A clinicopathological study of non-functioning pituitary neuroendocrine tumours using the World Health Organization 2022 classification.

Background: The 2022 World Health Organization (WHO) classification of pituitary neuroendocrine tumour (PitNET) supersedes the previous one in 2017 and further consolidates the role of transcription factors (TF) in the diagnosis of PitNET. Here, we investigated the clinical utility of the 2022 WHO classification, as compared to that of 2017, in a cohort of patients with non-functioning PitNET (NF-PitNET). Methods: A total of 113 NF-PitNET patients who underwent resection between 2010 and 2021, and had follow-up at Queen Mary Hospital, Hong Kong, were recruited. Surgical specimens were re-stained for the three TF: steroidogenic factor (SF-1), T-box family member TBX19 (TPIT) and POU class 1 homeobox 1 (Pit-1). The associations of different NF-PitNET subtypes with tumour-related outcomes were evaluated by logistic and Cox regression analyses. Results: Based on the 2022 WHO classification, the majority of NF-PitNET was SF-1-lineage tumours (58.4%), followed by TPIT-lineage tumours (18.6%), tumours with no distinct lineage (16.8%) and Pit-1-lineage tumours (6.2%). Despite fewer entities than the 2017 classification, significant differences in disease-free survival were present amongst these four subtypes (Log-rank test p=0.003), specifically between SF-1-lineage PitNET and PitNET without distinct lineage (Log-rank test p<0.001). In multivariable Cox regression analysis, the subtype of PitNET without distinct lineage (HR 3.02, 95% CI 1.28-7.16, p=0.012), together with tumour volume (HR 1.04, 95% CI 1.01-1.07, p=0.017), were independent predictors of a composite of residual or recurrent disease. Conclusion: The 2022 WHO classification of PitNET is a clinically useful TF and lineage-based system for subtyping NF-PitNET with different tumour behaviour and prognosis.

Optimal glycaemic control and the reduced risk of colorectal adenoma and cancer in patients with diabetes: a population-based cohort study.

OBJECTIVE: Whether varying degrees of glycaemic control impact colonic neoplasm risk in patients with diabetes mellitus (DM) remains uncertain. DESIGN: Patients with newly diagnosed DM were retrieved from 2005 to 2013. Optimal glycaemic control at baseline was defined as mean haemoglobin A1c (HbA1c)<7%. Outcomes of interest included colorectal cancer (CRC) and colonic adenoma development. We used propensity score (PS) matching with competing risk models to estimate subdistribution HRs (SHRs). We further analysed the combined effect of baseline and postbaseline glycaemic control based on time-weighted mean HbA1c during follow-up. RESULTS: Of 88 468 PS-matched patients with DM (mean (SD) age: 61.5 (±11.7) years; male: 47 127 (53.3%)), 1229 (1.4%) patients developed CRC during a median follow-up of 7.2 (IQR: 5.5-9.4) years. Optimal glycaemic control was associated with lower CRC risk (SHR 0.72; 95% CI 0.65 to 0.81). The beneficial effect was limited to left-sided colon (SHR 0.71; 95% CI 0.59 to 0.85) and rectum (SHR 0.71; 95% CI 0.57 to 0.89), but not right-sided colon (SHR 0.86; 95% CI 0.67 to 1.10). Setting suboptimal glycaemic control at baseline/postbaseline as a reference, a decreased CRC risk was found in optimal control at postbaseline (SHR 0.79), baseline (SHR 0.71) and both time periods (SHR 0.61). Similar associations were demonstrated using glycaemic control as a time-varying covariate (HR 0.75). A stepwise greater risk of CRC was found (Ptrend<0.001) with increasing HbA1c (SHRs 1.34, 1.30, 1.44, 1.58 for HbA1c 7.0% to <7.5%, 7.5% to <8.0%, 8.0% to <8.5% and ≥8.5%, respectively). Optimal glycaemic control was associated with a lower risk of any, non-advanced and advanced colonic adenoma (SHRs 0.73-0.87). CONCLUSION: Glycaemic control in patients with DM was independently associated with the risk of colonic adenoma and CRC development with a biological gradient.

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.

A Prospective 1-Year Follow-Up of Glycemic Status and C-Peptide Levels of COVID-19 Survivors with Dysglycemia in Acute COVID-19 Infection.

