Effects of ON101 for Hard-to-Heal Diabetic Foot Ulcers in A Randomized Phase III Trial: A Post hoc Analysis.

OBJECTIVE: Hard-to-heal diabetic foot ulcers (DFUs) are associated with higher mortality rates and an increased medical burden for patients. ON101, a new topical cream, exhibited better healing efficacy than the control dressing in a Phase III trial. In this post-hoc analysis, we further identify whether ON101 can improve the healing of ulcers with hard-to-heal risk factors in this cohort of DFU patients. APPROACH: To compare the efficacy of ON101 with absorbent dressing among various hard-to-heal wounds in patients with DFU, a post hoc analysis of a randomized phase III trial included 276 DFU patients was performed by subgrouping those patients based on ulcer depth, location, size, duration, and patients' glycated hemoglobin (HbA1c) levels and body mass index (BMI). RESULTS: In the full analysis set, the proportion of patients achieving healing was 61.7% in the ON101 group and 37.0% in the comparator (P =0.0001). In sub-group analysis according to risk factors, ON101 demonstrated superior healing capacity on Wagner grade 2 ulcers (P < 0.0001); plantar ulcers (P = 0.0016), ulcers size ≥5 cm² (P = 0.0122), ulcers duration ≥3 months (P = 0.0043); for patients with HbA1c ≥9% (P = 0.0285); and patients with BMI ≥25 (P = 0.0005). INNOVATION: ON101, a novel therapeutic drug, can modulate the functions of macrophages and demonstrate superior healing rates to conventional absorbent dressing in patients with hard-to-heal DFUs. CONCLUSIONS: The results of this post hoc study suggest that ON101 is a better therapeutic option than conventional dressing used in treatment for DFU patients with higher HbA1c, BMI, or ulcers with complex conditions such as longer duration, deeper wounds, larger size, and plantar location.

Pharmacogenomic analysis in adrenocortical carcinoma reveals genetic features associated with mitotane sensitivity and potential therapeutics.

Background: Adrenocortical carcinoma (ACC) is an aggressive endocrine malignancy with limited therapeutic options. Treating advanced ACC with mitotane, the cornerstone therapy, remains challenging, thus underscoring the significance to predict mitotane response prior to treatment and seek other effective therapeutic strategies. Objective: We aimed to determine the efficacy of mitotane via an in vitro assay using patient-derived ACC cells (PDCs), identify molecular biomarkers associated with mitotane response and preliminarily explore potential agents for ACC. Methods: In vitro mitotane sensitivity testing was performed in 17 PDCs and high-throughput screening against 40 compounds was conducted in 8 PDCs. Genetic features were evaluated in 9 samples using exomic and transcriptomic sequencing. Results: PDCs exhibited variable sensitivity to mitotane treatment. The median cell viability inhibition rate was 48.4% (IQR: 39.3-59.3%) and -1.2% (IQR: -26.4-22.1%) in responders (n=8) and non-responders (n=9), respectively. Median IC50 and AUC were remarkably lower in responders (IC50: 53.4 µM vs 74.7 µM, P<0.0001; AUC: 158.0 vs 213.5, P<0.0001). Genomic analysis revealed CTNNB1 somatic alterations were only found in responders (3/5) while ZNRF3 alterations only in non-responders (3/4). Transcriptomic profiling found pathways associated with lipid metabolism were upregulated in responder tumors whilst CYP27A1 and ABCA1 expression were positively correlated to in vitro mitotane sensitivity. Furthermore, pharmacologic analysis identified that compounds including disulfiram, niclosamide and bortezomib exhibited efficacy against PDCs. Conclusion: ACC PDCs could be useful for testing drug response, drug repurposing and guiding personalized therapies. Our results suggested response to mitotane might be associated with the dependency on lipid metabolism. CYP27A1 and ABCA1 expression could be predictive markers for mitotane response, and disulfiram, niclosamide and bortezomib could be potential therapeutics, both warranting further investigation.

Effect of 5:2 Regimens: Energy-Restricted Diet or Low-Volume High-Intensity Interval Training Combined With Resistance Exercise on Glycemic Control and Cardiometabolic Health in Adults With Overweight/Obesity and Type 2 Diabetes: A Three-Arm Randomized Controlled Trial.

