Asia-Pacific consensus on long-term and sequential therapy for osteoporosis.

Objectives: This study aimed to present the Asia-Pacific consensus on long-term and sequential therapy for osteoporosis, offering evidence-based recommendations for the effective management of this chronic condition. The primary focus is on achieving optimal fracture prevention through a comprehensive, individualized approach. Methods: A panel of experts convened to develop consensus statements by synthesizing the current literature and leveraging clinical expertise. The review encompassed long-term anti-osteoporosis medication goals, first-line treatments for individuals at very high fracture risk, and the strategic integration of anabolic and antiresorptive agents in sequential therapy approaches. Results: The panelists reached a consensus on 12 statements. Key recommendations included advocating for anabolic agents as the first-line treatment for individuals at very high fracture risk and transitioning to antiresorptive agents following the completion of anabolic therapy. Anabolic therapy remains an option for individuals experiencing new fractures or persistent high fracture risk despite antiresorptive treatment. In cases of inadequate response, the consensus recommended considering a switch to more potent medications. The consensus also addressed the management of medication-related complications, proposing alternatives instead of discontinuation of treatment. Conclusions: This consensus provides a comprehensive, cost-effective strategy for fracture prevention with an emphasis on shared decision-making and the incorporation of country-specific case management systems, such as fracture liaison services. It serves as a valuable guide for healthcare professionals in the Asia-Pacific region, contributing to the ongoing evolution of osteoporosis management.

Unveiling unique clinical phenotypes of hip fracture patients and the temporal association with cardiovascular events.

Cardiovascular events are the leading cause of death among hip fracture patients. This study aims to identify subphenotypes of hip fracture patients and investigate their association with incident cardiovascular events, all-cause mortality, and health service utilisation in Hong Kong and the United Kingdom populations. By the latent class analysis, we show three distinct clusters in the Hong Kong cohort (n = 78,417): Cluster 1 has cerebrovascular and hypertensive diseases, hyperlipidemia, and diabetes; Cluster 2 has congestive heart failure; Cluster 3 consists of relatively healthy patients. Compared to Cluster 3, higher risks of major adverse cardiovascular events are observed in Cluster 1 (hazard ratio 1.97, 95% CI 1.83 to 2.12) and Cluster 2 (hazard ratio 4.06, 95% CI 3.78 to 4.35). Clusters 1 and 2 are also associated with a higher risk of mortality, more unplanned accident and emergency visits and longer hospital stays. Self-controlled case series analysis shows a significantly elevated risk of major adverse cardiovascular events within 60 days post-hip fracture. Similar associations are observed in the United Kingdom cohort (n = 27,948). Pre-existing heart failure is identified as a unique subphenotype associated with poor prognosis after hip fractures.

Causal association of genetically determined caffeine intake from tea or coffee with bone health: a two-sample Mendelian randomization study.

BACKGROUND: Relationship of caffeine intake and consumption of caffeinated beverages, such as tea and coffee, with bone health remains controversial. This study aimed to evaluate whether genetically determined caffeine intake from tea or coffee has causal effects on overall total body bone mineral density (TB-BMD) and fracture. We also assessed the association with TB-BMD in five age strata. METHODS: Using two-sample Mendelian randomization approach, summary statistics were retrieved from genome-wide association studies (GWAS)/GWAS meta-analyses of caffeine intake from tea (n = 395 866)/coffee (n = 373 522), TB-BMD (n = 66 628), and fracture (n = 426 795). Inverse variance weighted method was adopted as the main univariable analysis. Multivariable analysis was conducted to evaluate whether the causal effect is independent. RESULTS: In univariable analysis, genetically determined caffeine intake from tea had positive association with overall TB-BMD (per SD increase in genetically determined caffeine intake, beta of TB-BMD [in SD]: 0.166; 95% confidence interval (CI): 0.006-0.326) and inverse association with fracture (OR = 0.79; 95% CI: 0.654-0.954). Genetically determined caffeine intake from coffee was also positively associated with overall TB-BMD (beta = 0.231; 95% CI: 0.093-0.369). The association remained significant after adjustment for smoking in multivariable analysis. Genetically determined caffeine intake from tea or coffee was both positively associated with TB-BMD in the age strata of 45-60 years, but we lacked evidence of association in other strata. CONCLUSIONS: Genetically, caffeine intake from tea or coffee may be beneficial to bone health. Due to the ascertainment method of caffeine intake from tea, our study also implied genetically higher tea consumption may improve TB-BMD and lower fracture risk.