Background: We evaluated changes in glycemic status, over 1 year, of coronavirus disease 2019 (COVID-19) survivors with dysglycemia in acute COVID-19. Methods: COVID-19 survivors who had dysglycemia (defined by glycosylated hemoglobin [HbA1c] 5.7% to 6.4% or random glucose ≥10.0 mmol/L) in acute COVID-19 were recruited from a major COVID-19 treatment center from September to October 2020. Matched non-COVID controls were recruited from community. The 75-g oral glucose tolerance test (OGTT) were performed at baseline (6 weeks after acute COVID-19) and 1 year after acute COVID-19, with HbA1c, insulin and C-peptide measurements. Progression in glycemic status was defined by progression from normoglycemia to prediabetes/diabetes, or prediabetes to diabetes. Results: Fifty-two COVID-19 survivors were recruited. Compared with non-COVID controls, they had higher C-peptide (P< 0.001) and trend towards higher homeostasis model assessment of insulin resistance (P=0.065). Forty-three COVID-19 survivors attended 1-year reassessment. HbA1c increased from 5.5%±0.3% to 5.7%±0.2% (P<0.001), with increases in glucose on OGTT at fasting (P=0.089), 30-minute (P=0.126), 1-hour (P=0.014), and 2-hour (P=0.165). At baseline, 19 subjects had normoglycemia, 23 had prediabetes, and one had diabetes. Over 1 year, 10 subjects (23.8%; of 42 non-diabetes subjects at baseline) had progression in glycemic status. C-peptide levels remained unchanged (P=0.835). Matsuda index decreased (P=0.007) and there was a trend of body mass index increase from 24.4±2.7 kg/m2 to 25.6±5.2 (P=0.083). Subjects with progression in glycemic status had more severe COVID-19 illness than non-progressors (P=0.030). Reassessment was not performed in the control group. Conclusion: Subjects who had dysglycemia in acute COVID-19 were characterized by insulin resistance. Over 1 year, a quarter had progression in glycemic status, especially those with more severe COVID-19. Importantly, there was no significant deterioration in insulin secretory capacity.

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 COVID-19-related fractures in older adults are lacking. This study aims to examine the risk of incident major osteoporotic fractures following COVID-19 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 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 COVID-19 infection are at a higher risk of suffering from major osteoporotic fractures, i.e. serious bone fractures related to osteoporosis, compared to those not infected. The study analysed 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.

Thyroid dysfunction in COVID-19.

The COVID-19 pandemic has affected over 772 million people globally. While lung damage is the major contributor to the morbidity and mortality of this disease, the involvement of multiple organs, including the endocrine glands, has been reported. This Review aims to provide an updated summary of evidence regarding COVID-19 and thyroid dysfunction, incorporating highlights of recent advances in the field, particularly in relation to long COVID and COVID-19 vaccination. Since subacute thyroiditis following COVID-19 was first reported in May 2020, thyroid dysfunction associated with COVID-19 has been increasingly recognized, secondary to direct and indirect effects on the hypothalamic-pituitary-thyroid axis. Here, we summarize the epidemiological evidence, pattern and clinical course of thyroid dysfunction following COVID-19 and examine radiological, molecular and histological evidence of thyroid involvement in SARS-CoV-2 infection. Beyond acute SARS-CoV-2 infection, it is also timely to examine the course and implication of thyroid dysfunction in the context of long COVID owing to the large population of survivors of COVID-19 worldwide. This Review also analyses the latest evidence on the relationship between the therapeutics and vaccination for COVID-19 and thyroid dysfunction. To conclude, evidence-based practice recommendations for thyroid function testing during and following COVID-19 and concerning COVID-19 vaccination are proposed.

Hemoglobin A1c in early pregnancy to identify preexisting diabetes mellitus and women at risk of hyperglycemic pregnancy complications.