OBJECTIVE: We aimed to examine the effects of a 5:2 diet (2 days per week of energy restriction by formula diet) or an exercise (2 days per week of high-intensity interval training and resistance training) intervention compared with routine lifestyle education (control) on glycemic control and cardiometabolic health among adults with overweight/obesity and type 2 diabetes. RESEARCH DESIGN AND METHODS: This two-center, open-label, three-arm, parallel-group, randomized controlled trial recruited 326 participants with overweight/obesity and type 2 diabetes and randomized them into 12 weeks of diet intervention (n = 109), exercise intervention (n = 108), or lifestyle education (control) (n = 109). The primary outcome was the change of glycemic control measured as glycated hemoglobin (HbA1c) between the diet or exercise intervention groups and the control group after the 12-week intervention. RESULTS: The diet intervention significantly reduced HbA1c level (%) after the 12-week intervention (-0.72, 95% CI -0.95 to -0.48) compared with the control group (-0.37, 95% CI -0.60 to -0.15) (diet vs. control -0.34, 95% CI -0.58 to -0.11, P = 0.007). The reduction in HbA1c level in the exercise intervention group (-0.46, 95% CI -0.70 to -0.23) did not significantly differ from the control group (exercise vs. control -0.09, 95% CI -0.32 to 0.15, P = 0.47). The exercise intervention group was superior in maintaining lean body mass. Both diet and exercise interventions induced improvements in adiposity and hepatic steatosis. CONCLUSIONS: These findings suggest that the medically supervised 5:2 energy-restricted diet could provide an alternative strategy for improving glycemic control and that the exercise regimen could improve body composition, although it inadequately improved glycemic control.

COVID-19 Rebound After VV116 vs Nirmatrelvir-Ritonavir Treatment: A Randomized Clinical Trial.

Importance: With the widespread use of anti-SARS-CoV-2 drugs, accumulating data have revealed potential viral load rebound after treatment. Objective: To compare COVID-19 rebound after a standard 5-day course of antiviral treatment with VV116 vs nirmatrelvir-ritonavir. Design, Setting, and Participants: This is a single-center, investigator-blinded, randomized clinical trial conducted in Shanghai, China. Adult patients with mild-to-moderate COVID-19 and within 5 days of SARS-CoV-2 infection were enrolled between December 20, 2022, and January 19, 2023, and randomly allocated to receive either VV116 or nirmatrelvir-ritonavir. Interventions: Participants in the VV116 treatment group received oral 600-mg VV116 tablets every 12 hours on day 1 and 300 mg every 12 hours on days 2 through 5. Participants in the nirmatrelvir-ritonavir treatment group received oral nirmatrelvir-ritonavir tablets with 300 mg of nirmatrelvir plus 100 mg of ritonavir every 12 hours for 5 days. Participants were followed up every other day until day 28 and every week until day 60. Main Outcomes and Measures: The primary outcome was viral load rebound (VLR), defined as a half-log increase in viral RNA copies per milliliter compared with treatment completion. Secondary outcomes included a reduction in the cycle threshold value of 1.5 or more, time until VLR, and symptom rebound, defined as an increase of more than 2 points in symptom score compared with treatment completion. The primary outcome and secondary outcomes were analyzed using the full analysis set. Sensitivity analyses were conducted using the per protocol set. Adverse events were analyzed using the safety analysis set. Results: The full analysis set included 345 participants (mean [SD] age, 53.2 [16.8] years; 175 [50.7%] were men) who received VV116 (n = 165) or nirmatrelvir-ritonavir (n = 180). Viral load rebound occurred in 33 patients (20.0%) in the VV116 group and 39 patients (21.7%) in the nirmatrelvir-ritonavir group (P = .70). Symptom rebound occurred in 41 of 160 patients (25.6%) in the VV116 group and 40 of 163 patients (24.5%) in the nirmatrelvir-ritonavir group (P = .82). Viral whole-genome sequencing of 24 rebound cases revealed the same lineage at baseline and at viral load rebound in each case. Conclusions and Relevance: In this randomized clinical trial of patients with mild-to-moderate COVID-19, viral load rebound and symptom rebound were both common after a standard 5-day course of treatment with either VV116 or nirmatrelvir-ritonavir. Prolongation of treatment duration might be investigated to reduce COVID-19 rebound. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2200066811.

NPC1 is required for postnatal islet ß cell differentiation by maintaining mitochondria turnover.

