Association of nirmatrelvir-ritonavir with post-acute sequelae and mortality in patients admitted to hospital with COVID-19: a retrospective cohort study.

BACKGROUND: Studies have established the short-term efficacy of nirmatrelvir-ritonavir in managing COVID-19, yet its effect on post-COVID-19 condition, especially in patients admitted to hospital, remains understudied. This study aimed to examine the effect of nirmatrelvir-ritonavir on post-COVID-19 condition among patients admitted to hospital in Hong Kong. METHODS: This retrospective cohort study used real-world, territory-wide inpatient records, vaccination records, and confirmed COVID-19 case data from the Hong Kong Hospital Authority and Department of Health, The Government of the Hong Kong Special Administrative Region. Patients aged 18 years and older who tested positive for SARS-CoV-2 between March 11, 2022, and Oct 10, 2023, and who were admitted to hospital with COVID-19 were included. The treatment group included patients prescribed nirmatrelvir-ritonavir within 5 days of symptom onset, excluding those prescribed molnupiravir within 21 days, and the control group had no exposure to either nirmatrelvir-ritonavir or molnupiravir. The outcomes were post-acute inpatient death and 13 sequelae (congestive heart failure, atrial fibrillation, coronary artery disease, deep vein thrombosis, chronic pulmonary disease, acute respiratory distress syndrome, interstitial lung disease, seizure, anxiety, post-traumatic stress disorder, end-stage renal disease, acute kidney injury, and pancreatitis). These outcomes were evaluated starting at 21 days after the positive RT-PCR date in each respective cohort constructed for the outcome. Standardised mortality ratio weights were applied to balance covariates, and Cox proportional hazards regression was used to investigate the relationship between nirmatrelvir-ritonavir and outcomes. FINDINGS: 136 973 patients were screened for inclusion, among whom 50 055 were eligible and included in the analysis (24 873 [49·7%] were female and 25 182 [50·3%] were male). 15 242 patients were prescribed nirmatrelvir-ritonavir during acute COVID-19 and 23 756 patients were included in the control group; 11 057 patients did not meet our definition for the exposed and unexposed groups. Patients were followed up for a median of 393 days (IQR 317-489). In the nirmatrelvir-ritonavir group compared with the control group, there was a significantly lower hazard of post-acute inpatient death (hazard ratio 0·62 [95% CI 0·57-0·68]; p<0·0001), congestive heart failure (0·70 [0·58-0·85]; p=0·0002), atrial fibrillation (0·63 [0·52-0·76]; p<0·0001), coronary artery disease (0·71 [0·59-0·85]; p=0·0002), chronic pulmonary disease (0·68 [0·54-0·86]; p=0·0011), acute respiratory distress syndrome (0·71 [0·58-0·86]; p=0·0007), interstitial lung disease (0·17 [0·04-0·75]; p=0·020), and end-stage renal disease (0·37 [0·18-0·74]; p=0·0049). There was no evidence indicating difference between the groups in deep vein thrombosis, seizure, anxiety, post-traumatic stress disorder, acute kidney injury, and pancreatitis. INTERPRETATION: This study showed extended benefits of nirmatrelvir-ritonavir for reducing the risk of post-acute inpatient death as well as cardiovascular and respiratory complications among patients admitted to hospital with COVID-19. Further research is essential to uncover the underlying mechanisms responsible for these observed negative associations and to devise effective strategies for preventing the onset of post-acute sequelae. FUNDING: Health and Medical Research Fund, Research Grants Council theme-based research schemes, and Research Grants Council Collaborative Research Fund.

Temporal Trend of Serum Perfluorooctanoic Acid and Perfluorooctane Sulfonic Acid among U.S. Adults with or without Comorbidities in NHANES 1999-2018.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are associated with adverse health effects. This study examined the trend of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) levels in individuals with and without pre-existing comorbidities. We analyzed the characteristics of 13,887 participants across nine U.S. NHANES cycles (1999-2000 to 2017-2018) and calculated the geometric mean (GM) of PFOA and PFOS levels, standardized by sex and age. A joinpoint regression model was used to analyze the temporal trends of serum PFOA and PFOS levels. We observed declining PFOA and PFOS serum levels among adults in NHANES from 1999-2000 to 2017-2018. Serum PFOA and PFOS concentrations were higher in men, smokers, and individuals with pre-existing CKD, hyperlipidemia, CVD, and cancer. We observed faster decline rates in PFOA levels among individuals with diabetes and CKD and faster decline rates in PFOS levels among individuals with diabetes and those without CKD. This study provided evidence of varying levels and changing trends of PFOA and PFOS between groups with and without established chronic disease, highlighting the role of environmental chemicals in the onset and development of chronic diseases.

Association of dipeptidyl peptidase-4 inhibitor initiation at glycated haemoglobin <7.5% with reduced major clinical events mediated by low glycated haemoglobin variability.