Low Bone Mineral Density as a Risk Factor for Liver Cirrhosis: A Prospective Cohort Study.

CONTEXT: Bone metabolism interplays with liver metabolism, also known as the liver-bone axis. Osteoporosis is a common complication of cirrhosis, but whether bone mineral density (BMD) can predict cirrhosis development is unknown. OBJECTIVE: This study aims to investigate the relationship between BMD and the risk of incident cirrhosis in the Hong Kong Osteoporosis Study (HKOS). METHODS: BMD was measured at the lumbar spine, femoral neck, total hip, and trochanter of 7,752 participants by the dual-energy X-ray absorptiometer (DXA), and the incidence of cirrhosis and mortality were followed by linking to the territory-wide electronic health records database. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% CI. RESULTS: With a median follow-up of 18.43 years, 42 incident cirrhosis were identified. Higher BMD T-scores at the femoral neck, total hip and trochanter were significantly associated with a reduced risk of cirrhosis (femoral neck: HR 0.56, 95% CI 0.39 to 0.82; total hip: HR 0.60, 95% CI 0.44 to 0.82; trochanter: HR 0.63, 95% CI 0.46 to 0.88). Similar associations were observed in participants without risk factors of cirrhosis at the baseline and further adjusting for the baseline level of alkaline phosphatase, albumin, and alanine transaminase. Consistent relationships in multiple sensitivity analyses suggest the robustness of the results. CONCLUSION: Low BMD could be a novel risk factor and early predictor for cirrhosis, with consistent associations observed in multiple sensitivity analyses.

Effect of vitamin D in addition to letrozole on the ovulation rate of women with polycystic ovary syndrome: protocol of a multicentre randomised double-blind controlled trial.

INTRODUCTION: Low vitamin D status is prevalent among women with polycystic ovary syndrome (PCOS). The objective of the study is to assess the effect of vitamin D supplementation on (1) the ovulation rate to letrozole and (2) other reproductive, endocrine and metabolic outcomes after 1 year of supplementation in women with PCOS. METHODS AND ANALYSIS: This is a multicentre, randomised, double-blind, controlled clinical trial. A total of 220 anovulatory women with PCOS diagnosed by the Rotterdam criteria will be recruited. They will be randomly assigned to either the (1) vitamin D supplementation group or (2) placebo group. Those in the vitamin D group will take oral Vitamin D3 50 000 IU/week for 4 weeks, followed by 50 000 IU once every 2 weeks for 52 weeks. Those who remain anovulatory after 6 months will be treated with a 6-month course of letrozole (2.5 mg to 7.5 mg for 5 days per cycle titrated according to response) for ovulation induction. The primary outcome is the ovulation rate. All statistical analyses will be performed using intention-to-treat and per protocol analyses. ETHICS AND DISSEMINATION: Ethics approval was sought from the Institutional Review Board of the participating units. All participants will provide written informed consent before joining the study. The results of the study will be submitted to scientific conferences and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04650880.

COVID-19 vaccine effectiveness against the Omicron variant of SARS-CoV-2 in multimorbidity: A territory-wide case-control study.

Multimorbidity entails a higher risk of SARS-CoV-2 infection and COVID-19 complications. We examined vaccine effectiveness (VE) stratified by multimorbidity using a case-control study of territory-wide electronic health records in Hong Kong. Cases of infection (testing positive), hospitalization, and mortality were identified from January to March 2022. Controls were matched by age, sex, outpatient attendance/hospitalization date, and Charlson Comorbidity Index. We demonstrated a consistently good VE among people with increased multimorbidity burden; even more so than among those with minimal such burden. There was also a significantly greater VE after a third dose of BNT162b2 or CoronaVac against infection. The difference in VE between those with multimorbidity and those without was less pronounced for hospitalization, and such difference for COVID-19-related mortality was negligible. In conclusion, VE of both examined vaccines against SARS-CoV-2 infection among people with more complex multimorbidity burden is significant. Further vaccine roll-out should prioritize people with multimorbidity.

Effects of SARS-CoV-2 infection on incidence and treatment strategies of hepatocellular carcinoma in people with chronic liver disease.