Rationale: NPC1 is a protein localized on the lysosome membrane regulating intracellular cholesterol transportation and maintaining normal lysosome function. GWAS studies have found that NPC1 variants in T2D was a pancreatic islet expression quantitative trait locus, suggesting a potential role of NPC1 in T2D islet pathophysiology. Methods: Two-week-old Npc1-/- mice and wild type littermates were employed to examine pancreatic ß cell morphology and functional changes induced by loss of Npc1. Single cell RNA sequencing was conducted on primary islets. Npc1-/- Min6 cell line was generated using CRISPR/Cas9 gene editing. Seahorse XF24 was used to analyze primary islet and Min6 cell mitochondria respiration. Ultra-high-resolution cell imaging with Lattice SIM2 and electron microscope imaging were used to observe mitochondria and lysosome in primary islet ß and Min6 cells. Mitophagy Dye and mt-Keima were used to measure ß cell mitophagy. Results: In Npc1-/- mice, we found that ß cell survival and pancreatic ß cell mass expansion as well as islet glucose induced insulin secretion in 2-week-old mice were reduced. Npc1 loss retarded postnatal ß cell differentiation and growth as well as impaired mitochondria oxidative phosphorylation (OXPHOS) function to increase mitochondrial superoxide production, which might be attributed to impaired autophagy flux particularly mitochondria autophagy (mitophagy) induced by dysfunctional lysosome in Npc1 null ß cells. Conclusion: Our study revealed that NPC1 played an important role in maintaining normal lysosome function and mitochondria turnover, which ensured establishment of sufficient mitochondria OXPHOS for islet ß cells differentiation and maturation.

Body size, insulin sensitivity, metabolic health and risk of cardiovascular disease in Chinese adults: Insights from the China Cardiometabolic Disease and Cancer Cohort (4C) study.

AIMS: To assess the excess risk of cardiovascular disease (CVD) associated with different criteria for metabolic health, and the interplay of body size, insulin sensitivity and metabolic health with CVD risk. MATERIALS AND METHODS: We conducted a prospective study involving 115 638 participants from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. Metabolic health was defined using three different definitions: (1) insulin sensitivity defined by homeostatic model assessment of insulin resistance index; (2) absence of metabolic syndrome according to the National Cholesterol Education Program Adult Treatment Panel III criteria; and (3) simultaneous absence of metabolic abnormalities (diabetes, hypertension, dyslipidaemia). The primary endpoint was a composite of incident CVD events comprising the first occurrence of myocardial infarction, stroke, heart failure, or cardiovascular death. RESULTS: During a mean 3.61-year follow-up period, obese individuals with insulin sensitivity (multivariable-adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.37-2.08), or without metabolic syndrome (HR 1.46, 95% CI 1.13-1.89) still exhibited increased CVD risks, when compared to their normal-weight counterparts. Otherwise, those with obesity but simultaneous absence of metabolic abnormalities demonstrated similar CVD risk compared to normal-weight individuals (HR 0.91, 95% CI 0.53-1.59). CVD risk increased with the number of abnormalities across body mass index categories, regardless of insulin sensitivity. CONCLUSIONS: This study emphasizes the need for refined definitions of metabolic health and advocates for meticulous screening for metabolic abnormalities to reduce cardiovascular risks, even in individuals with normal weight and insulin sensitivity.

The Association between Educational Attainment and the Risk of Nonalcoholic Fatty Liver Disease among Chinese Adults: Findings from the REACTION Study.

Background/Aims: : Low educational attainment is a well-established risk factor for nonalcoholic fatty liver disease (NAFLD) in developed areas. However, the association between educational attainment and the risk of NAFLD is less clear in China. Methods: : A cross-sectional study including over 200,000 Chinese adults across mainland China was conducted. Information on education level and lifestyle factors were obtained through standard questionnaires, while NAFLD and advanced fibrosis were diagnosed using validated formulas. Outcomes included the risk of NAFLD in the general population and high probability of fibrosis among patients with NAFLD. Logistic regression analysis was employed to estimate the risk of NAFLD and fibrosis across education levels. A causal mediation model was used to explore the potential mediators. Results: : Comparing with those receiving primary school education, the multi-adjusted odds ratios (95% confidence intervals) for NAFLD were 1.28 (1.16 to 1.41) for men and 0.94 (0.89 to 0.99) for women with college education after accounting for body mass index. When considering waist circumference, the odds ratios (95% CIs) were 0.94 (0.86 to 1.04) for men and 0.88 (0.80 to 0.97) for women, respectively. The proportions mediated by general and central obesity were 51.00% and 68.04% for men, while for women the proportions were 48.58% and 32.58%, respectively. Furthermore, NAFLD patients with lower educational attainment showed an incremental increased risk of advanced fibrosis in both genders. Conclusions: : In China, a low education level was associated with a higher risk of prevalent NAFLD in women, as well as high probability of fibrosis in both genders.