AIM: Therapeutic inertia, hypoglycaemia and poor treatment persistence can lead to glycaemic fluctuation and poor outcomes in type 2 diabetes (T2D). We compared glycated haemoglobin (HbA1c) variability, insulin initiation, severe hypoglycaemia and clinical events in patients with T2D initiated dipeptidyl peptidase-4 inhibitors (DPP4is) at low versus high HbA1c thresholds. METHODS: Using territory-wide electronic medical records in Hong Kong, we curated a propensity score-matched cohort of patients initiated DPP4i at HbA1c <7.5% versus ≥7.5% in 2007-2019. We expressed the HbA1c variability score (HVS) as a proportion of HbA1c varied by ≥0.5% compared with preceding values. We used the Cox model to compare the risks of insulin initiation and clinical outcomes, adjusted for time-varying variables between the two groups. Mediation analysis estimated the effects of HbA1c variability on outcomes. RESULTS: Among 6874 insulin-naïve patients who initiated DPP4i, 88.7% were treated with metformin and 79.6% with sulphonylureas at baseline (54.9% men; mean age 65.2 ± 11.4 years). After a median follow-up of 4.6 years, compared with the high-threshold plus high-HVS group (≥50%), the low-threshold plus low-HVS (<50%) group had reduced hazard ratios (95% confidence interval) of insulin initiation (0.35, 0.31-0.40), severe hypoglycaemia (0.38, 0.34-0.44), major adverse cardiovascular endpoints (0.76, 0.66-0.88), heart failure (0.42, 0.36-0.49), end-stage kidney disease (0.65, 0.36-0.49) and mortality (0.45, 0.35-0.57). Reduced HbA1c variability explained 31.1%-81.2% of the effect size of DPP4i initiation at HbA1c <7.5% versus ≥7.5% on outcomes. CONCLUSIONS: In Chinese patients with T2D, avoiding therapeutic inertia with intensified glycaemic control at HbA1c <7.5% using drugs with low risk of hypoglycaemia and good tolerability, such as DPP4i, delayed insulin treatment, reduced HbA1c variability and improved clinical events.

The use of potentially interacting supplement-drug pairs in adults with type 2 diabetes: A large population-based cohort study in the UK Biobank.

AIMS: To examine the patterns of use of potentially interacting supplement-drug pairs in adults with type 2 diabetes (T2D) in real-world settings, and to explore the impact of potentially interacting supplement-drug pairs on downstream outcomes. METHODS: Potentially interacting supplement-drug pairs were identified from four tertiary databases. We categorized the potential pharmacodynamic interactions into different clinical types according to their related outcomes and explored their associations with incident outcomes using Cox models. RESULTS: 26,394 participants with T2D in the UK Biobank were included. Half (48.5 %) were supplement users, of whom 85.0 % were taking potentially interacting supplement-drug pairs. The potential pharmacodynamic interactions were related to various clinical outcomes, including reducing the effects of glucose-lowering drugs (50.7 %), hypotension (49.8 %), bleeding (50.4 %) and hepatotoxicity (34.8 %). Exploratory analyses found that the use of potentially interacting supplement-drug pairs was associated with incident hepatic diseases (hazard ratio = 1.26, 95 % confidence interval 1.10-1.44, P < 0.001). CONCLUSIONS: Real-world data suggests that most adults with T2D who concurrently used supplements and drugs were on potentially interacting supplement-drug combinations, with the potential of causing adverse outcomes such as incident hepatic diseases. Clinicians should communicate with patients and assess the potential risk of supplement-drug interactions in clinical settings.

A novel electronic health record-based, machine-learning model to predict severe hypoglycemia leading to hospitalizations in older adults with diabetes: A territory-wide cohort and modeling study.