BACKGROUND: Unrecognized diabetes mellitus during pregnancy could pose serious maternal and neonatal complications. A hemoglobin A1c level of ≥6.5% was used to diagnose both diabetes mellitus in nonpregnant individuals and diabetes in pregnancy. As the hemoglobin A1c level could be influenced by maternal physiological changes, the optimal cutoff in early pregnancy to detect women with diabetes in pregnancy and associated complications remains unclear. OBJECTIVE: This study aimed to evaluate the diagnostic performance of various hemoglobin A1c levels and the optimal hemoglobin A1c cutoff to identify mothers with diabetes in pregnancy diagnosed by the gold standard 75 g oral glucose tolerance test before 24 weeks of gestation. In addition, the pregnancy and neonatal outcomes were compared using the optimal hemoglobin A1c cutoff. STUDY DESIGN: A retrospective cohort study was conducted between 2004 and 2019. Women with at least 1 risk factor of gestational diabetes mellitus received an oral glucose tolerance test before 24 weeks of gestation. Terminology of hyperglycemia first detected during pregnancy by oral glucose tolerance test was classified as either diabetes in pregnancy or gestational diabetes mellitus following the World Health Organization's recommendation. Women who met the diagnostic criteria of diabetes in pregnancy and early-onset gestational diabetes mellitus (ie, before 24 weeks of gestation) and had a paired hemoglobin A1c measurement within 4 weeks of their early oral glucose tolerance test were studied. Sensitivity, specificity, and positive and negative predictive values at various hemoglobin A1c cutoffs were calculated for the detection of diabetes in pregnancy. The optimal hemoglobin A1c level was identified from the constructed receiver operating characteristic curves. Multivariate binary logistic regression analyses were performed to calculate the unadjusted and adjusted odds ratios for pregnancy complications. RESULTS: There were 63,111 deliveries, and 22,949 women underwent an oral glucose tolerance test before 24 weeks of gestation. A total of 157 and 3210 women met the diagnostic criteria of diabetes in pregnancy and early-onset gestational diabetes mellitus using an oral glucose tolerance test, respectively. Only 346 participants had a paired hemoglobin A1c and oral glucose tolerance test measurement (82 cases with diabetes in pregnancy and 264 cases with early-onset gestational diabetes mellitus). The receiver operating characteristic curve identified an optimal hemoglobin A1c cutoff of 5.7% to diagnose diabetes in pregnancy, with a sensitivity of 64.6%, specificity of 81.1%, positive predictive value of 51.5%, and negative predictive value of 88.1%. A hemoglobin A1c cutoff of either 5.9% or 6.5% could miss 47.6% or 73.2% of women with diabetes in pregnancy. In multivariate logistic regression analysis, a hemoglobin A1c level of ≥5.7% increased the risk of maternal insulin use (adjusted odds ratio, 6.69; 95% confidence interval, 3.44-12.99), macrosomia (adjusted odds ratio, 7.43; 95% confidence interval, 1.90-29.00), and shoulder dystocia (adjusted odds ratio, 6.56; 95% confidence interval, 1.161-37.03). CONCLUSION: The optimal hemoglobin A1c cutoff to detect diabetes in pregnancy diagnosed using an oral glucose tolerance test before 24 weeks of gestation was 5.7%, but this cutoff could not reliably identify diabetes in pregnancy owing to the low sensitivity. However, an early hemoglobin A1c level of ≥5.7% indicated increased risks of pregnancy and neonatal complications.

Risk of hyperkalaemia in patients with type 2 diabetes mellitus prescribed with SGLT2 versus DPP-4 inhibitors.

AIMS: To investigate the risk of hyperkalaemia in new users of sodium-glucose cotransporter 2 (SGLT2) inhibitors vs. dipeptidyl peptidase-4 (DPP-4) inhibitors among patients with type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: Patients with T2DM who commenced treatment with an SGLT2 or a DPP-4 inhibitor between 2015 and 2019 were collected. A multivariable Cox proportional hazards analysis was applied to compare the risk of central laboratory-determined severe hyperkalaemia, hyperkalaemia, hypokalaemia (serum potassium ≥6.0, ≥5.5, and <3.5 mmol/L, respectively), and initiation of a potassium binder in patients newly prescribed an SGLT2 or a DPP-4 inhibitor. A total of 28 599 patients (mean age 60 ± 11 years, 60.9% male) were included after 1:2 propensity score matching, of whom 10 586 were new users of SGLT2 inhibitors and 18 013 of DPP-4 inhibitors. During a 2-year follow-up, severe hyperkalaemia developed in 122 SGLT2 inhibitor users and 325 DPP-4 inhibitor users. Use of SGLT2 inhibitors was associated with a 29% reduction in incident severe hyperkalaemia [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.58-0.88] compared with DPP-4 inhibitors. Risk of hyperkalaemia (HR 0.81, 95% CI 0.71-0.92) and prescription of a potassium binder (HR 0.74, 95% CI 0.67-0.82) were likewise decreased with SGLT2 inhibitors compared with DPP-4 inhibitors. Occurrence of incident hypokalaemia was nonetheless similar between those prescribed an SGLT2 inhibitor and those prescribed a DPP-4 inhibitor (HR 0.90, 95% CI 0.81-1.01). CONCLUSION: Our study provides real-world evidence that compared with DPP-4 inhibitors, SGLT2 inhibitors were associated with lower risk of hyperkalaemia and did not increase the incidence of hypokalaemia in patients with T2DM.