Association Between Age at Diabetes Diagnosis and Subsequent Incidence of Cancer: A Longitudinal Population-Based Cohort.

OBJECTIVE: Diabetes presenting at a younger age has a more aggressive nature. We aimed to explore the association of age at type 2 diabetes mellitus (T2DM) diagnosis with subsequent cancer incidence in a large Chinese population. RESEARCH DESIGN AND METHODS: The prospective population-based longitudinal cohort included 428,568 newly diagnosed T2DM patients from 2011 to 2018. Participants were divided into six groups according to their age at diagnosis: 20-54, 55-59, 60-64, 65-69, 70-74, and ≥75 years. The incidence of overall and 14 site-specific cancers was compared with the Shanghai general population including 100,649,346 person-years. RESULTS: A total of 18,853 and 582,643 overall cancer cases were recorded in the T2DM cohort and the general population. The age-standardized rate of overall cancer in T2DM patients was 501 (95% CI: 491, 511) per 100,000 person-years, and the standardized incidence ratio (SIR) was 1.10 (1.09, 1.12). Younger age at T2DM diagnosis was associated with higher incidence of overall and site-specific cancers. SIRs for overall cancer with T2DM diagnosis at ages 20-54, 55-59, 60-64, 65-69, 70-74, and ≥75 years were 1.48 (1.41, 1.54), 1.30 (1.25, 1.35), 1.19 (1.15, 1.23), 1.16 (1.12, 1.20), 1.06 (1.02, 1.10), and 0.86 (0.84, 0.89), respectively. Similar trends were observed for site-specific cancers, including respiratory, colorectum, stomach, liver, pancreatic, bladder, central nervous system, kidney, and gallbladder cancer and lymphoma among both males and females. CONCLUSIONS: Our findings highlight the necessity of stratifying management for T2DM according to age of diagnosis. As with a range of vascular outcomes, age-standardized cancer risks are greater in earlier compared with later onset T2DM.

Sex-stratified genome-wide association and transcriptome-wide Mendelian randomization studies reveal drug targets of heart failure.

The prevalence of heart failure (HF) subtypes, which are classified by left ventricular ejection fraction (LVEF), demonstrate significant sex differences. Here, we perform sex-stratified genome-wide association studies (GWASs) on LVEF and transcriptome-wide Mendelian randomization (MR) on LVEF, all-cause HF, HF with reduced ejection fraction (HFrEF), and HF with preserved ejection fraction (HFpEF). The sex-stratified GWASs of LVEF identified three sex-specific loci that were exclusively detected in the sex-stratified GWASs. Three drug target genes show sex-differential effects on HF/HFrEF via influencing LVEF, with NPR2 as the target gene for the HF drug Cenderitide under phase 2 clinical trial. Our study highlights the importance of considering sex-differential genetic effects in sex-balanced diseases such as HF and emphasizes the value of sex-stratified GWASs and MR in identifying putative genetic variants, causal genes, and candidate drug targets for HF, which is not identifiable using a sex-combined strategy.

A higher TyG index level is more likely to have enhanced incidence of T2DM and HTN comorbidity in elderly Chinese people: a prospective observational study from the reaction study.

