotropy residual sum and outlier (MR PRESSO), with more pronounced associations in men. CONCLUSIONS: Our novel findings indicate sleep increases both Hgb and Hct, particularly in men, perhaps contributing to its restorative qualities. Potential difference by sex and the implications of these findings warrant investigation.

The effect of liver enzymes on adiposity: a Mendelian randomization study.

Poorer liver function is positively associated with diabetes in Mendelian randomization (MR) studies. Observationally, adiposity is associated with poorer liver function. To clarify the etiology, we assessed the association of liver enzymes with adiposity observationally and using two-sample MR for validation. In the "Children of 1997" birth cohort, we used multivariable linear regression to assess the associations of alanine transaminase (ALT) and alkaline phosphatase (ALP) at ~17.5 years with body mass index (BMI) (n = 3,458). Using MR, genetic predictors of ALT, ALP and gamma glutamyltransferase (GGT), were applied to genome-wide association studies of BMI (n = 681,275), waist circumference (WC) (n = 224,459) and waist-hip ratio (WHR) (n = 224,459) to obtain unconfounded estimates. Observationally, ALT was positively associated with BMI (0.10 kg/m2 per IU/L, 95% confidence interval (CI) 0.09 to 0.11). ALP was inversely associated with BMI (-0.018 kg/m2 per IU/L, 95% CI -0.024 to -0.012). Using MR, ALT was inversely associated with BMI (-0.14 standard deviation per 100% change in concentration, 95% CI -0.20 to -0.07), but not WC or WHR. ALP and GGT were unrelated to adiposity. Poorer liver function might not cause adiposity; instead higher ALT might reduce BMI, raising the question as to the role of ALT in body composition.

The effect of birth weight on body composition: Evidence from a birth cohort and a Mendelian randomization study.

BACKGROUND: Lower birth weight is associated with diabetes although the underlying mechanisms are unclear. Muscle mass could be a modifiable link and hence a target of intervention. We assessed the associations of birth weight with muscle and fat mass observationally in a population with little socio-economic patterning of birth weight and using Mendelian randomization (MR) for validation. METHODS: In the population-representative "Children of 1997" birth cohort (n = 8,327), we used multivariable linear regression to assess the adjusted associations of birth weight (kg) with muscle mass (kg) and body fat (%) at ~17.5 years. Genetically predicted birth weight (effect size) was applied to summary genetic associations with fat-free mass and fat mass (kg) from the UK Biobank (n = ~331,000) to obtain unconfounded estimates using inverse-variance weighting. RESULTS: Observationally, birth weight was positively associated with muscle mass (3.29 kg per kg birth weight, 95% confidence interval (CI) 2.83 to 3.75) and body fat (1.09% per kg birth weight, 95% CI 0.54 to 1.65). Stronger associations with muscle mass were observed in boys than in girls (p for interaction 0.004). Using MR, birth weight was positively associated with fat-free mass (0.77 kg per birth weight z-score, 95% CI 0.22 to 1.33) and fat mass (0.58, 95% CI 0.01 to 1.15). No difference by sex was evident. CONCLUSION: Higher birth weight increasing muscle mass may be relevant to lower birth weight increasing the risk of diabetes and suggests post-natal muscle mass as a potential target of intervention.

Sleep duration and risk of diabetes: Observational and Mendelian randomization studies.

Inadequate sleep could contribute to type 2 diabetes, but observational studies are inconsistent and open to biases, particularly from confounding. We used Mendelian randomization (MR) to obtain an unconfounded estimate of the effect of sleep duration on diabetes, fasting glucose (FG) and hemoglobin A1c (HbA1c), and an observation study to assess differences by sex. Using MR, we assessed the effects of genetically instrumented sleep on diabetes, based on 68 single nucleotide polymorphisms (SNPs), applied to the DIAbetes Genetics Replication and meta-analysis case (n = 26,676)-control (n = 132,532) study and on FG and HbA1c, based on 55 SNPs, applied to the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) study of FG (n = 122,743) and HbA1c (n = 123,665). In the population-representative Hong Kong Chinese "Children of 1997" birth cohort we assessed whether associations of sleep duration at ~17.5 years with FG and HbA1c differed by sex. Using inverse variance weighting with multiplicative random effects, sleep duration was not associated with diabetes (odds ratio (OR) 0.85 per hour of sleep, 95% confidence interval (CI) 0.64 to 1.13), FG (-0.032 mmol/l per hour of sleep, 95% CI -0.126 to 0.063) or HbA1c (-0.022% per hour of sleep, 95% CI -0.069 to 0.024). In "Children of 1997", the associations of sleep duration with FG differed by sex (p for interaction 0.05) but not with HbA1c. Overall sleep duration does not appear to be related to diabetes, FG or HbA1c, but the possibility of sex differences merits investigation.

Birth weight, gestational age and late adolescent liver function using twin status as instrumental variable in a Hong Kong Chinese birth cohort: "Children of 1997".

Birth weight (BW) is inversely associated with diabetes and liver function in Mendelian Randomization studies. Observationally, lower BW is usually also associated with poorer liver function. However, these studies could be confounded by socioeconomic position. Here we assessed if BW is associated with liver function in a unique population with little socio-economic patterning of BW, using both instrumental variable and an observational analysis. We used instrumental variable analysis (IVA) to assess the association of BW with liver function (alanine transaminase (ALT), alkaline phosphatase (ALP), bilirubin, and albumin) at ~17 years with twin status as an instrumental variable in the prospective population-representative "Children of 1997" birth cohort (n = 8327). We also conducted an observational analysis adjusted for sex, maternal age, maternal migrant status, smoking and parental socio-economic position. A generalized linear model with gamma family was used for ALT, ALP, and bilirubin because they are not normally distributed. Using IVA, BW was not associated with ALT, ALP or bilirubin, but was possibly negatively associated with albumin (-1.12 g/L, 95% confidence interval (CI) -2.08 to -0.16). Observationally, BW was negatively associated with ALT (-1.23 IU/L, 95% CI -2.16 to -0.30), ALP (-1.72 IU/L, 95% CI -3.43 to -0.01) and higher albumin (-0.23 g/L, 95% CI -0.40 to -0.06). Poor liver function may be a pathway by which the risks of lower BW are actuated. This insight might help identify post-natal targets of intervention to mitigate the adverse health effects of lower birth weight.

Age at menarche and depressive symptoms in older Southern Chinese women: A Mendelian randomization study in the Guangzhou Biobank Cohort Study.

To clarify the causal role of age at menarche in depressive symptoms we conducted a Mendelian randomization study using a large Southern Chinese cohort (n = 12,233). A genetic allele score was derived using stepwise regression with cross validation. Older age at menarche was not associated with geriatric depression scale score. Our findings suggest that higher rates of depression in women are likely attributable to other factors which require investigation.