BACKGROUND: Older adults with diabetes are at high risk of severe hypoglycemia (SH). Many machine-learning (ML) models predict short-term hypoglycemia are not specific for older adults and show poor precision-recall. We aimed to develop a multidimensional, electronic health record (EHR)-based ML model to predict one-year risk of SH requiring hospitalization in older adults with diabetes. METHODS AND FINDINGS: We adopted a case-control design for a retrospective territory-wide cohort of 1,456,618 records from 364,863 unique older adults (age ≥65 years) with diabetes and at least 1 Hong Kong Hospital Authority attendance from 2013 to 2018. We used 258 predictors including demographics, admissions, diagnoses, medications, and routine laboratory tests in a one-year period to predict SH events requiring hospitalization in the following 12 months. The cohort was randomly split into training, testing, and internal validation sets in a 7:2:1 ratio. Six ML algorithms were evaluated including logistic-regression, random forest, gradient boost machine, deep neural network (DNN), XGBoost, and Rulefit. We tested our model in a temporal validation cohort in the Hong Kong Diabetes Register with predictors defined in 2018 and outcome events defined in 2019. Predictive performance was assessed using area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC) statistics, and positive predictive value (PPV). We identified 11,128 SH events requiring hospitalization during the observation periods. The XGBoost model yielded the best performance (AUROC = 0.978 [95% CI 0.972 to 0.984]; AUPRC = 0.670 [95% CI 0.652 to 0.688]; PPV = 0.721 [95% CI 0.703 to 0.739]). This was superior to an 11-variable conventional logistic-regression model comprised of age, sex, history of SH, hypertension, blood glucose, kidney function measurements, and use of oral glucose-lowering drugs (GLDs) (AUROC = 0.906; AUPRC = 0.085; PPV = 0.468). Top impactful predictors included non-use of lipid-regulating drugs, in-patient admission, urgent emergency triage, insulin use, and history of SH. External validation in the HKDR cohort yielded AUROC of 0.856 [95% CI 0.838 to 0.873]. Main limitations of this study included limited transportability of the model and lack of geographically independent validation. CONCLUSIONS: Our novel-ML model demonstrated good discrimination and high precision in predicting one-year risk of SH requiring hospitalization. This may be integrated into EHR decision support systems for preemptive intervention in older adults at highest risk.

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

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

Clinical outcomes following discontinuation of metformin in patients with type 2 diabetes and advanced chronic kidney disease in Hong Kong: a territory-wide, retrospective cohort and target trial emulation study.

Background: Current labelling advises discontinuation of metformin when estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2 due to increased risk of lactic acidosis. However, in real-world practice, the risk-benefit ratios remain uncertain. We examined the risk associations of discontinued-metformin use with cardiorenal and clinical outcomes in patients with type 2 diabetes (T2D) and advanced chronic kidney disease. Methods: In this territory-wide, retrospective cohort and target trial emulation study, we included Chinese patients attending the Hong Kong Hospital Authority (HA) and enrolled in the Risk-Assessment-and-Management-Programme-for-Diabetes-Mellitus (RAMP-DM) from 2002 to 2019. Patients were stratified by discontinuation of metformin within six months after reaching eGFR < 30 ml/min/1.73 m2 from January 1, 2002 to December 31, 2018, and followed up until December 31 2019. We excluded patients who had observational time <6 months from eGFR < 30 ml/min/1.73 m2, and had their eGFR measured during a hospitalisation episode due to acute kidney injury, or missing diagnosis date of diabetes. We compared the risk associations of metformin discontinuation with clinical outcomes. The primary outcomes were major adverse cardiovascular events (MACE), end-stage kidney disease (ESKD), cancer, and all-cause mortality. A Cox-model with time-dependent exposure and covariates was used to estimate the hazard ratio (HR) of outcomes in a propensity-score overlap-weighted cohort. The risk of occurrence of lactic acidosis (serum lactate > 5.0 mmol/L with a concomitant blood pH < 7.35 or ICD-9 codes of 276.2) in discontinued-metformin versus continued-metformin users was assessed in a separate register-based cohort. Findings: A total of 33,586 metformin users with new-onset eGFR < 30 ml/min/1.73 m2 were included in the study, 7500 (22.3%) of whom discontinued metformin within 6 months whereas 26,086 (77.7%) continued use of metformin. During a median follow-up of 3.8 (IQR: 2.2-6.1) years, 16.4% (5505/33,586), 30.1% (10,113/33,586), and 7.1% (2171/30,682) had incident MACE, ESKD, and cancer respectively, and 44.4% (14,917/33,586) died. Compared to continued-metformin use, discontinuation was associated with higher risk of MACE (weighted and adjusted HR = 1.40, 95% CI: 1.29-1.52), ESKD (HR = 1.52, 1.42-1.62), and death (HR = 1.22, 1.18-1.27). No association was observed for cancer (HR = 0.93, 0.85-1.01). Discontinued-metformin users had higher change in HbA1c change at 6-month of follow-up versus continued-metformin users (weighted mean HbA1c level change: 0.5% [0.4-0.6%] versus 0.2% [0.1-0.2]). In the separate register-based cohort (n = 3235), null association was observed between metformin use and risk of lactic acidosis (weighted HR = 0.94 [0.53-1.64]). Interpretation: Our results suggest that discontinuation of metformin in patients with T2D and chronic kidney disease may be associated with increased risk of cardiovascular-renal events. Use of metformin below eGFR of 30 ml/min/1.73 m2 may be associated with cardiovascular, renal, and mortality benefits that need to be weighed against the risk of lactic acidosis, but further research is needed to validate these findings. Funding: CUHK Impact Research Fellowship Scheme.

Health impacts of new-onset diabetes in women post-gestational diabetes mellitus: Insights from Hong Kong's territory-wide data.