BACKGROUND: Triglyceride glucose index (TyG index) was related with both type 2 diabetes (T2DM) and hypertension (HTN). Prospective studies linking the TyG index to the incidence of T2DM and HTN comorbidity remain unclear. This study aimed to to explore the longitudinal association between TyG and new-onset T2DM with HTN. METHODS: 4,434 subjects (1249 males and 3185 females) without initial T2DM and HTN were followed up for 7 years. This study was conducted from November 2011 to August 2018 in the Gucheng, Laoshan and Jinding communities of Beijing. The incidence of T2DM with HTN during the 7-year follow-up was identified as the endpoint. The TyG index was divided into four quartiles: the < 25% level, the 25-50% level, the 50-75% level and the ≥ 75% level. The relationships between the TyG index and T2DM with HTN were evaluated by Cox proportional hazards regression models. RESULTS: During 7 years, the augmented trend of T2DM with HTN was observed in the participants. After adjusting for all confounding factors, compared with those in the lowest quartile of TyG index, the population in the highest quartile of TyG index had a higher risk of T2DM with HTN (hazard ratio (HR), 2.878; 95% confidence intervals (95% CI), 1.230-6.731, P = 0.015), however, the association remained significant only in the female population (HR 2.753, 95% CI, 1.061-7.139, p = 0.037). The TyG had superior predictive ability of increased risk of T2DM with HTN for the populations of older age (≥ 65 years) (HR 2.694, 95% CI 1.212-5.989, p = 0.015), higher eGFR (≥ 90 mL/(min·1.73 m2)) (HR 2.603, 95% CI 1.164-5.818, p = 0.020) or obesity (BMI ≥ 28 kg/m2) (HR 2.547, 95% CI 1.001-6.478, p = 0.020). CONCLUSION: A population with a higher TyG index level was more likely to have an enhanced incidence of T2DM and HTN comorbidity. TyG index could have the significance of clinical in early protection against T2DM with HTN.

Association between updated cardiovascular health construct and risks of non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: The American Heart Association (AHA) updated the construct and algorithm of cardiovascular health (CVH) recently. We aimed to explore the relationship between the new CVH score and the development of non-alcoholic fatty liver disease (NAFLD). METHODS AND RESULTS: 3266 adults free of NAFLD identified via ultrasound were recruited in this prospective study. A modified AHA "Life's Essential 8" (mLE8, i.e., physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure) were collected to evaluate the CVH score. Then participants were categorized into low, moderate, and high CVH subgroups based on overall mLE8 CVH score. According to modified Life's Simple 7 (mLS7) CVH construct, participants were also subdivided into poor, intermediate, and ideal CVH subgroups. During a median 4.3 years follow-up, 623 incident cases of NAFLD were recorded. Compared to those with high CVH, participants with low CVH (adjusted OR = 2.56, 95% CI 1.55-4.24) and moderate CVH (adjusted OR = 1.83, 95% CI 1.17-2.85) had a significantly increased risk of incident NAFLD. Participants with poor CVH (mLS7) but without low CVH (mLE8) did not show a significant elevated risk of incident NAFLD (P = 0.1053). A significant trend was found between increased changes in mLE8 score and a lower risk of NAFLD occurrence. CONCLUSION: Our findings suggested high mLE8 CVH score was associated with a lower risk of NAFLD incidence. The new CVH construct showed a more reasonable classification of CVH status and was more robust in association with NAFLD risks compared with the original one.

Mettl3-Mediated m6A Methylation Controls Pancreatic Bipotent Progenitor Fate and Islet Formation.

The important role of m6A RNA modification in ß-cell function has been established; however, how it regulates pancreatic development and endocrine differentiation remains unknown. Here, we generated transgenic mice lacking RNA methyltransferase-like 3 (Mettl3) specifically in Pdx1+ pancreatic progenitor cells and found the mice with the mutation developed hyperglycemia and hypoinsulinemia at age 2 weeks, along with an atrophic pancreas, reduced islet mass, and abnormal increase in ductal formation. At embryonic day 15.5, Mettl3 deletion had caused a significant loss of Ngn3+ endocrine progenitor cells, which was accompanied by increased Sox9+ ductal precursor cells. We identified histone deacetylase 1 (Hdac1) as the critical direct m6A target in bipotent progenitors, the degeneration of which caused abnormal activation of the Wnt/Notch signaling pathway and blocked endocrine differentiation. This transformation could be manipulated in embryonic pancreatic culture in vitro through regulation of the Mettl3-Hdac1-Wnt/Notch signaling axis. Our finding that Mettl3 determines endocrine lineage by modulating Hdac1 activity during the transition of bipotent progenitors might help in the development of targeted endocrine cell protocols for diabetes treatment.

Diabesity phenotype in relation to the incidence and resolution of nonalcoholic fatty liver disease: A prospective cohort study.