BACKGROUND: Chronic liver disease (CLD) was associated with adverse clinical outcomes among people with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. AIM: To determine the effects of SARS-CoV-2 infection on the incidence and treatment strategy of hepatocellular carcinoma (HCC) among patients with CLD. METHODS: A retrospective, territory-wide cohort of CLD patients was identified from an electronic health database in Hong Kong. Patients with confirmed SARS-CoV-2 infection [coronavirus disease 2019 (COVID-19)+CLD] between January 1, 2020 and October 25, 2022 were identified and matched 1:1 by propensity-score with those without (COVID-19-CLD). Each patient was followed up until death, outcome event, or November 15, 2022. Primary outcome was incidence of HCC. Secondary outcomes included all-cause mortality, adverse hepatic outcomes, and different treatment strategies to HCC (curative, non-curative treatment, and palliative care). Analyses were further stratified by acute (within 20 d) and post-acute (21 d or beyond) phases of SARS-CoV-2 infection. Incidence rate ratios (IRRs) were estimated by Poisson regression models. RESULTS: Of 193589 CLD patients (> 95% non-cirrhotic) in the cohort, 55163 patients with COVID-19+CLD and 55163 patients with COVID-19-CLD were included after 1:1 propensity-score matching. Upon 249-d median follow-up, COVID-19+CLD was not associated with increased risk of incident HCC (IRR: 1.19, 95%CI: 0.99-1.42, P = 0.06), but higher risks of receiving palliative care for HCC (IRR: 1.60, 95%CI: 1.46-1.75, P < 0.001), compared to COVID-19-CLD. In both acute and post-acute phases of infection, COVID-19+CLD were associated with increased risks of all-cause mortality (acute: IRR: 7.06, 95%CI: 5.78-8.63, P < 0.001; post-acute: IRR: 1.24, 95%CI: 1.14-1.36, P < 0.001) and adverse hepatic outcomes (acute: IRR: 1.98, 95%CI: 1.79-2.18, P < 0.001; post-acute: IRR: 1.24, 95%CI: 1.13-1.35, P < 0.001), compared to COVID-19-CLD. CONCLUSION: Although CLD patients with SARS-CoV-2 infection were not associated with increased risk of HCC, they were more likely to receive palliative treatment than those without. The detrimental effects of SARS-CoV-2 infection persisted in post-acute phase.

Risks of incident major osteoporotic fractures following SARS-CoV-2 infection among older individuals: a population-based cohort study in Hong Kong.

Population-based epidemiological studies on post-acute phase coronavirus 2019 (COVID-19)-related fractures in older adults are lacking. This study aims to examine the risk of incident major osteoporotic fractures following SARS-CoV-2 infection among individuals aged ≥50, compared to individuals without COVID-19. It was a retrospective, propensity-score matched, population-based cohort study of COVID-19 patients and non-COVID individuals identified from the electronic database of the Hong Kong Hospital Authority from January 2020 to March 2022. The primary outcome was a composite of major osteoporotic fractures (hip, clinical vertebral, and upper limb). COVID-19 patients were 1:1 matched to controls using propensity-score according to age, sex, vaccination status, medical comorbidities and baseline medications. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. A total of 429 459 COVID-19 patients were included, 1:1 matched to non-COVID individuals. Upon median follow-up of 11 months, COVID-19 patients had higher risks of major osteoporotic fractures (5.08 vs 3.95 per 1000 persons; HR 1.22 95%CI [1.15-1.31]), hip fractures (2.71 vs 1.94; 1.33 [1.22-1.46]), clinical vertebral fractures (0.42 vs 0.31; 1.29 [1.03-1.62]), and falls (13.83 vs 10.36; 1.28 [1.23-1.33]). Subgroup analyses revealed no significant interaction. In acute (within 30 days) and post-acute phases (beyond 30 days) following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we consistently observed a significant increase in fractures and falls risks. Our study demonstrated increased risk of major osteoporotic fractures after SARS-CoV-2 infection in both acute and post-acute phases in older adults, partly due to increased fall risk. Clinicians should be aware of musculoskeletal health of COVID-19 survivors.