AIMS/INTRODUCTION: To determine the population health burden attributable to the development of diabetes among women with a history of gestational diabetes mellitus (GDM). MATERIALS AND METHODS: We conducted a retrospective analysis of women with a history of GDM attending the Hong Kong Hospital Authority between 2000 and 2019. The time-varying population attributable fraction was calculated. RESULTS: A total of 76,181 women with a history of gestational diabetes mellitus were included, 6,606 of them developed diabetes during a median follow-up of 8.6 years. The respective hazard ratios (95% confidence interval) among women with GDM who developed diabetes vs those with GDM only were 2.8 (2.2, 3.7) for cardiovascular disease (CVD), 4.8 (3.0, 7.7) for end-stage kidney disease (ESKD), 2.2 (1.9, 2.6) for infection-related hospitalization, and 1.8 (1.3, 2.4) for all-cause mortality. The development of diabetes was associated with 1.3 (0.8, 1.7), 0.6 (0.3, 0.8), 3.2 (2.4, 4.0), and 0.5 (0.2, 0.9) additional incident cases per 1,000 person-years, accounting for 24.0% (13.2%, 35.9%), 42.0% (22.5%, 58.8%), 10.8% (7.1%, 14.9%), and 6.0% (-3.1%, 16.1%) of absolute number of CVD, ESKD, infection-related hospitalization, and all-cause mortality over 20 years after GDM, respectively. CONCLUSIONS: Diabetes is a significant contributor to the population health burden of some clinical outcomes in women with a history of gestational diabetes mellitus, but other risk factors need to be considered.

Distributions and Trends of the Global Burden of DKD Attributable to Lead Exposure: A Systematic Analysis of GBD from 1990 to 2019.

Long-term exposure to lead is associated with an increased risk of diabetic kidney disease (DKD). However, limited data exist on global trends in DKD burden attributable to lead exposure, especially across diverse regions categorized by socioeconomic level. We aimed to assess the spatiotemporal changes in DKD burden attributable to lead exposure from 1990 to 2019 across 204 countries and regions with varying socio-demographic index (SDI) metrics. This retrospective analysis utilized data from the Global Burden of Disease Study 2019 (GBD2019) database. We estimated the burden of DKD attributable to lead exposure using the age-standardized mortality rate (ASMR) and age-standardized disability-adjusted life year rate (ASDR), accounting for sex, age, nationality, and SDI. The annual percentage change (APC) and average annual percentage change (AAPC) were calculated using the Joinpoint model to evaluate trends in the ASMR and ASDR attributable to lead exposure from 1990 to 2019. Gaussian process regression was used to model the relationship between the SDI and ASMR/ASDR. Globally, the burden of DKD attributable to lead exposure has significantly increased since 1990, especially among elderly men and in regions such as Asia, Central Latin America, North Africa, the Middle East, and low-SDI regions. In 2019, the ASMR and ASDR of DKD attributable to lead exposure were 0.68 (95% CI: 0.40, 0.98) per 100,000 people and 15.02 (95% CI: 8.68, 22.26) per 100,000 people, respectively. From 1990 to 2019, the global ASMR and ASDR attributable to lead-associated DKD changed by 15.45% and -1.78%, respectively. The global AAPCs of the ASMR and ASDR were 0.55 (95% CI: 0.45, 0.65) and -0.01 (95% CI: -0.12, 0.1), respectively. Significant declining trends were observed in the high-income Asia Pacific region, eastern sub-Saharan Africa, North Africa, the Middle East, and other regions with high SDIs. Over this 30-year study period, the global burden of DKD attributable to lead exposure has increased, particularly in regions with low SDI. Lead exposure remains a significant concern in the global burden of diabetic kidney disease.

Identification novel mutations and phenotypic spectrum expanding in PATL2 in infertile women with IVF/ICSI failure.

AIM: Abnormalities in oocyte maturation, fertilization, and early embryonic development are major causes of primary infertility in women who are undergoing IVF/ICSI attempts. Although many genetic factors responsible for these abnormal phenotypes have been identified, there are more additional pathogenic genes and variants yet to be discovered. Previous studies confirmed that bi-allelic PATL2 deficiency is an important factor for female infertility. In this study, 935 infertile patients with IVF/ICSI failure were selected for whole-exome sequencing, and 18 probands carrying PATL2 variants with a recessive inheritance pattern were identified. METHODS: We estimated that the prevalence contributed by PATL2 was 1.93% (18/935) in our study cohort. RESULTS: 15 novel variants were found in those families, including c.1093C > T, c.1609dupA, c.1204C > T, c.643dupG, c.877-2A > G, c.1228C > G, c.925G > A, c.958G > A, c.4A > G, c.1258T > C, c.1337G > A, c.1264dupA, c.88G > T, c.1065-2A > G, and c.1271T > C. The amino acids altered by the corresponding variants were highly conserved in mammals, and in silico analysis and 3D molecular modeling suggested that the PATL2 mutants impaired the physiologic function of the resulting proteins. Diverse clinical phenotypes, including oocyte maturation defect, fertilization failure, and early embryonic arrest might result from different variants of PATL2. CONCLUSIONS: These results expand the spectrum of PATL2 variants and provide an important reference for genetic counseling for female infertility, and they increase our understanding of the mechanisms of oocyte maturation arrest caused by PATL2 deficiency.