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.

Serum Tsukushi Level Is Associated With the Severity of Liver Fibrosis Independent of Type 2 Diabetes.

BACKGROUND AND AIMS: Tsukushi (TSK) is a recently identified hepatokine, and we aimed to investigate the association between systemic TSK and the severity of nonalcoholic fatty liver disease (NAFLD) in subjects with and without type 2 diabetes mellitus (DM). METHODS: Three hundred ninety-three DM and 289 without DM individuals were recruited for transient elastography assessment to determine liver steatosis and fibrosis. Serum TSK was measured by ELISA. The presence of NAFLD was defined as controlled attenuation parameter ≥ 248 dB/m. RESULTS: NAFLD was present in 276 (70.2%) and 129 (44.6%) subjects with and without DM respectively, and they had higher serum TSK levels than those without NAFLD [DM group: 91.0 ng/mL (61.7-133.8) vs 82.5 (60.9-118.5), P < .01 respectively; without DM group: 97.1 ng/mL (69.3-148.6) vs 80.8 (53.4-111.6) respectively, P < .01]. Univariate analysis showed that serum TSK significantly correlated with the degree of steatosis and fibrosis both in subjects with and without DM. On multivariable regression analysis, only liver stiffness and estimated glomerular filtration rate were significant determinants of TSK level, and the relationship was independent of diabetes and serum adiponectin. Out of 405 subjects with NAFLD, 49 had either advanced fibrosis or cirrhosis. The area under receiver operating characteristic curve of serum TSK to indicate advanced fibrosis or cirrhosis was 0.70 (95% CI .62-.77), which was significantly better than that of fibrosis-4 index, 0.64 (95% CI .55-.72), P < .05. CONCLUSION: Serum TSK levels were increased in subjects with NAFLD and reflected the severity of liver fibrosis.

Serum thrombospondin-2 level changes with liver stiffness improvement in patients with type 2 diabetes.

OBJECTIVE: Baseline circulating thrombospondin-2 (TSP2) level was identified as a potential novel hepatic fibrosis biomarker that associates with development and progression of hepatic fibrosis in patients with nonalcoholic fatty liver disease and type 2 diabetes. Here, we investigated whether circulating TSP2 levels changed with improvement in liver stiffness (LS), which reflects liver fibrosis on transient elastography. DESIGN: Serum TSP2 levels were measured in participants from a randomized, open-label intervention study, at baseline and after 24-weeks treatment of either dapagliflozin 10 mg (N = 30) or sitagliptin 100 mg daily (N = 30). Vibration-controlled transient elastography was performed to evaluate the severity of hepatic fibrosis and steatosis using LS and controlled attenuation parameter (CAP), respectively. PATIENTS AND MEASUREMENTS: Among all 60 participants with similar clinical characteristics at baseline (mean HbA1c 8.9%, CAP 289 dB/m and LS 5.8 kPa), despite similar HbA1c lowering, treatment with dapagliflozin, but not sitagliptin, led to significant improvements in body weight (BW) (p = .012), CAP (p = .015) and LS (p = .011) after 24 weeks. RESULTS: Serum TSP2 level decreased significantly from baseline in dapagliflozin-treated participants (p = .035), whereas no significant change was observed with sitagliptin. In correlation analysis, change in serum TSP2 levels only positively correlated with change in LS (r = .487, p = .006), but not with changes in BW, CAP or HbA1c after dapagliflozin treatment. CONCLUSIONS: Serum TSP2 level decreased with LS after dapagliflozin treatment, and was independent of improvements in BW, glycemic control and hepatic steatosis, further supporting the potential of serum TSP2 level as a novel hepatic fibrosis biomarker in type 2 diabetes.

