Oral emergency contraception with levonorgestrel plus piroxicam: a randomised double-blind placebo-controlled trial.

BACKGROUND: Levonorgestrel, a standard drug for emergency contraception (EC), is not effective if administered post-ovulation. A cyclo-oxygenase inhibitor could contribute synergistic effects. We investigated whether a single 40 mg oral dose of piroxicam as co-treatment with levonorgestrel improved emergency contraceptive efficacy. METHODS: This was a randomised double-blind placebo-controlled trial carried out in a major community sexual and reproductive health service in Hong Kong. Women who required levonorgestrel EC within 72 h of unprotected sexual intercourse were recruited and block-randomised in a 1:1 ratio to receive a single supervised dose of levonorgestrel 1·5 mg plus either piroxicam 40 mg or placebo orally. Group assignment was concealed in opaque envelopes and masked to the women, clinicians, and investigators. At follow-up 1-2 weeks after the next expected period, the pregnancy status was noted by history or pregnancy test. The primary efficacy outcome was the proportion of pregnancies prevented out of those expected based on an established model. All women randomised to receive the study drug and who completed the follow-up were analysed. The trial was registered with ClinicalTrials.gov, NCT03614494. FINDINGS: 860 women (430 in each group) were recruited between Aug 20, 2018, and Aug 30, 2022. One (0·2%) of 418 efficacy-eligible women in the piroxicam group were pregnant, compared with seven (1·7%) of 418 in the placebo group (odds ratio 0·20 [95% CI 0·02-0·91]; p=0·036). Levonorgestrel plus piroxicam prevented 94·7% of expected pregnancies compared with 63·4% for levonorgestrel plus placebo. We noted no significant difference between the two groups in the proportion of women with advancement or delay of their next period, or in the adverse event profile. INTERPRETATION: Oral piroxicam 40 mg co-administered with levonorgestrel improved efficacy of EC in our study. Piroxicam co-administration could be considered clinically where levonorgestrel EC is the option of choice. FUNDING: None.

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.

Circulating thrombospondin-2 level for identifying individuals with rapidly declining kidney function trajectory in type 2 diabetes: a prospective study of the Hong Kong West Diabetes Registry.

BACKGROUND: Thrombospondin-2 (TSP2) is a matricellular protein with tissue expression induced by hyperglycaemia. TSP2 has been implicated in non-diabetic renal injury in preclinical studies and high circulating levels were associated with worse kidney function in cross-sectional clinical studies. Therefore, we investigated the prospective associations of circulating TSP2 level with kidney function decline and the trajectories of estimated glomerular filtration rate (eGFR) in type 2 diabetes. METHODS: Baseline serum TSP2 level was measured in 5471 patients with type 2 diabetes to evaluate its association with incident eGFR decline, defined as ≥ 40% sustained eGFR decline, using multivariable Cox regression analysis. Among participants with relatively preserved kidney function (Baseline eGFR ≥ 60 ml/min/1.73m2), joint latent class modelling was employed to identify three different eGFR trajectories. Their associations with baseline serum TSP2 was evaluated using multinomial logistic regression analysis. The predictive performance of serum TSP2 level was examined using time-dependent c-statistics and calibration statistics. RESULTS: Over a median follow-up of 8.8 years, 1083 patients (19.8%) developed eGFR decline. Baseline serum TSP2 level was independently associated with incident eGFR decline (HR 1.21, 95%CI 1.07-1.37, P = 0.002). With internal validation, incorporating serum TSP2 to a model of clinical risk factors including albuminuria led to significant improvement in c-statistics from 83.9 to 84.4 (P < 0.001). Among patients with eGFR ≥ 60 ml/min/1.73m2, baseline serum TSP2 level was independently associated with a rapidly declining eGFR trajectory (HR 1.63, 95%CI 1.26-2.10, P < 0.001). CONCLUSION: Serum TSP2 level was independently associated with incident eGFR decline, particularly a rapidly declining trajectory, in type 2 diabetes.

Specific triacylglycerol, diacylglycerol, and lyso-phosphatidylcholine species for the prediction of type 2 diabetes: a ~ 16-year prospective study in Chinese.