BACKGROUND: Diabesity is a term used to emphasize the dual epidemic and the combined detrimental effects of diabetes and obesity. We aimed to investigate the associations of diabesity with the incidence and resolution of nonalcoholic fatty liver disease (NAFLD). METHODS: This prospective cohort study included 5549 participants with a median follow-up of 4.3 years (2010-2015). Diabesity was defined as six categories by the combinations of glucose tolerance status (normal glucose tolerance [NGT], prediabetes, and diabetes) diagnosed by fasting and oral glucose tolerance test 2-h glucose and hemoglobin A1c and general or abdominal obesity status. We examined the odds ratios (ORs) for the incidence and resolution of NAFLD associated with diabesity categories, respectively. RESULTS: For NAFLD incidence, compared with the diabesity category of NGT with nonobesity, the categories of either glucose intolerance or general obesity were associated with higher risks of NAFLD, of which the categories with obesity, regardless of glucose intolerance status, exhibited greater risks (ORs ranged from 3.19 to 4.49) than the categories of nonobesity. For NAFLD resolution, the categories of prediabetes or diabetes with obesity were associated with decreased likelihoods of a resolution of NAFLD (ORs ranged from 0.40 to 0.58). These association patterns were consistent across various definitions of diabesity by glucose tolerance status diagnosed by different combinations of glycemic parameters and general or abdominal obesity. CONCLUSIONS: The diabesity association pattern with NAFLD incidence was mainly determined by obesity, while that with NAFLD resolution was driven by the combined phenotype of glucose intolerance and obesity.

Bacteroides methylmalonyl-CoA mutase produces propionate that promotes intestinal goblet cell differentiation and homeostasis.

Propionate is a short-chain fatty acid that is generated upon microbiome-mediated fiber fermentation in the intestine. By modulating immune and metabolic pathways, propionate exerts many health benefits. Key bacterial species, such as Bacteroides thetaiotaomicron, generate propionate, but the biochemical pathways and specific functions remain undetermined. We identified a gene operon-encoding methylmalonyl-CoA mutase (MCM) that contributes to propionate biosynthesis in B. thetaiotaomicron. Colonization of germ-free mice with wild-type or MCM-deficient strains as well as in vitro examination demonstrated that MCM-mediated propionate production promotes goblet cell differentiation and mucus-related gene expression. Intestinal organoids lacking the propionate receptor, GPR41, showed reduced goblet cell differentiation upon MCM-mediated propionate production. Furthermore, although wild-type B. thetaiotaomicron alleviated DSS-induced intestinal inflammation, this effect was abolished in mice receiving the MCM-deficient strain but restored upon propionate supplementation. These data emphasize the critical role of MCM-mediated propionate biosynthesis in goblet cell differentiation, offering potential pathways to ameliorate colitis.

Age-specific difference in the temporal relationships between updated cardiovascular health construct and arterial stiffness in middle-aged and older adults.

Previous studies have found that the association between modifiable risk factors and arterial stiffness varied with age. We aimed to explore the age-specific difference in the relationship between new cardiovascular health (CVH) score and arterial stiffness and further detected the age-specific temporal relationships in a prospective cohort study. During a median 4.3 years follow-up, 3757 participants were recruited in this study. A modified AHA "Life's Essential 8" construct (mLE8 with lacking information on diet habits) was used to evaluate CVH. Branchial-ankle pulse wave velocity (baPWV) was measured to assess arterial stiffness. Data were analyzed with logistic regression models, restricted cubic splines (RCS), and cross-lagged path analysis (age < 60 vs. age ≥ 60). In age-stratified analysis, moderate (OR = 2.21, 95% CI 1.11-4.43) and low (OR = 3.37, 95% CI 1.63-7.00) CVH were related with a higher incidence of elevated baPWV compared to high CVH in middle-aged adults, while this association was not detected in older adults. RCS curve showed a steeper linear association between CVH score and elevated baPWV in middle-aged adults than older individuals. In the cross-lagged path analysis, the decline in CVH score preceded the increment in arterial stiffness in middle-aged adults, but they appeared to alter simultaneously in older adults. Our study detected an age-specific difference in the relationship between mLE8 CVH score and elevated baPWV and showed that low CVH preceded alterations of baPWV in middle-aged adults, suggesting the importance of improvement in CVH during the early stage of the lifespan.

Cushing Syndrome Is Associated With Gut Microbial Dysbiosis and Cortisol-Degrading Bacteria.