Our study showed that older individuals with coronavirus 2019 (COVID-19) infection are at a higher risk of suffering from major osteoporotic fractures, ie serious bone fractures related to osteoporosis, compared to those not infected. The study analyzed the health records of 429 459 patients aged 50 and older in Hong Kong who had been diagnosed with COVID-19 between January 2020 and March 2022. These patients were compared with a matched group without COVID-19, considering age, sex, vaccination status, medical comorbidities, and concomitant medications. Findings indicated that individuals who had contracted COVID-19 experienced a higher risk of major osteoporotic fractures, hip fractures, and clinical vertebral fractures. The risk of falls, a common cause of these fractures, was also higher in the COVID-19 group. This increased risk of major osteoporotic fractures and falls persists both shortly after infection and in the following months, underscoring the lasting impact of COVID-19 on the bone health of older adults. These results support the recommendations for the assessment of bone health and fall risks, and an urgent review of the requirement for interventions to reduce the risk of fragility fractures in older adult COVID-19 survivors.

Risk of Incident Thyroid Dysfunction in the Post-Acute Phase of COVID-19: A Population-Based Cohort Study in Hong Kong.

OBJECTIVE: The evidence of thyroid dysfunction in the post-acute phase of SARS-CoV-2 infection is limited. This study aimed to evaluate the risk of incident thyroid dysfunction in the post-acute phase of COVID-19. METHODS: This retrospective, propensity-score matched, population-based study included COVID-19 patients and non-COVID-19 individuals between January 2020 and March 2022, identified from the electronic medical records of the Hong Kong Hospital Authority. The cohort was followed up until the occurrence of outcomes, death, or 31 January 2023, whichever came first. Patients with COVID-19 were 1:1 matched to controls based on various variables. The primary outcome was a composite of thyroid dysfunction (hyperthyroidism, hypothyroidism, initiation of antithyroid drug or levothyroxine, and thyroiditis). Cox regression was employed to evaluate the risk of incident thyroid dysfunction during the post-acute phase. RESULTS: A total of 84 034 COVID-19 survivors and 84 034 matched controls were identified. Upon a median follow-up of 303 days, there was no significant increase in the risk of diagnosed thyroid dysfunction in the post-acute phase of COVID-19 (hazard ratio [HR] 1.058, 95% confidence interval 0.979-1.144, P = .154). Regarding the secondary outcomes, patients with COVID-19 did not have increased risk of hyperthyroidism (HR 1.061, P = .345), hypothyroidism (HR 1.062, P = .255), initiation of antithyroid drug (HR 1.302, P = .070), initiation of levothyroxine (HR 1.086, P = .426), or thyroiditis (P = .252). Subgroup and sensitivity analyses were largely consistent with the main analyses. CONCLUSION: Our population-based cohort study provided important reassuring data that COVID-19 was unlikely to be associated with persistent effects on thyroid function.

Prevalence, incidence, and survival analysis of interstitial lung diseases in Hong Kong: a 16-year population-based cohort study.

Background: Published data on the epidemiology of interstitial lung disease (ILD) in Asia is scarce. Understanding the epidemiology is important for authorities in the health management planning. This study aimed to estimate the prevalence, incidence, and survival of ILD in Hong Kong from 2005 to 2020 and evaluate the change of trend over time. Methods: In this retrospective cohort study, we identified ILD patients between 2005 and 2020 using a territory-wide electronic health record database. Prevalence, incidence rates, and age- and sex-standardised incidence rates with United Nations population in 2020 as a reference were estimated. Trends in prevalence and incidence were analysed using joinpoint regression and the average annual percent change (AAPC) was estimated. Median survival, and risk factors of mortality were evaluated using Cox proportional hazard regression. Findings: We identified 5924 patients and included 5884 of them for analysis. The prevalence of ILD increased from 24.7 to 33.6 per 100,000 population from 2005 to 2020 with an AAPC of 1.94 (95% confidence interval, CI: 1.69-2.34). The standardized incidence rate decreased from 5.36 to 2.57 per 100,000 person from 2005 to 2020 (AAPC -3.56, 95% CI, -4.95 to -1.78). The median survival of ILD was 2.50 (95% CI, 2.32-2.69) years. Male, older age, higher Charlson comorbidity index, and IIP subtype were associated with increased mortality with statistical significance. Interpretation: This study provided the first epidemiological evaluation of ILD in Hong Kong. Further studies on ILD in multiple Asian cities and countries are warranted. Funding: None.

The trends in lung cancer prevalence, incidence, and survival in Hong Kong over the past two decades (2002-2021): a population-based study.