BACKGROUND: Bioactive lipids play an important role in insulin secretion and sensitivity, contributing to the pathophysiology of type 2 diabetes (T2D). This study aimed to identify novel lipid species associated with incident T2D in a nested case-control study within a long-term prospective Chinese community-based cohort with a median follow-up of ~ 16 years. METHODS: Plasma samples from 196 incident T2D cases and 196 age- and sex-matched non-T2D controls recruited from the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS) were first analyzed using untargeted lipidomics. Potential predictive lipid species selected by the Boruta analysis were then verified by targeted lipidomics. The associations between these lipid species and incident T2D were assessed. Effects of novel lipid species on insulin secretion in mouse islets were investigated. RESULTS: Boruta analysis identified 16 potential lipid species. After adjustment for body mass index (BMI), triacylglycerol/high-density lipoprotein (TG/HDL) ratio and the presence of prediabetes, triacylglycerol (TG) 12:0_18:2_22:6, TG 16:0_11:1_18:2, TG 49:0, TG 51:1 and diacylglycerol (DG) 18:2_22:6 were independently associated with increased T2D risk, whereas lyso-phosphatidylcholine (LPC) O-16:0, LPC P-16:0, LPC O-18:0 and LPC 18:1 were independently associated with decreased T2D risk. Addition of the identified lipid species to the clinical prediction model, comprised of BMI, TG/HDL ratio and the presence of prediabetes, achieved a 3.8% improvement in the area under the receiver operating characteristics curve (AUROC) (p = 0.0026). Further functional study revealed that, LPC O-16:0 and LPC O-18:0 significantly potentiated glucose induced insulin secretion (GSIS) in a dose-dependent manner, whereas neither DG 18:2_22:6 nor TG 12:0_18:2_22:6 had any effect on GSIS. CONCLUSIONS: Addition of the lipid species substantially improved the prediction of T2D beyond the model based on clinical risk factors. Decreased levels of LPC O-16:0 and LPC O-18:0 may contribute to the development of T2D via reduced insulin secretion.

Coronavirus Disease 2019 (COVID-19) Re-infection by a Phylogenetically Distinct Severe Acute Respiratory Syndrome Coronavirus 2 Strain Confirmed by Whole Genome Sequencing.

BACKGROUND: Waning immunity occurs in patients who have recovered from Coronavirus Disease 2019 (COVID-19). However, it remains unclear whether true re-infection occurs. METHODS: Whole genome sequencing was performed directly on respiratory specimens collected during 2 episodes of COVID-19 in a patient. Comparative genome analysis was conducted to differentiate re-infection from persistent viral shedding. Laboratory results, including RT-PCR Ct values and serum Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) IgG, were analyzed. RESULTS: The second episode of asymptomatic infection occurred 142 days after the first symptomatic episode in an apparently immunocompetent patient. During the second episode, there was evidence of acute infection including elevated C-reactive protein and SARS-CoV-2 IgG seroconversion. Viral genomes from first and second episodes belong to different clades/lineages. The virus genome from the first episode contained a a stop codon at position 64 of ORF8, leading to a truncation of 58 amino acids. Another 23 nucleotide and 13 amino acid differences located in 9 different proteins, including positions of B and T cell epitopes, were found between viruses from the first and second episodes. Compared to viral genomes in GISAID, the first virus genome was phylogenetically closely related to strains collected in March/April 2020, while the second virus genome was closely related to strains collected in July/August 2020. CONCLUSIONS: Epidemiological, clinical, serological, and genomic analyses confirmed that the patient had re-infection instead of persistent viral shedding from first infection. Our results suggest SARS-CoV-2 may continue to circulate among humans despite herd immunity due to natural infection. Further studies of patients with re-infection will shed light on protective immunological correlates for guiding vaccine design.

Role of non-thyroidal illness syndrome in predicting adverse outcomes in COVID-19 patients predominantly of mild-to-moderate severity.