CONTEXT: Cushing syndrome (CS) is a severe endocrine disease characterized by excessive secretion of cortisol with multiple metabolic disorders. While gut microbial dysbiosis plays a vital role in metabolic disorders, the role of gut microbiota in CS remains unclear. OBJECTIVE: The objective of this work is to examine the alteration of gut microbiota in patients with CS. METHODS: We performed shotgun metagenomic sequencing of fecal samples from 78 patients with CS and 78 healthy controls matched for age and body mass index. Furthermore, we verify the cortisol degradation capacity of Ruminococcus gnavus in vitro and identify the potential metabolite by LC-MC/MS. RESULTS: We observed significant differences in microbial composition between CS and controls in both sexes, with CS showing reduced Bacteroidetes (Bacteroides vulgatus) and elevated Firmicutes (Erysipelotrichaceae_bacterium_6_1_45) and Proteobacteria (Enterobacter cloacae). Despite distinct causes of hypercortisolism in ACTH-dependent and ACTH-independent CS, we found no significant differences in metabolic profiles or gut microbiota between the 2 subgroups. Furthermore, we identified a group of gut species, including R. gnavus, that were positively correlated with cortisol levels in CS. These bacteria were found to harbor cortisol-degrading desAB genes and were consistently enriched in CS. Moreover, we demonstrated the efficient capacity of R. gnavus to degrade cortisol to 11-oxygenated androgens in vitro. CONCLUSION: This study provides evidence of gut microbial dysbiosis in patients with CS and identifies a group of CS-enriched bacteria capable of degrading cortisol. These findings highlight the potential role of gut microbiota in regulating host steroid hormone levels, and consequently host health.

CRCS: An automatic image processing pipeline for hormone level analysis of Cushing's disease.

Due to the abnormal secretion of adreno-cortico-tropic-hormone (ACTH) by tumors, Cushing's disease leads to hypercortisonemia, a precursor to a series of metabolic disorders and serious complications. Cushing's disease has high recurrence rate, short recurrence time and undiscovered recurrence reason after surgical resection. Qualitative or quantitative automatic image analysis of histology images can potentially in providing insights into Cushing's disease, but still no software has been available to the best of our knowledge. In this study, we propose a quantitative image analysis-based pipeline CRCS, which aims to explore the relationship between the expression level of ACTH in normal cell tissues adjacent to tumor cells and the postoperative prognosis of patients. CRCS mainly consists of image-level clustering, cluster-level multi-modal image registration, patch-level image classification and pixel-level image segmentation on the whole slide imaging (WSI). On both image registration and classification tasks, our method CRCS achieves state-of-the-art performance compared to recently published methods on our collected benchmark dataset. In addition, CRCS achieves an accuracy of 0.83 for postoperative prognosis of 12 cases. CRCS demonstrates great potential for instrumenting automatic diagnosis and treatment for Cushing's disease.

Sex-specific causality of MRI-derived body compositions on glycaemic traits: Mendelian randomization and observational study.

AIM: To investigate the sex-specific causality of body compositions in type 2 diabetes and related glycaemic traits using Mendelian randomization (MR). MATERIALS AND METHODS: We leveraged sex-specific summary-level statistics from genome-wide association studies for three adipose deposits adjusted for body mass index and height, including abdominal subcutaneous adipose tissue, visceral adipose tissue (VATadj) and gluteofemoral adipose tissue (GFATadj), measured by MRI (20 038 women; 19 038 men), and fat mass-adjusted appendicular lean mass (ALMadj) (244 730 women; 205 513 men) in the UK Biobank. Sex-specific statistics of type 2 diabetes were from the Diabetes Genetics Replication and Meta-analysis Consortium and those for fasting glucose and insulin were from the Meta-analyses of Glucose and Insulin-related Traits Consortium. Univariable and multivariable MR (MVMR) were performed. We also performed MR analyses of anthropometric traits and genetic association analyses using individual-level data of body composition as validation. RESULTS: Univariable MR analysis showed that, in women, higher GFATadj and ALMadj exerted a causally protective effect on type 2 diabetes (GFATadj: odds ratio [OR] 0.59, 95% confidence interval [CI; 0.50, 0.69]; ALMadj: OR 0.84, 95% CI [0.77, 0.91]) and VATadj to be riskier in glycaemic traits. MVMR showed that GFATadj retained a robust effect on type 2 diabetes (OR 0.57, 95% CI [0.42, 0.77]; P = 2.6 × 10-4 ) in women, while it was nominally significant in men (OR 0.58, 95% CI [0.35, 0.96]; P = 3.3 × 10-2 ), after adjustment for ASATadj and VATadj. MR analyses of anthropometric measures and genetic association analyses of glycaemic traits confirmed the results. CONCLUSIONS: Body composition has a sex-specific effect on type 2 diabetes, and higher GFATadj has an independent protective effect on type 2 diabetes in both sexes.