Background: Over the past decades, significant progress in lung cancer management has been made. However, the trends in prevalence and survival of lung cancer in the Chinese population over the last decade remain unexplored. This study utilised a territory-wide electronic medical database in Hong Kong to provide the most up-to-date and comprehensive analysis of the trends in prevalence, incidence, and survival over the past two decades. Methods: Descriptive epidemiology study using a retrospective cohort of lung cancer patients from the Clinical Data Analysis and Reporting System (CDARS). 10-year limited-duration prevalence, incidence, and relative period survival were calculated between 2002 and 2021. Sub-groups of age, sex, and comorbidity were examined. The annual percent change (APC) and average annual percent change (AAPC) were estimated using joinpoint regression. Findings: This study included 87,259 incident cases between 2002 and 2021. The 10-year limited duration prevalence (per 100,000 persons) of lung cancer increased from 153.4 to 228.7 (AAPC: 3.08%). Crude incidence (per 100,000 persons) increased from 55.0 to 70.3 (APC: 1.23%), while age-standardised incidence decreased from 42.9 to 33.2 (APC: -1.32%). The 1-year and 5-year relative period survivals showed an increasing trend but remained low. Disparity in trends was observed among different sex and age groups. Interpretation: Lung cancer burden has been increasing partly due to population ageing. Although survival showed improvement over the years, it remained low, highlighting the potential need for interventions. Further study exploring the disparity in sex-specific trends is warranted. Funding: The Innovation and Technology Commission, Hong Kong.

Effectiveness and Respiratory Adverse Events Following Inactivated and mRNA COVID-19 Vaccines in Patients with COPD and Asthma: A Chinese Population-Based Study.

INTRODUCTION: Effectiveness and respiratory adverse events following coronavirus disease-2019 (COVID-19) vaccines have not been well investigated in Chinese patients with chronic obstructive pulmonary disease (COPD) and asthma. METHODS: Using electronic health care records in Hong Kong, we included adults with COPD or asthma or both and hospitalised for severe respiratory exacerbation in a self-controlled case series (SCCS) study between 23/02/2021 and 30/11/2022. Conditional Poisson regression models were used to estimate the incidence of outcomes within exposure periods (28 days after each dose) compared with baseline periods. Cox proportional hazard models evaluated vaccine effectiveness (VE) against COVID-related mortality, hospitalisation, and severe complications, including admission to intensive care units or ventilatory support. The VE assessment was based on vaccine types and the number of doses. RESULTS: In the SCCS, 343 CoronaVac recipients and 212 BNT162b2 recipients were included. No increased risk of outcomes was observed within the exposure periods. In the cohort study, 108,423 and 83,323 patients received ≥ 2 doses of CoronaVac and BNT162b2, respectively. The VE (95% CI) against COVID-related mortality, hospitalisation, and severe complications after two-dose CoronaVac was 77% (74-80%), 18% (6-23%), and 29% (12-43%), respectively, while for the two-dose regimen of BNT162b2, it was 92% (91-94%), 33% (30-37%), and 57% (45-66%), respectively. Higher VE against COVID-related mortality, hospitalisation, and severe complications was found for the three-dose regimen of CoronaVac (94%, 40%, and 71%) and BNT162b2 (98%, 65%, and 83%). Administering a fourth dose of either vaccine showed additional reductions in COVID-related outcomes. CONCLUSIONS: Among people with COPD and asthma, the COVID-19 vaccines CoronaVac and BNT162b2 did not increase severe exacerbations and achieved moderate-to-high effectiveness against COVID-related outcomes. COVID-19 vaccination remains essential and should be encouraged to protect this vulnerable population in future epidemic waves.

Clinical characteristics, densitometric parameters and outcomes of patients with atypical femoral fractures related to bisphosphonate treatment for osteoporosis.

PURPOSE: We described the clinical and densitometric characteristics and treatment outcomes of patients who developed atypical femoral fractures (AFF) while on bisphosphonate for osteoporosis. METHODS: We performed a retrospective cohort study including all adults aged ≥50 years who developed AFF while on bisphosphonates between 1 January 2008 and 31 December 2020, and subsequently managed in the Osteoporosis Centre at Queen Mary Hospital in Hong Kong. A control group of patients who developed fragility hip fractures while on bisphosphonates in the same period was included for comparison. We compared the clinical and densitometric characteristics between the two groups, and described the clinical outcomes for the AFF group. RESULTS: In total, 75 patients were included (AFF: n = 35; fragility hip fracture: n = 40). All were related to oral bisphosphonates. The AFF group was characterised by a longer duration of bisphosphonate use (median of 5 years), higher bone mineral density (BMD) and more acute neck-shaft angle (all p < 0.05). Following AFF, 8 patients (22.9%) did not receive any subsequent bone-active agents: due to refusal to use an injectable, or BMD out of osteoporotic range. Most of those who received bone-active agents were given teriparatide, followed by raloxifene, and achieved stable BMD. However, subsequent fragility risk remained high. Nonetheless, AFF did not confer excess morbidity and mortality. CONCLUSION: AFF was characterised by usually long duration of bisphosphonate use, higher BMD and more acute neck-shaft angle. AFF did not confer significant impairment in mobility or mortality. Nonetheless, further research work is necessary to optimise bone health among patients who develop AFF.