Trends in all-cause and cause-specific mortality in older adults with and without diabetes: A territory-wide analysis in one million older adults in Hong Kong.

AIMS: Direct comparisons of population-level trends in all-cause and cause-specific mortalities among older adults with and without diabetes are lacking. METHODS: We performed a territory-wide analysis of 1,142,000 unique older adults aged ≥ 65 years (31.7 % with diabetes) with at least one attendance in the Hong Kong Hospital Authority in 2014-2018. We used Joinpoint regression to describe trends of age- and sex-standardised all-cause and cause-specific mortalities (cardiovascular disease [CVD], cancer, and non-CVD and non-cancer) in older adults with and without diabetes. RESULTS: All-cause mortality decreased in older adults with (average annual percent change [AAPC] = -1.6, 95 % confidence interval [-2.7, -0.4]) and without (AAPC = -3.1 [-4.2, -2.1]) diabetes. Largest declines were seen for CVD-cause mortalities for people with and without diabetes (AAPC = -5.5 [-6.8, -4.1] vs AAPC = -5.8 [-8.6, -2.9], respectively). Cancer-cause mortalities were similar in both groups with no change. Men with diabetes showed less favourable improvements. An increasing mortality trend was seen only in the 65-69 age-group regardless of diabetes status. CONCLUSIONS: Mortality continued to decline in older adults with and without diabetes, mainly driven by a decline in CVD deaths, with no narrowing of the mortality gap. Our findings call for continued actions to address excess mortalities especially in older men with diabetes and younger older adults.

99mTc-methoxyisobutylisonitrile single-photon emission computed tomography/computed tomography parathyroid imaging in the diagnosis of functional parathyroid cysts: an initial experience.

Background: Functional parathyroid cysts (FPCs) are rare and difficult to diagnose with noninvasive methods. The aim of this study was to evaluate the diagnostic value of 99mTc-methoxyisobutylisonitrile (99mTc-MIBI) single-photon emission computed tomography/computerized tomography (SPECT/CT) parathyroid imaging in the diagnosis of FPCs and to account for its performance. Methods: The data from 10 patients with suspected parathyroid cysts (PCs) who underwent 99mTc-MIBI SPECT/CT parathyroid imaging between 2012 and 2022 were retrospectively evaluated. The diagnostic value of 99mTc-MIBI SPECT/CT parathyroid imaging for FPCs was analyzed. Results: Surgical resection was performed in six cases and parathyroid puncture was performed in four cases. The sensitivity of 99mTc-MIBI SPECT/CT for FPCs was 100.0% (3/3), with a specificity of 100.0% (7/7) and an accuracy of 100.0% (10/10). The postoperative pathological findings in three cases of FPCs were parathyroid adenoma, parathyroid adenoma with hemorrhage, and parathyroid adenoma with cystic degeneration, respectively. The diagnostic accuracy of ultrasound and CT for PCs was only 22.22% (2/9) and 25.0% (1/4), respectively, and neither modality could indicate whether the cysts were functional or not. Conclusions: 99mTc-MIBI parathyroid SPECT/CT imaging has a high value in the diagnosis of FPCs in patients with suspected PCs, and an intense ring-shaped accumulation of radioactivity in the cyst wall on 99mTc-MIBI imaging suggests that the patient may have FPCs.

Nonlinear relationship between gonadotropin total dose applied and live birth rates in non-PCOS patients: a retrospective cohort study.

The purpose of this article is to explore the relationship between the total dose of follicle-stimulating hormone (FSH) applied during controlled ovulation stimulation and the live birth rates (LBRs) in non-PCOS population. Many studies have found no difference between the dose of FSH application and pregnancy outcomes such as clinical pregnancy rates after fresh embryo transfer. However, a recent large retrospective analysis found a negative correlation between live birth rates and increasing dose of FSH. It is still controversial about the association between FSH dose and LBRs. In addition, no studies have yet explored the nonlinear relationship between FSH and LBRs. This cohort study included a total of 11,645 patients who had accepted IVF/intracytoplasmic sperm injection (ICSI) at the second hospital of Hebei medical university between December 2014 to December 2019. PCOS was identified by Rotterdam PCOS criteria. We researched the association between FSH total dose and live birth rates (LBRs) using multivariate regression analysis. In addition, a model for nonlinear relationships based on a two-part linear regression was applied. The analysis of threshold effects indicated that LBR increased with every 1000 IU FSH when the concentration of FSH was lower than 1410 IU (OR 1.55, 95% CI [1.05, 2.28]); however, a negative association between FSH dose and LBR (OR 0.94, 95% CI [0.89, 0.99]) was found when the FSH total dose was higher than 1410 IU. It is worth noting that the relationship between LBR and FSH dose varied among patients of different ages (OR 0.92 vs 1.06, P for interaction < 0.05).