OBJECTIVE: Existing studies reported the potential prognostic role of non-thyroidal illness syndrome (NTIS), characterized by low triiodothyronine (T3) with normal/low thyroid-stimulating hormone (TSH), mainly in severe COVID-19. None considered the significant impact of SARS-CoV-2 viral load on adverse outcomes. We aimed to clarify the prognostic role of NTIS among predominantly mild-to-moderate COVID-19 patients. DESIGN: A prospective study of COVID-19 patients. PATIENTS AND MEASUREMENTS: Consecutive adults admitted to Queen Mary Hospital for confirmed COVID-19 from July to December 2020 were prospectively recruited. SARS-CoV-2 viral load was represented by cycle threshold (Ct) values from real-time reverse transcription-polymerase chain reaction of the respiratory specimen on admission. Serum TSH, free thyroxine and free T3 were measured on admission. The outcome was deterioration in clinical severity, defined as worsening in ≥1 category of clinical severity according to the Chinese National Health Commission guideline. RESULTS: We recruited 367 patients. At baseline, 75.2% had mild disease, and 27 patients (7.4%) had NTIS. Fifty-three patients (14.4%) had clinical deterioration. Patients with NTIS were older, had more comorbidities, worse symptomatology, higher SARS-CoV-2 viral loads and worse profiles of inflammatory and tissue injury markers. They were more likely to have clinical deterioration (p < .001). In multivariable stepwise logistic regression analysis, NTIS independently predicted clinical deterioration (adjusted odds ratio 3.19, p = .017), in addition to Ct value <25 (p < .001), elevated C-reactive protein (p = .004), age >50 years (p = .011) and elevated creatine kinase (p = .017). CONCLUSIONS: Non-thyroidal illness syndrome was not uncommon even in mild-to-moderate COVID-19 patients. NTIS on admission could predict clinical deterioration in COVID-19, independent of SARS-CoV-2 viral load, age and markers of inflammation and tissue injury.

Different glycaemia-related risk factors for incident Alzheimer's disease in men and women with type 2 diabetes-A sex-specific analysis of the Hong Kong diabetes database.

AIMS: Sexual dimorphism has been reported in the epidemiology, neurobiologic susceptibility and clinical presentation of Alzheimer's disease (AD). As poor glycaemic control is associated with increased risks of AD, we aimed to investigate whether glycaemia-related risk factors also differ between men and women, using a retrospective, sex-specific analysis of a large Chinese cohort with diabetes. MATERIALS & METHODS: A total of 85,514 Chinese individuals with type 2 diabetes (T2D; 46,783 women and 38,731 men), aged ≥60 years, were identified from electronic health records and observed for incident AD. Multivariable Cox regression analysis was used to evaluate the associations with incident AD of several glycaemia-related risk factors, including severe hypoglycaemia, mean HbA1c and indices of HbA1c variability, in men and women separately. RESULTS: Over a median follow-up of 6 years, women had a higher incidence of AD than men (2.3% vs. 1.2%, p < 0.001). Both men and women shared the same independent non-glycaemic clinical predictors, which included older age, lower body mass index and longer duration of diabetes. However, for glycaemia-related risk factors, we observed that severe hypoglycaemia and indices of HbA1c variability were independent predictors of incident AD in women but not in men, and the associations were irrespective of their baseline glycaemic control and duration of diabetes. CONCLUSIONS: Our findings highlighted that glycaemia-related risk factors for incident AD differ between men and women with T2D. Strategies to maintain glycaemic stability and avoid severe hypoglycaemia might be especially important to preserve healthy cognition in older women with diabetes.

The Potential Role of Preoperative Trabecular Bone Score in Predicting Changes in Bone Mineral Density After Parathyroidectomy.

BACKGROUND: The skeletal indication for parathyroidectomy for primary hyperparathyroidism (PHPT) is based on bone mineral density (BMD) T-score < - 2.5. Whether trabecular bone score (TBS) additionally identifies patients who benefit from parathyroidectomy in terms of bone health is unknown. We aimed to study changes in BMD and TBS among Chinese who underwent curative parathyroidectomy for PHPT, in relation to their preoperative parameters, especially in those with worst site BMD T-score ≥ - 2.5 (non-osteoporotic range). METHODS: We included consecutive Chinese individuals who underwent curative parathyroidectomy during 2002-2015 for PHPT and completed preoperative and postoperative BMD and TBS measurements in Queen Mary Hospital. Correlations between preoperative parameters and changes in densitometric parameters were studied. RESULTS: 45 Chinese individuals (13 men, 32 women) were included (mean age 62.0 ± 10.0 years and BMI 24.6 ± 4.7 kg/m2). After parathyroidectomy, BMD at lumbar spine (LS) improved by 6.7% (p < 0.001) while TBS did not change. Among women, peak preoperative parathyroid hormone and calcium levels independently predicted LS BMD gain. Among women with BMD in non-osteoporotic range, LS BMD also improved after parathyroidectomy, where preoperative TBS was the only significant variable inversely correlating with percentage change in LS BMD (ρ - 0.775, p = 0.005). Particularly, those with preoperative TBS ≤ 1.25 gained 7.1% LS BMD post-parathyroidectomy (p = 0.003). CONCLUSIONS: LS BMD, but not TBS, improved after parathyroidectomy. Among non-osteoporotic PHPT women, preoperative TBS inversely correlated with postoperative BMD improvement. Hence, low preoperative TBS may be an additional indication for surgical benefit with parathyroidectomy in non-osteoporotic PHPT women, as those with worse preoperative TBS tend to benefit more from surgery.