Illicit drug use is associated with lower bone mineral density and bone strength.

Objectives: To evaluate the association of illicit drug use with bone mineral density (BMD) and hip geometric parameters at the narrow neck. Methods: This is a cross-sectional matched cohort study conducted in the Hong Kong Chinese population. Associations with illicit drug use were estimated using linear regression for BMD (lumbar spine and femoral neck) and hip geometrical parameters (cross-sectional area [CSA], cross-sectional moment of inertia [CSMI], section modulus [SM], average cortical thickness [ACT] and BMD at the narrow neck) after adjusting for age, body mass index (BMI), smoking status, drinking status, physical activity, and history of antipsychotic and antidepressant use. Mean difference and 95% confidence intervals (95% CI) were calculated between 108 illicit drug users and 108 controls using an adjusted linear model and cluster-robust standard errors after matching by age and sex. The false discovery rate was used to correct for multiple testing. Results: Illicit drug users had a significantly lower BMD (g/cm2) at the lumbar spine (mean difference: -0.062; 95% CI: -0.108 to -0.015), and femoral neck (mean difference: -0.058; 95% CI: -0.106 to -0.010) in the fully adjusted model. Illicit drug users also had a significantly lower CSA (mean difference: -0.238 cm2; 95% CI: -0.462 to -0.013), ACT (mean difference: -0.018 cm; 95% CI: -0.030 to -0.006) and BMD (mean difference: -0.070 g/cm2; 95% CI: -0.128 to -0.012) at the narrow neck. Conclusions: Illicit drug use is associated with lower BMD and bone strength. Future studies evaluating the risk of illicit drug use with fragility fracture are warranted.

Levothyroxine Treatment Among Pregnant Women and Risk of Seizure in Children: A Population-Based Cohort Study.

INTRODUCTION AND OBJECTIVE: The risk of seizure in offspring following prenatal exposure to levothyroxine is not well investigated. This study aimed to evaluate the association between levothyroxine treatment among pregnant women and the risk of seizure in their offspring. METHODS: This population-based cohort study included all pregnant women who delivered a live birth between January 2001 to January 2018, with a follow-up to December 2020, using data from the Hong Kong Clinical Data Analysis and Reporting System. Propensity score fine-stratification weighted hazard ratios (wHR) with 95% confidence intervals (CIs) were presented to assess the association between maternal levothyroxine use during pregnancy and seizures in children. RESULTS: Among 528,343 included mother-child pairs, 3044 children were prenatally exposed to levothyroxine at any time during the pregnancy period. A significantly increased risk of seizure was observed in children of the prenatally exposed group compared with the prenatally unexposed group (wHR 1.12, 95% CI 1.02-1.22). An increased risk of seizure was observed when comparing the prenatally exposed group with euthyroid mothers who had no history of thyroid-related diagnosis or prescriptions (wHR 1.12, 95% CI 1.02-1.23). However, no significant difference was observed between the prenatally exposed group and those previously exposed to levothyroxine but had stopped during pregnancy (wHR 0.97, 95% CI 0.66-1.44). No significant difference was observed in the sibling-matched analysis either (wHR 1.23, 95% CI 0.76-2.01). CONCLUSION: The observed increased risk of seizure in children born from mothers exposed to levothyroxine during pregnancy might be due to residual confounding by maternal thyroid disease. The findings support the current guidelines on the safe use of levothyroxine treatment during pregnancy.

Association of Bone Mineral Density and Bone Turnover Markers with the Risk of Diabetes: Hong Kong Osteoporosis Study and Mendelian Randomization.