1-year weight change after diabetes diagnosis and long-term incidence and sustainability of remission of type 2 diabetes in real-world settings in Hong Kong: An observational cohort study.

BACKGROUND: Clinical trials have demonstrated that remission of type 2 diabetes can be achieved following sustained weight loss. However, the feasibility of achieving diabetes remission through weight management in real-world settings remains unclear. In this study, we aimed to examine the association of weight change at 1 year after diabetes diagnosis with long-term incidence and sustainability of type 2 diabetes remission in real-world settings in Hong Kong. METHODS AND FINDINGS: This was a population-based observational cohort study. The territory-wide Risk Assessment and Management Programme for Diabetes Mellitus (RAMP-DM) provides regular comprehensive assessments of metabolic control and complication screening for people with diabetes in Hong Kong. We included 37,326 people with newly diagnosed type 2 diabetes who were enrolled in the RAMP-DM between 2000 and 2017, followed until 2019. Diabetes remission was defined as 2 consecutive HbA1c <6.5% measurements at least 6 months apart in the absence of glucose-lowering drugs (GLDs) and with no record of GLDs at least 3 months before these measurements. During a median follow-up of 7.9 years, 6.1% (2,279) of people achieved diabetes remission, with an incidence rate of 7.8 (95% CI: 7.5, 8.1) per 1,000 person-years. After adjusting for age at diabetes diagnosis, sex, assessment year, body mass index, other metabolic indices, smoking, alcohol drinking, and medication use, the hazard ratio (HR) for diabetes remission was 3.28 (95% CI: 2.75, 3.92; p < 0.001) for people with ≥10% weight loss within 1 year of diagnosis, 2.29 (95% CI: 2.03, 2.59; p < 0.001) for those with 5% to 9.9% weight loss, and 1.34 (95% CI: 1.22, 1.47; p < 0.001) for those with 0% to 4.9% weight loss compared to people with weight gain. During a median follow-up of 3.1 years, 67.2% (1,531) of people who had achieved diabetes remission returned to hyperglycaemia, with an incidence rate of 184.8 (95% CI: 175.5, 194.0) per 1,000 person-years. The adjusted HR for returning to hyperglycaemia was 0.52 (95% CI: 0.41, 0.65; p < 0.001) for people with ≥10% weight loss, 0.78 (95% CI: 0.68, 0.92; p = 0.002) for those with 5% to 9.9% weight loss, and 0.90 (95% CI: 0.80, 1.01; p = 0.073) for those with 0% to 4.9% weight loss compared to people with weight gain. Diabetes remission was associated with a 31% (HR: 0.69, 95% CI: 0.52, 0.93; p = 0.014) decreased risk of all-cause mortality. The main limitation of the study is that the reliability of HbA1c used to define diabetes remission can be affected by other medical conditions. Furthermore, we did not have data on bariatric surgery. CONCLUSIONS: In this study, greater weight loss within the first year of diabetes diagnosis was associated with an increased likelihood of achieving diabetes remission and a decreased risk of returning to hyperglycaemia among those who had achieved diabetes remission. However, both the incidence of diabetes remission and the probability of its long-term sustainability were low with conventional management in real-world settings, in an era when the importance of weight loss was not fully appreciated. Our study provides evidence for policymakers to design and implement early weight management interventions and diabetes remission initiatives.

Epidemic-specific association of maternal exposure to per- and polyfluoroalkyl substances (PFAS) and their components with maternal glucose metabolism: A cross-sectional analysis in a birth cohort from Hong Kong.