Thyroid Immune-Related Adverse Events in Patients with Cancer Treated with anti-PD1/anti-CTLA4 Immune Checkpoint Inhibitor Combination: Clinical Course and Outcomes.

OBJECTIVE: Thyroid immune-related adverse events (irAEs) have been reported to have prognostic significance among patients with cancer treated with anti-programmed cell death-1 (PD1) and anti-programmed death-ligand 1 monotherapies. We evaluated the clinical course and predictors of thyroid irAEs in relation to outcomes of patients with advanced cancer treated with combination anti-PD1/anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4). METHODS: We conducted a regional study and identified patients with advanced cancer who received ≥1 cycle of combination anti-PD1/anti-CTLA4 between 2015 and 2019 in Hong Kong. Thyroid function tests (TFTs) were monitored every 3 weeks. Thyroid irAE was defined by ≥2 abnormal TFTs after initiation of combination anti-PD1/anti-CTLA4 in the absence of other causes. RESULTS: One hundred and three patients were included (median age: 59 years; 71.8% men). About 45% had prior anti-PD1 exposure. Upon median follow-up of 6.8 months, 17 patients (16.5%) developed thyroid irAEs, where 6 initially presented with thyrotoxicosis (overt, n = 4; subclinical, n = 2) and 11 with hypothyroidism (overt, n = 2; subclinical, n = 9). Eventually, 10 patients (58.8%) required continuous thyroxine replacement. Systemic steroid was not required in all cases. Prior anti-PD1 exposure (odds ratio, 3.67; 95% CI, 1.19-11.4; P = .024) independently predicted thyroid irAEs. Multivariable Cox regression analysis revealed that occurrence of thyroid irAEs was independently associated with better overall survival (adjusted hazard ratio, 0.34; 95% CI, 0.17-0.71; P = .004). CONCLUSION: Thyroid irAEs are common in routine clinical practice among patients with advanced cancer treated with anti-PD1/anti-CTLA4 combination and might have potential prognostic significance. Regular TFT monitoring is advised for timely treatment of thyroid irAEs to prevent potential morbidities.

Long COVID in Patients With Mild to Moderate Disease: Do Thyroid Function and Autoimmunity Play a Role?

OBJECTIVE: Post-acute sequelae of coronavirus disease 2019 (COVID-19) or long COVID (LC) is an emerging global health issue. Fatigue is a common feature. Whether thyroid function and autoimmunity play a role is uncertain. We aimed to evaluate the prevalence and predictors of LC and the potential role of thyroid function and autoimmunity in LC. METHODS: We included consecutive adults without a known thyroid disorder who were admitted to a major COVID-19 center for confirmed COVID-19 from July to December 2020. Thyroid function tests and antithyroid antibodies were measured for all patients on admission and at follow-up. LC was defined by the presence or persistence of symptoms upon follow-up. RESULTS: In total, 204 patients (median age, 55.0 years; 95 men [46.6%]) were reassessed at a median of 89 days (interquartile range, 69-99) after acute COVID-19. Of the 204 patients, 41 (20.1%) had LC. Female sex (adjusted odds ratio, 2.48; P = .018) and severe acute respiratory syndrome coronavirus 2 polymerase chain reaction cycle threshold value of <25 on admission (adjusted odds ratio, 2.84; P = .012) independently predicted the occurrence of LC. Upon follow-up, most abnormal thyroid function tests in acute COVID-19 resolved, and incident thyroid dysfunction was rare. Nonetheless, we observed incident antithyroid peroxidase (anti-TPO) positivity. Although baseline or follow-up thyroid function tests were not associated with the occurrence of LC, among 172 patients with symptomatic acute COVID-19, symptom resolution was more likely in those with positive anti-TPO upon follow-up (P = .043). CONCLUSION: LC is common among COVID-19 survivors, with females and those with higher viral load in acute COVID-19 particularly being vulnerable. The observation of incident anti-TPO positivity warrants further follow-up for thyroid dysfunction. Whether anti-TPO plays a protective role in LC remains to be elucidated.