Preclinical studies demonstrated that bone plays a central role in energy metabolism. However, how bone metabolism is related to the risk of diabetes in humans is unknown. We investigated the association of bone health (bone mineral density [BMD] and bone turnover markers) with incident type-2 diabetes mellitus (T2DM) based on the Hong Kong Osteoporosis Study (HKOS). A total of 993 and 7160 participants from the HKOS were studied for the cross-sectional and prospective analyses, respectively. The cross-sectional study evaluated the association of BMD and bone biomarkers with fasting glucose and glycated hemoglobin (HbA1c ) levels, whereas the prospective study examined the associations between BMD at study sites and the risk of T2DM by following subjects a median of 16.8 years. Body mass index (BMI) was adjusted in all full models. Mendelian randomization (MR) was conducted for causal inference. In the cross-sectional analysis, lower levels of circulating bone turnover markers and higher BMD were significantly associated with increased fasting glucose and HbA1c levels. In the prospective analysis, higher BMD (0.1 g/cm2 ) at the femoral neck and total hip was associated with increased risk of T2DM with hazard ratios (HRs) of 1.10 (95% confidence interval [CI], 1.03 to 1.18) and 1.14 (95% CI, 1.08 to 1.21), respectively. The presence of osteoporosis was associated with a 30% reduction in risk of T2DM compared to those with normal BMD (HR = 0.70; 95% CI, 0.55 to 0.90). The MR results indicate a robust genetic causal association of estimated BMD (eBMD) with 2-h glucose level after an oral glucose challenge test (estimate = 0.043; 95% CI, 0.007 to 0.079) and T2DM (odds ratio = 1.064; 95% CI, 1.036 to 1.093). Higher BMD and lower levels of circulating bone biomarkers were cross-sectionally associated with poor glycemic control. Moreover, higher BMD was associated with a higher risk of incident T2DM and the association is probably causal. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

COVID-19 and cognitive performance: a Mendelian randomization study.

Background: A substantial proportion of individuals with COVID-19 experienced cognitive impairment after resolution of SARS-CoV-2 infection. We aimed to evaluate whether genetic liability to SARS-CoV-2 infection per se, or more severe COVID-19, is causally linked to cognitive deficit. Methods: We firstly performed univariable Mendelian randomization (MR) analysis to examine whether genetic liability to SARS-CoV-2 infection, hospitalized and severe COVID-19 is causally associated with cognitive performance. To dissect the causal pathway, multivariable MR (MVMR) analysis was conducted by adjusting for five inflammatory markers [C-reactive protein, interleukin (IL)-1ß, IL-6, IL-8, and tumour necrosis factor α, as proxies of systemic inflammation]. Results: In univariable MR analysis, host genetic liability to SARS-CoV-2 infection was associated with lower cognitive performance [inverse variance weighted (IVW) analysis, estimate: -0.023; 95% Confidence Interval (CI): -0.038 to -0.009]. Such causal association was attenuated in MVMR analysis when we adjusted for the five correlated inflammatory markers in one analysis (IVW analysis, estimate: -0.022; 95% CI: -0.049 to 0.004). There was insufficient evidence of association for genetic liability to hospitalized and severe COVID-19 with cognitive performance. Conclusion: The causal effect of host genetic liability to SARS-CoV-2 infection on reduced cognitive performance may be mediated by systemic inflammation. Future studies examining whether anti-inflammatory agents could alleviate cognitive impairment in SARS-CoV-2-infected individuals are warranted.

Long-term effects of coronavirus disease 2019 on diabetes complications and mortality in people with diabetes: Two cohorts in the UK and Hong Kong.