Per- and polyfluoroalkyl substances (PFAS) are persistent chemicals that have been linked to increased risk of gestational diabetes mellitus (GDM) and may affect glucose metabolisms during pregnancy. We examined the associations between maternal PFAS exposure and maternal glucose metabolisms and GDM risk among 1601 mothers who joined the Hyperglycaemia-and-Adverse-Pregnancy-Outcome (HAPO) Study in Hong Kong in 2001-2006. All mothers underwent a 75 g-oral-glucose-tolerance test at 24-32 weeks of gestation. We measured serum concentrations of six PFAS biomarkers using high-performance liquid-chromatography-coupled-with-tandem-mass-spectrometry (LC-MS-MS). We fitted conventional and advanced models (quantile-g-computation [qgcomp] and Bayesian-kernel machine regression [BKMR]) to assess the associations of individual and a mixture of PFAS with glycaemic traits. Subgroup analyses were performed based on the enrollment period by the severe-acute-respiratory-syndrome (SARS) epidemic periods in Hong Kong between March 2003 and May 2004. PFOS and PFOA were the main components of PFAS mixture among 1601 pregnant women in the Hong Kong HAPO study, with significantly higher median PFOS concentrations (19.09 ng/mL), compared to Chinese pregnant women (9.40 ng/mL) and US women (5.27 ng/mL). Maternal exposure to PFAS mixture was associated with higher HbA1c in the qgcomp (ß = 0.04, 95 % CI: 0.01-0.06) model. We did not observe significant associations of PFAS mixture with fasting plasma glucose (PG), 1-h and 2-h PG in either model, except for 2-h PG in the qgcmop model (ß = 0.074, 95 % CI: 0.01-0.15). PFOS was the primary contributor to the overall positive effects on HbA1c. Epidemic-specific analyses showed specific associations between PFAS exposure and the odds of GDM in the pre-SARS epidemic period. The median concentration of PFOS was highest during the peri-SARS epidemic (21.2 [14.5-43.6] ng/mL) compared with the pre-SARS (12.3 [9.2-19.9] ng/mL) and post-SARS (20.3 [14.2-46.3] ng/mL) epidemic periods. Potential interactions and exposure-response relationships between PFOA and PFNA with elevated HbA1c were observed in the peri-SARS period in BKMR model. Maternal exposure to PFAS mixture was associated with altered glucose metabolism during pregnancy. SARS epidemic-specific associations call for further studies on its long-term adverse health effects, especially potential modified associations by lifestyle changes during the COVID-19 pandemic.

Expression profile analysis of LncRNAs and mRNAs in pre-receptive endometrium of women with polycystic ovary syndrome undergoing in vitro fertilization-embryo transfer.

BACKGROUND: To compare the expression levels of long non-coding RNA (lncRNA) and messenger RNA (mRNA) in pre-receptive endometrium between patients with Polycystic Ovary Syndrome (PCOS)and normal ovulation undergoing in vitro fertilization-embryo transfer (IVF-ET). METHODS: Endometrial tissues were collected with endometrial vacuum curette in pre-receptive phase (3 days after oocytes retrieval) from PCOS and control groups. LncRNAs and mRNAs of endometrium were identified via RNA sequencing and alignments. A subset of 9 differentially expressed lncRNAs and 11 mRNAs were validated by quantitative reverse transcription polymerase chain reaction(qRT-PCR)in 22 PCOS patients and 18 ovulation patients. The function of mRNAs with differential expression patterns were explored using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). RESULTS: We found out 687 up-regulated and 680 down-regulated mRNAs, as well as 345 up-regulated and 63 down-regulated lncRNAs in the PCOS patients in contrast to normal ovulation patients. qRT-PCR was used to detect the expression of 11 mRNAs, and validated that the expression of these 6 mRNAs CXCR4, RABL6, OPN3, SYBU, IDH1, NOP10 were significantly elevated among PCOS patients, and the expression of ZEB1 was significantly decreased. qRT-PCR was performed to detect the expression of 9 lncRNAs, and validated that the expression of these 7 lncRNAs IDH1-AS1, PCAT14, FTX, DANCR, PRKCQ-AS1, SNHG8, TPT1-AS1 were significantly enhanced among PCOS patients. Bioinformatics analysis showed that differentially expressed genes (DEGs) involved KEGG pathway were tyrosine metabolism, PI3K-Akt pathway, metabolic pathway, Jak-STAT pathway, pyruvate metabolism, protein processing in endoplasmic reticulum, oxidative phosphorylation and proteasome. The up-regulation of GO classification was involved in ATP metabolic process, oxidative phosphorylation, RNA catabolic process, and down-regulation of GO classification was response to corticosteroid, steroid hormone, and T cell activation. CONCLUSION: Our results determined the characteristics and expression profile of endometrial lncRNAs and mRNAs in PCOS patients in pre-receptive phase, which is the day 3 after oocytes retrival. The possible pathways and related genes of endometrial receptivity disorders were found, and those lncRNAs may be developed as a predictive biomarker of endometrium in pre-receptive phase.

Early treatment with dipeptidyl-peptidase 4 inhibitors reduces glycaemic variability and delays insulin initiation in type 2 diabetes: A propensity score-matched cohort study.