Improved Detection of Antibodies against SARS-CoV-2 by Microsphere-Based Antibody Assay.

Currently available COVID-19 antibody tests using enzyme immunoassay (EIA) or immunochromatographic assay have variable sensitivity and specificity. Here, we developed and evaluated a novel microsphere-based antibody assay (MBA) for detecting immunoglobulin G (IgG) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleoprotein (NP) and spike protein receptor binding domain (RBD). The seropositive cutoff value was set using a cohort of 294 anonymous serum specimens collected in 2018. The specificity was assessed using serum specimens collected from organ donors or influenza patients before 2020. Seropositive rate was determined among COVID-19 patients. Time-to-seropositivity and signal-to-cutoff (S/CO) ratio were compared between MBA and EIA. MBA had a specificity of 100% (93/93; 95% confidence interval (CI), 96-100%) for anti-NP IgG, 98.9% (92/93; 95% CI 94.2-100%) for anti-RBD IgG. The MBA seropositive rate for convalescent COVID-19 patients was 89.8% (35/39) for anti-NP IgG and 79.5% (31/39) for anti-RBD IgG. The time-to-seropositivity was shorter with MBA than EIA. MBA could better differentiate between COVID-19 patients and negative controls with higher S/CO ratio for COVID-19 patients, lower S/CO ratio with negative controls and fewer specimens in the equivocal range. MBA is robust, simple and is suitable for clinical microbiology laboratory for the accurate determination of anti-SARS-CoV-2 antibodies for diagnosis, serosurveillance, and vaccine trials.

Prospective associations of circulating adipocyte fatty acid-binding protein levels with risks of renal outcomes and mortality in type 2 diabetes.

AIMS/HYPOTHESIS: Elevated circulating adipocyte fatty acid-binding protein (AFABP) levels have been found to correlate with diabetic nephropathy staging in cross-sectional studies. However, it remains unclear whether these higher serum levels reflect a role of AFABP in the development of diabetic kidney disease (DKD), or simply result from its impaired renal clearance in DKD. Here we investigated prospectively the prognostic importance of serum AFABP level in the development of adverse renal outcomes in a large clinic-based cohort of participants with type 2 diabetes. METHODS: Baseline serum AFABP levels were measured in 5454 Chinese participants from the Hong Kong West Diabetes Registry. The association between circulating AFABP levels and incident adverse renal outcomes-defined as a composite endpoint of a sustained 40% decline in eGFR, end-stage renal disease requiring renal replacement therapy or kidney transplantation, or renal deaths-was evaluated using multivariable Cox regression analysis. RESULTS: Over a median follow-up of 5 years, 754 of the 5454 participants developed incident adverse renal outcomes. Elevated circulating AFABP levels were independently associated with incident adverse renal outcomes (HR 1.43, 95% CI 1.31, 1.57, p < 0.001) after adjustments for conventional risk factors for DKD progression. Importantly, the prognostic role of serum AFABP was independent of the baseline albuminuria status or eGFR levels of the study participants. CONCLUSIONS/INTERPRETATION: Circulating AFABP levels were predictive of incident adverse renal outcomes, even in participants with relatively well-preserved kidney function at baseline, suggesting its potential to be a useful marker for early risk stratification in DKD.

Assessment of population susceptibility to upcoming seasonal influenza epidemic strain using interepidemic emerging influenza virus strains.

Seasonal influenza virus epidemics have a major impact on healthcare systems. Data on population susceptibility to emerging influenza virus strains during the interepidemic period can guide planning for resource allocation of an upcoming influenza season. This study sought to assess the population susceptibility to representative emerging influenza virus strains collected during the interepidemic period. The microneutralisation antibody titers (MN titers) of a human serum panel against representative emerging influenza strains collected during the interepidemic period before the 2018/2019 winter influenza season (H1N1-inter and H3N2-inter) were compared with those against influenza strains representative of previous epidemics (H1N1-pre and H3N2-pre). A multifaceted approach, incorporating both genetic and antigenic data, was used in selecting these representative influenza virus strains for the MN assay. A significantly higher proportion of individuals had a ⩾four-fold reduction in MN titers between H1N1-inter and H1N1-pre than that between H3N2-inter and H3N2-pre (28.5% (127/445) vs. 4.9% (22/445), P < 0.001). The geometric mean titer (GMT) of H1N1-inter was significantly lower than that of H1N1-pre (381 (95% CI 339-428) vs. 713 (95% CI 641-792), P < 0.001), while there was no significant difference in the GMT between H3N2-inter and H3N2-pre. Since A(H1N1) predominated the 2018-2019 winter influenza epidemic, our results corroborated the epidemic subtype.