Cushing's syndrome caused by ACTH precursors secreted from a pancreatic yolk sac tumor in an adult-a case report and literature review.

Here, we report the first adult case of pancreatic yolk sac tumor with ectopic adrenocorticotropic hormone (ACTH) syndrome. The patient was a 27-year-old woman presenting with abdominal distension, Cushingoid features, and hyperpigmentation. Endogenous Cushing's syndrome was biochemically confirmed. The ACTH level was in the normal range, which raised the suspicion of ACTH precursor-dependent disease. Elevated ACTH precursors were detected, supporting the diagnosis of ectopic ACTH syndrome. Functional imaging followed by tissue sampling revealed a pancreatic yolk sac tumor. The final diagnosis was Cushing's syndrome due to a yolk sac tumor. The patient received a steroidogenesis inhibitor and subsequent bilateral adrenalectomy for control of hypercortisolism. Her yolk sac tumor was treated with chemotherapy and targeted therapy. Cushing's syndrome secondary to a yolk sac tumor is extremely rare. This case illustrated the utility of ACTH precursor measurement in confirming an ACTH-related pathology and distinguishing an ectopic from a pituitary source for Cushing's syndrome.

Ten metabolites-based algorithm predicts the future development of type 2 diabetes in Chinese.

INTRODUCTION: Type 2 diabetes (T2D) is a heterogeneous metabolic disease with large variations in the relative contributions of insulin resistance and ß-cell dysfunction across different glucose tolerance subgroups and ethnicities. A more precise yet feasible approach to categorize risk preceding T2D onset is urgently needed. This study aimed to identify potential metabolic biomarkers that could contribute to the development of T2D and investigate whether their impact on T2D is mediated through insulin resistance and ß-cell dysfunction. METHODS: A non-targeted metabolomic analysis was performed in plasma samples of 196 incident T2D cases and 196 age- and sex-matched non-T2D controls recruited from a long-term prospective Chinese community-based cohort with a follow-up period of âˆ¼ 16 years. RESULTS: Metabolic profiles revealed profound perturbation of metabolomes before T2D onset. Overall metabolic shifts were strongly associated with insulin resistance rather than ß-cell dysfunction. In addition, 188 out of the 578 annotated metabolites were associated with insulin resistance. Bi-directional mediation analysis revealed putative causal relationships among the metabolites, insulin resistance and T2D risk. We built a machine-learning based prediction model, integrating the conventional clinical risk factors (age, BMI, TyG index and 2hG) and 10 metabolites (acetyl-tryptophan, kynurenine, γ-glutamyl-phenylalanine, DG(18:2/22:6), DG(38:7), LPI(18:2), LPC(P-16:0), LPC(P-18:1), LPC(P-20:0) and LPE(P-20:0)) (AUROC = 0.894, 5.6% improvement comparing to the conventional clinical risk model), that successfully predicts the development of T2D. CONCLUSIONS: Our findings support the notion that the metabolic changes resulting from insulin resistance, rather than ß-cell dysfunction, are the primary drivers of T2D in Chinese adults. Metabolomes as a valuable phenotype hold potential clinical utility in the prediction of T2D.

Identification and multicentric validation of soluble CDCP1 as a robust serological biomarker for risk stratification of NASH in obese Chinese.

The definitive diagnosis of non-alcoholic steatohepatitis (NASH) currently relies on invasive and labor-intensive liver biopsy. Here, we identified soluble CUB domain-containing protein 1 (sCDCP1) as a top-ranked non-invasive biomarker for NASH using Olink-based proteomics in 238 obese individuals with liver biopsies. Both the circulating concentration and hepatic mRNA abundance of sCDCP1 were significantly elevated in patients with NASH and correlated closely with each histological feature of NASH. In the pooled multicenter validation cohort, sCDCP1 as a standalone biomarker achieved an area under the receiver operating characteristic (AUROC) of 0.838 (95% confidence interval [CI] 0.789-0.887) for diagnosing NASH, which is better than those achieved with cytokeratin-18 and other non-invasive tests. Furthermore, the C-DAG model established by the combination of sCDCP1 with diabetes, aspartate aminotransferase (AST), and gender accurately rules in and rules out both NASH and fibrotic NASH (gray zones <20%). Thus, sCDCP1-based non-invasive tests can be potentially implemented for screening and early diagnosis of NASH and for ruling out low-risk individuals to avoid unnecessary liver biopsies.