AIMS: To examine whether early treatment intensification using dipeptidyl-peptidase 4 inhibitors (DPP4i) delays insulin initiation in Chinese patients diagnosed with type 2 diabetes for less than 5 years. MATERIALS AND METHODS: In a territory-wide prospective cohort study, patients with type 2 diabetes initiating DPP4i at diabetes duration <2 years (early intensification) and 3-5 years (late intensification) were matched using 1:1 propensity-score matching (n = 908 in each arm). We used Cox regression to compare the risk of insulin initiation between the two groups. We explored the interactive and mediation effects of glycated haemoglobin (HbA1c) variability score (HVS), defined as the percentage of HbA1c varying by ≥0.5% compared with preceding values. RESULTS: Of 1816 patients (60.7% men, mean age 54.4 ± 11.9 years), 92.4% and 71.9% were treated with metformin and sulphonylureas respectively at DPP4i initiation. Early DPP4i intensification [hazard ratio (HR) 0.71, (95% CI 0.58-0.68)] and low HVS (<50%) (HR = 0.40, 0.33-0.50) were associated with delayed insulin initiation during a median 4.08 years of follow-up. Early intensification with low HVS had the lowest risk versus late intensification with high HVS (HR = 0.30, 0.22-0.40) (pinteraction  = 0.013). HVS mediated 19.5% of the total effect of early DPP4i intensification on delaying insulin initiation. The late and early intensification groups had similar HbA1c at month 0 (8.4 ± 1.3% vs. 8.4 ± 1.5%) and month 3 (7.6 ± 1.2% vs. 7.6 ± 1.3%) after DPP4i initiation. By month 12, HbA1c in the late intensification group deteriorated (7.9 ± 1.4%) but remained stable in the early intensification group (7.6 ± 1.4%, p = 0.001) with persistent between-group difference over 72 months (8.2 ± 1.7% vs. 7.7 ± 1.6%, p = 0.001). CONCLUSIONS: In type 2 diabetes, early DPP4i intensification delayed insulin initiation, partially explained by reduced glycaemic variability.

S-acylation regulates SQSTM1/p62-mediated selective autophagy.

Macroautophagy/autophagy is a highly conserved metabolic process that degrades intracellular components and recycles bioenergetic substrates. SQSTM1/p62 (sequestosome 1) is a classical autophagy receptor that participates in selective autophagy to eliminate abnormal intracellular components and recycle bioenergetic substrates. In autophagy, SQSTM1 recruits ubiquitinated substrates to form SQSTM1 droplets and delivers these cargoes to phagophores, the precursors to autophagosomes. Recently, we reported a previously unidentified SQSTM1 S-acylation, which is catalyzed by S-acyltransferase ZDHHC19 and reversed by LYPLA1/APT1. S-acylation of SQSTM1 enhances the affinity of SQSTM1 droplets with the phagophore membrane, thereby promoting efficient autophagic degradation of ubiquitinated substrates. Our study uncovers the role of the S-acylation-deacylation cycle in regulating SQSTM1-mediated selective autophagy.

Analysis of false-positive and false-negative results in 99mTc-MIBI SPECT/CT parathyroid imaging.

Background: Exact preoperative localization is desirable to perform minimally invasive parathyroidectomy for hyperparathyroidism (HPT). This study aimed to evaluate the diagnostic values of 99mTc-methoxyisobutylisonitrile (99mTc-MIBI) single photon emission computed tomography/computed tomography (SPECT/CT) of parathyroid glands by analyzing the relationship between lesion weight and false-negative (FN) results, as well as to explain the possible reason. Methods: The data from 314 patients with suspected HPT who underwent 99mTc-MIBI SPECT/CT parathyroid imaging between 2011 and 2022 were retrospectively evaluated. The sensitivity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of parathyroid 99mTc-MIBI SPECT/CT were calculated, and the false-positive (FP) and FN findings were analyzed. Results: Accurate localization by 99mTc-MIBI SPECT/CT was significantly associated with the parathyroid hormone (PTH) level. The 99mTc-MIBI SPECT/CT for diagnosis/lesion location reached a sensitivity of 84.6%/56.8%, a PPV of 97.3%/98.4%, an NPV of only 23.7%/4.18%, and an accuracy of 83.4%/57.1%, respectively. The largest diameter, shortest diameter, and lesion volume were lower in the FN group than in the TP group. A total of 7 FP cases were found, including 2 cases of thyroid nodules, 4 cases of thyroid tissue, and 1 case of hibernoma. A total of 45 FN patients, including 321 FN lesions, were confirmed, of which parathyroid hyperplasia accounted for 97.8%. Lesion weights greater than 20 µg were able to be detected, but lightweight lesions less than 100 mg were the principal source of FN results, accounting for approximately 39.3%. With lesion weights 0-100, 101-300, 301-1,000, and >1,000 mg, the FN rate was 70.8% (126/178), 51.8% (103/199), 34.6% (81/234), and 8.33% (11/132), respectively. Conclusions: 99mTc-MIBI SPECT/CT parathyroid imaging provides good sensitivity and high specificity in HPT location. Correct localization by 99mTc-MIBI SPECT/CT correlates positively with lesion weight and PTH levels. The smaller the lesion, the higher the FN rate in 99mTc-MIBI SPECT/CT parathyroid imaging, and lesions weighing less than 100 mg are the main source of FN results in 99mTc-MIBI SPECT/CT parathyroid imaging.