Circulating Adipocyte Fatty Acid-Binding Protein Concentrations Predict Multiple Mortality Outcomes among Men and Women with Diabetes.

INTRODUCTION: Raised circulating adipocyte fatty acid-binding protein (AFABP) concentrations are associated with various adverse health conditions. However, their relationship with mortality remains to be defined, especially in view of the sexual dimorphism of circulating AFABP concentrations. Here we investigated prospectively whether serum AFABP concentrations predict multiple mortality outcomes in men and women alike, using a large clinic-based cohort of individuals with type 2 diabetes, a condition with raised AFABP concentrations. METHODS: Baseline serum AFABP concentrations were measured in 5305 research participants with a monoclonal antibody-based sandwich immunoassay. The role of circulating AFABP concentrations in predicting mortality outcomes was evaluated by multivariable Cox regression analysis. RESULTS: Among the 5305 participants (59% men) in this study, over a median follow-up of 5 years, there were 512 deaths (19.3 deaths per 1000 person-years). Circulating AFABP concentrations, with higher levels in women at baseline, predicted all-cause mortality (P < 0.001), cardiovascular mortality (P = 0.037), and infection-related deaths (P < 0.002) among all participants. In sex-specific analyses, circulating AFABP concentration was an independent predictor of all-cause mortality in both men and women and a predictor of cancer-related deaths and infection-related deaths in men only. Furthermore, the addition of serum AFABP concentrations improved the time-dependent c statistics in predicting all-cause mortality in participants with type 2 diabetes (P = 0.008). CONCLUSIONS: Circulating AFABP concentration was an independent predictor of various mortality outcomes in type 2 diabetes over and above known risk factors of reduced survival in men and women. The role of AFABP as a prognostic biomarker and therapeutic target warrants further investigation.

Exome-chip association analysis reveals an Asian-specific missense variant in PAX4 associated with type 2 diabetes in Chinese individuals.

AIMS/HYPOTHESIS: Genome-wide association studies (GWASs) have identified many common type 2 diabetes-associated variants, mostly at the intronic or intergenic regions. Recent advancements of exome-array genotyping platforms have opened up a novel means for detecting the associations of low-frequency or rare coding variants with type 2 diabetes. We conducted an exomechip association analysis to identify additional type 2 diabetes susceptibility variants in the Chinese population. METHODS: An exome-chip association study was conducted by genotyping 5640 Chinese individuals from Hong Kong, using a custom designed exome array, the Asian Exomechip. Single variant association analysis was conducted on 77,468 single nucleotide polymorphisms (SNPs). Fifteen SNPs were subsequently genotyped for replication analysis in an independent Chinese cohort comprising 12,362 individuals from Guangzhou. A combined analysis involving 7189 cases and 10,813 controls was performed. RESULTS: In the discovery stage, an Asian-specific coding variant rs2233580 (p.Arg192His) in PAX4, and two variants at the known loci, CDKN2B-AS1 and KCNQ1, were significantly associated with type 2 diabetes with exome-wide significance (p discovery < 6.45 × 10-7). The risk allele (T) of PAX4 rs2233580 was associated with a younger age at diabetes diagnosis. This variant was replicated in an independent cohort and demonstrated a stronger association that reached genome-wide significance (p meta-analysis [p meta] = 3.74 × 10-15) in the combined analysis. CONCLUSIONS/INTERPRETATION: We identified the association of a PAX4 Asian-specific missense variant rs2233580 with type 2 diabetes in an exome-chip association analysis, supporting the involvement of PAX4 in the pathogenesis of type 2 diabetes. Our findings suggest PAX4 is a possible effector gene of the 7q32 locus, previously identified from GWAS in Asians.

I kappa B kinase alpha (IKKα) activity is required for functional maturation of dendritic cells and acquired immunity to infection.