Scaling-Up Insights for Zinc-Air Battery Technologies Realizing Reversible Zinc Anodes.

Zinc-air battery (ZAB) technology is considered one of the promising candidates to complement the existing lithium-ion batteries for future large-scale high-energy-storage demands. The scientific literature reveals many efforts for the ZAB chemistries, materials design, and limited accounts for cell design principles with apparently superior performances for liquid and solid-state electrolytes. However, along with the difficulty of forming robust solid-electrolyte interphases, the discrepancy in testing methods and assessment metrics severely challenges the realistic evaluation/comparison and commercialization of ZABs. Here, strategies to formulate reversible zinc anodes are proposed and specific cell-level energy metrics (100-500 Wh kg-1 ) and realistic long-cycling operations are realized. Stabilizing anode/electrolyte interfaces results in a cumulative capacity of 25 Ah cm-2 and Coulomb efficiency of >99.9% for 5000 plating/stripping cycles. Using 1-10 Ah scale (≈500 Wh kg-1 at cell level) solid-state zinc-air pouch cells, scale-up insights for Ah-level ZABs that can progress from lab-scale research to practical production are also offered.

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.

Opportunistic screening for asymptomatic left ventricular dysfunction in type 2 diabetes mellitus.

BACKGROUND: International guidelines recommend natriuretic peptide biomarker-based screening for patients at high heart failure (HF) risk to allow early detection. There have been few reports about the incorporation of screening procedure to existing clinical practice. OBJECTIVE: To implement screening of left ventricular dysfunction in patients with type 2 diabetes mellitus (DM). METHOD: A prospective screening study at the DM complication screening centre was performed. RESULTS: Between 2018 and 2019, 1043 patients (age: 63.7±12.4 years; male: 56.3%) with mean glycated haemoglobin of 7.25%±1.34% were recruited. 81.8% patients had concomitant hypertension, 31.1% had coronary artery disease, 8.0% had previous stroke, 5.5% had peripheral artery disease and 30.7% had chronic kidney disease (CKD) stages 3-5. 43 patients (4.1%) had an elevated N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentration above the age-specific diagnostic thresholds for HF, and 43 patients (4.1%) had newly detected atrial fibrillation (AF). The prevalence of elevated NT-proBNP increased with age from 0.85% in patients aged <50 years to 7.14% in those aged 70-79 years and worsening kidney function from 0.43% in patients with CKD stage 1 to 42.86% in CKD stage 5. In multivariate logistic regression, male gender (OR: 3.67 (1.47-9.16), p = 0.005*), prior stroke (OR: 3.26 (1.38-7.69), p = 0.007*), CKD (p<0.001*) and newly detected AF (OR: 7.02 (2.65-18.57), p<0.001*) were significantly associated with elevated NT-proBNP. Among patients with elevated NT-proBNP, their mean left ventricular ejection fraction (LVEF) was 51.4%±14.7%, and 45% patients had an LVEF <50%. CONCLUSION: NT-proBNP and ECG screening could be implemented with relative ease to facilitate early detection of cardiovascular complication and improve long-term outcomes.

Heterointerface promoted trifunctional electrocatalysts for all temperature high-performance rechargeable Zn-air batteries.

The rational design of wide-temperature operating Zn-air batteries is crucial for their practical applications. However, the fundamental challenges remain; the limitation of the sluggish oxygen redox kinetics, insufficient active sites, and poor efficiency/cycle lifespan. Here we present heterointerface-promoted sulfur-deficient cobalt-tin-sulfur (CoS1-δ/SnS2-δ) trifunctional electrocatalysts by a facile solvothermal solution-phase approach. The CoS1-δ/SnS2-δ displays superb trifunctional activities, precisely a record-level oxygen bifunctional activity of 0.57 V (E1/2 = 0.90 V and Ej=10 = 1.47 V) and a hydrogen evolution overpotential (41 mV), outperforming those of Pt/C and RuO2. Theoretical calculations reveal the modulation of the electronic structures and d-band centers that endorse fast electron/proton transport for the hetero-interface and avoid the strong adsorption of intermediate species. The alkaline Zn-air batteries with CoS1-δ/SnS2-δ manifest record-high power density of 249 mW cm-2 and long-cycle life for >1000 cycles under harsh operations of 20 mA cm-2, surpassing those of Pt/C + RuO2 and previous state-of-the-art catalysts. Furthermore, the solid-state flexible Zn-air battery also displays remarkable performance with an energy density of 1077 Wh kg-1, >690 cycles for 50 mA cm-2, and a wide operating temperature from +80 to -40 °C with 85% capacity retention, which provides insights for practical Zn-air batteries.