AIM: To evaluate the long-term associations between coronavirus disease 2019 (COVID-19) and diabetes complications and mortality, in patients with diabetes. MATERIALS AND METHODS: People with diabetes diagnosed with COVID-19 infection (exposed group), from 16 March 2020 to 31 May 2021 from the UK Biobank (UKB cohort; n = 2456), and from 1 April 2020 to 31 May 2022 from the electronic health records in Hong Kong (HK cohort; n = 80 546), were recruited. Each patient was randomly matched with participants with diabetes but without COVID-19 (unexposed group), based on age and sex (UKB, n = 41 801; HK, n = 391 849). Patients were followed for up to 18 months until 31 August 2021 for UKB, and up to 28 months until 15 August 2022 for HK. Characteristics between cohorts were further adjusted with Inverse Probability Treatment Weighting. Long-term association of COVID-19 with multi-organ disease complications and all-cause mortality after 21 days of diagnosis was evaluated by Cox regression. RESULTS: Compared with uninfected participants, patients with COVID-19 infection with diabetes were consistently associated with higher risks of cardiovascular diseases (coronary heart disease [CHD]: hazard ratio [HR] [UKB]: 1.6 [95% confidence interval {CI}: 1.0, 2.4], HR [HK]: 1.2 [95% CI: 1.0, 1.5]; and stroke: HR [UKB]: 2.0 [95% CI: 1.1, 3.6], HR [HK]: 1.5 [95% CI: 1.3, 1.8]), microvascular disease (end stage renal disease: HR [UKB]: 2.1 [95% CI: 1.1, 4.0], HR [HK]: 1.2 [95% CI: 1.1, 1.4]) and all-cause mortality (HR [UKB]: 4.6 [95% CI: 3.8, 5.5], HR [HK]: 2.6 [95% CI: 2.5, 2.8]), in both cohorts. CONCLUSIONS: COVID-19 infection is associated with long-term increased risks of diabetes complications (especially cardiovascular complications, and mortality) in people with diabetes. Monitoring for signs/symptoms of developing these long-term complications post-COVID-19 infection in the infected patient population of people with diabetes may be beneficial in minimizing their morbidity and mortality.

Incidence of diabetes following COVID-19 vaccination and SARS-CoV-2 infection in Hong Kong: A population-based cohort study.

BACKGROUND: The risk of incident diabetes following Coronavirus Disease 2019 (COVID-19) vaccination remains to be elucidated. Also, it is unclear whether the risk of incident diabetes after Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is modified by vaccination status or differs by SARS-CoV-2 variants. We evaluated the incidence of diabetes following mRNA (BNT162b2), inactivated (CoronaVac) COVID-19 vaccines, and after SARS-CoV-2 infection. METHODS AND FINDINGS: In this population-based cohort study, individuals without known diabetes were identified from an electronic health database in Hong Kong. The first cohort included people who received ≥1 dose of COVID-19 vaccine and those who did not receive any COVID-19 vaccines up to September 2021. The second cohort consisted of confirmed COVID-19 patients and people who were never infected up to March 2022. Both cohorts were followed until August 15, 2022. A total of 325,715 COVID-19 vaccine recipients (CoronaVac: 167,337; BNT162b2: 158,378) and 145,199 COVID-19 patients were 1:1 matched to their respective controls using propensity score for various baseline characteristics. We also adjusted for previous SARS-CoV-2 infection when estimating the conditional probability of receiving vaccinations, and vaccination status when estimating the conditional probability of contracting SARS-CoV-2 infection. Hazard ratios (HRs) and 95% confidence intervals (CIs) for incident diabetes were estimated using Cox regression models. In the first cohort, we identified 5,760 and 4,411 diabetes cases after receiving CoronaVac and BNT162b2 vaccines, respectively. Upon a median follow-up of 384 to 386 days, there was no evidence of increased risks of incident diabetes following CoronaVac or BNT162b2 vaccination (CoronaVac: 9.08 versus 9.10 per 100,000 person-days, HR = 0.998 [95% CI 0.962 to 1.035]; BNT162b2: 7.41 versus 8.58, HR = 0.862 [0.828 to 0.897]), regardless of diabetes type. In the second cohort, we observed 2,109 cases of diabetes following SARS-CoV-2 infection. Upon a median follow-up of 164 days, SARS-CoV-2 infection was associated with significantly higher risk of incident diabetes (9.04 versus 7.38, HR = 1.225 [1.150 to 1.305])-mainly type 2 diabetes-regardless of predominant circulating variants, albeit lower with Omicron variants (p for interaction = 0.009). The number needed to harm at 6 months was 406 for 1 additional diabetes case. Subgroup analysis revealed no evidence of increased risk of incident diabetes among fully vaccinated COVID-19 survivors. Main limitations of our study included possible misclassification bias as type 1 diabetes was identified through diagnostic coding and possible residual confounders due to its observational nature. CONCLUSIONS: There was no evidence of increased risks of incident diabetes following COVID-19 vaccination. The risk of incident diabetes increased following SARS-CoV-2 infection, mainly type 2 diabetes. The excess risk was lower, but still statistically significant, for Omicron variants. Fully vaccinated individuals might be protected from risks of incident diabetes following SARS-CoV-2 infection.