Dendritic cells (DC) are required for priming antigen-specific T cells and acquired immunity to many important human pathogens, including Mycobacteriuim tuberculosis (TB) and influenza. However, inappropriate priming of auto-reactive T cells is linked with autoimmune disease. Understanding the molecular mechanisms that regulate the priming and activation of naïve T cells is critical for development of new improved vaccines and understanding the pathogenesis of autoimmune diseases. The serine/threonine kinase IKKα (CHUK) has previously been shown to have anti-inflammatory activity and inhibit innate immunity. Here, we show that IKKα is required in DC for priming antigen-specific T cells and acquired immunity to the human pathogen Listeria monocytogenes. We describe a new role for IKKα in regulation of IRF3 activity and the functional maturation of DC. This presents a unique role for IKKα in dampening inflammation while simultaneously promoting adaptive immunity that could have important implications for the development of new vaccine adjuvants and treatment of autoimmune diseases.

Serum fibroblast growth factor 21 is a superior biomarker to other adipokines in predicting incident diabetes.

OBJECTIVE: Fibroblast growth factor 21 (FGF21) improves glucose and lipid metabolism, but high circulating levels are found in type 2 diabetes, suggesting FGF21 resistance. Serum FGF21 predicts incident diabetes, but its performance compared to established and emerging predictors is not known. We aimed to study the performance of FGF21 in diabetes prediction, relative to other adipokines and established risk factors including 2-h plasma glucose (2hG) during the oral glucose tolerance test (OGTT). DESIGN/PARTICIPANTS/MEASUREMENTS: We studied 1380 nondiabetic subjects from the Hong Kong Cardiovascular Risk Factor Prevalence Study using the second visit (2000-2004) as baseline when serum levels of FGF21 and other adipokines were measured. Glycaemic status was assessed by OGTT. Incident diabetes was defined as fasting glucose level (FG) ≥ 7 mmol/l or 2hG ≥ 11·1 mmol/l or use of antidiabetic agents, at subsequent visits. RESULTS: A total of 123 participants developed diabetes over 9·0 years (median). On multivariable logistic regression analysis, FGF21 (P = 0·003), adipocyte fatty acid-binding protein (P = 0·003) and adiponectin (P = 0·035) were independent predictors of incident diabetes. FGF21 had the best change in log likelihood when added to a diabetes prediction model (DP) based on age, family history, smoking, hypertension, BMI, dyslipidaemia and FG. It also improved the area under ROC curve (AUROC) of diabetes prediction (DP) from 0·797 to 0·819 (P = 0·0072), rendering its performance comparable to the 'DP + 2hG' model (AUROC=0·838, P = 0·19). CONCLUSIONS: As a biomarker for diabetes prediction, serum FGF21 appeared to be superior to other adipokines and, on its own, could be considered as an alternative to the OGTT.

Serum fibroblast growth factor-21 levels are associated with carotid atherosclerosis independent of established cardiovascular risk factors.

OBJECTIVE: Serum levels of fibroblast growth factor-21 (FGF21), a metabolic hormone, have been shown to be elevated in subjects with adverse lipid profiles, obesity, metabolic syndrome, impaired glucose tolerance, type 2 diabetes mellitus, and hypertension. Recently, elevated serum FGF21 levels have also been reported in subjects with coronary heart disease or carotid artery plaques. However, whether serum FGF21 is independently associated with atherosclerotic diseases remains unclear. In this study, we examined the relationship between serum FGF21 levels and carotid intima-media thickness (IMT) in a large cohort of Southern Chinese subjects. APPROACH AND RESULTS: The cohort consisted of 670 subjects who underwent carotid IMT measurement. Serum FGF21 levels were measured with an ELISA kit. Serum FGF21 levels positively correlated with carotid IMT in women (r=0.32; P<0.001), but not in men (r=0.06; P=0.305). On multiple linear regression analysis, elevated serum FGF21 level in women was an independent risk factor for increased carotid IMT (P=0.039), together with age (P<0.001) and hypertension (P=0.011), in a model comprising also waist circumference, smoking history, serum creatinine, high sensitive C-reactive protein, dysglycemia, and dyslipidemia (adjusted R(2)=35.8%; P<0.001). Elevated serum FGF21 levels were also a significant independent risk factor of carotid IMT on multiple stepwise regression analysis (P=0.01). CONCLUSIONS: The present study is the first demonstration that elevated serum FGF21 levels are associated with carotid atherosclerosis in humans, independent of established risk factors including adverse lipid profiles and C-reactive protein. The role of FGF21 as a biomarker or therapeutic target of atherosclerotic diseases warrants further investigation.

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

BACKGRUOUND: 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.

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.