Analysis of All-Cause Hospitalization and Death Among Nonhospitalized Patients With Type 2 Diabetes and SARS-CoV-2 Infection Treated With Molnupiravir or Nirmatrelvir-Ritonavir During the Omicron Wave in Hong Kong.

Importance: Diabetes and COVID-19 are both global pandemics, and type 2 diabetes is a common comorbidity in patients with acute COVID-19 and is proven to be a key determinant of COVID-19 prognosis. Molnupiravir and nirmatrelvir-ritonavir are oral antiviral medications recently approved for nonhospitalized patients with mild to moderate COVID-19, following demonstration of their efficacies in reducing adverse outcomes of the disease; it is crucial to clarify whether both oral antiviral medications are efficacious in a population consisting exclusively of patients with type 2 diabetes. Objective: To evaluate the effectiveness of molnupiravir and nirmatrelvir-ritonavir in a contemporary population-based cohort comprising exclusively nonhospitalized patients with type 2 diabetes and SARS-CoV-2 infection. Design, Setting, and Participants: This retrospective cohort study was performed using population-based electronic medical record data for patients in Hong Kong with type 2 diabetes and confirmed SARS-CoV-2 infection between February 26 and October 23, 2022. Each patient was followed up until death, outcome event, crossover of oral antiviral treatment, or end of the observational period (October 30, 2022), whichever came first. Outpatient oral antiviral users were divided into molnupiravir and nirmatrelvir-ritonavir treatment groups, respectively, and nontreated control participants were matched through 1:1 propensity score matching. Data analysis was performed on March 22, 2023. Exposures: Molnupiravir (800 mg twice daily for 5 days) or nirmatrelvir-ritonavir (300 mg nirmatrelvir and 100 mg ritonavir twice daily for 5 days, or 150 mg nirmatrelvir and 100 mg ritonavir for patients with an estimated glomerular filtration rate of 30-59 mL/min per 1.73 m2). Main Outcomes and Measures: The primary outcome was a composite of all-cause mortality and/or hospitalization. The secondary outcome was in-hospital disease progression. Hazard ratios (HRs) were estimated with Cox regression. Results: This study identified 22 098 patients with type 2 diabetes and COVID-19. A total of 3390 patients received molnupiravir and 2877 received nirmatrelvir-ritonavir in the community setting. After application of exclusion criteria followed by 1:1 propensity score matching, this study comprised 2 groups. One group included 921 molnupiravir users (487 men [52.9%]), with a mean (SD) age of 76.7 (10.8) years, and 921 control participants (482 men [52.3%]), with a mean (SD) age of 76.6 (11.7) years. The other group included 793 nirmatrelvir-ritonavir users (401 men [50.6%]), with a mean (SD) age of 71.7 (11.5) years, and 793 control participants (395 men [49.8%]), with a mean (SD) age of 71.9 (11.6) years. At a median follow-up of 102 days (IQR, 56-225 days), molnupiravir use was associated with a lower risk of all-cause mortality and/or hospitalization (HR, 0.71 [95% CI, 0.64-0.79]; P < .001) and in-hospital disease progression (HR, 0.49 [95% CI, 0.35-0.69]; P < .001) compared with nonuse. At a median follow-up of 85 days (IQR, 56-216 days), nirmatrelvir-ritonavir use was associated with a lower risk of all-cause mortality and/or hospitalization (HR, 0.71 [95% CI, 0.63-0.80]; P < .001) and a nonsignificantly lower risk of in-hospital disease progression (HR, 0.92 [95% CI, 0.59-1.44]; P = .73) compared with nonuse. Conclusions and Relevance: These findings suggest that both molnupiravir and nirmatrelvir-ritonavir oral antiviral medications were associated with a lower risk of all-cause mortality and hospitalization among patients with COVID-19 and type 2 diabetes. Further studies in specific populations, such as individuals in residential care homes and individuals with chronic kidney disease, are suggested.