[Gene-gene/gene-environment interaction of transforming growth factor-ß signaling pathway and the risk of non-syndromic oral clefts].

OBJECTIVE: To explore the association between polymorphisms of transforming growth factor-ß (TGF-ß) signaling pathway and non-syndromic cleft lip with or without cleft palate (NSCL/P) among Asian populations, while considering gene-gene interaction and gene-environment interaction. METHODS: A total of 1 038 Asian NSCL/P case-parent trios were ascertained from an international consortium, which conducted a genome-wide association study using a case-parent trio design to investigate the genes affec-ting risk to NSCL/P. After stringent quality control measures, 343 single nucleotide polymorphism (SNP) spanning across 10 pivotal genes in the TGF-ß signaling pathway were selected from the original genome-wide association study(GWAS) dataset for further analysis. The transmission disequilibrium test (TDT) was used to test for SNP effects. The conditional Logistic regression models were used to test for gene-gene interaction and gene-environment interaction. Environmental factors collected for the study included smoking during pregnancy, passive smoking during pregnancy, alcohol intake during pregnancy, and vitamin use during pregnancy. Due to the low rates of exposure to smoking during pregnancy and alcohol consumption during pregnancy (<3%), only the interaction between maternal smoking during pregnancy and multivitamin supplementation during pregnancy was analyzed. The threshold for statistical significance was rigorously set at P =1.46×10-4, applying Bonferroni correction to account for multiple testing. RESULTS: A total of 23 SNPs in 4 genes yielded nominal association with NSCL/P (P<0.05), but none of these associations was statistically significant after Bonferroni' s multiple test correction. However, there were 6 pairs of SNPs rs4939874 (SMAD2) and rs1864615 (TGFBR2), rs2796813 (TGFB2) and rs2132298 (TGFBR2), rs4147358 (SMAD3) and rs1346907 (TGFBR2), rs4939874 (SMAD2) and rs1019855 (TGFBR2), rs4939874 (SMAD2) and rs12490466 (TGFBR2), rs2009112 (TGFB2) and rs4075748 (TGFBR2) showed statistically significant SNP-SNP interaction (P<1.46×10-4). In contrast, the analysis of gene-environment interactions did not yield any significant results after being corrected by multiple testing. CONCLUSION: The comprehensive evaluation of SNP associations and interactions within the TGF-ß signaling pathway did not yield any direct associations with NSCL/P risk in Asian populations. However, the significant gene-gene interactions identified suggest that the genetic architecture influencing NSCL/P risk may involve interactions between genes within the TGF-ß signaling pathway. These findings underscore the necessity for further investigations to unravel these results and further explore the underlying biological mechanisms.

[A ssociations of short-term ambient particulate matter exposure and MTNR1B gene with triglyceride-glucose index: A family-based study].

OBJECTIVE: To explore the effects of short-term particulate matter (PM) exposure and the melatonin receptor 1B (MTNR1B) gene on triglyceride-glucose (TyG) index utilizing data from Fang-shan Family-based Ischemic Stroke Study in China (FISSIC). METHODS: Probands and their relatives from 9 rural areas in Fangshan District, Beijing, were included in the study. PM data were obtained from fixed monitoring stations of the National Air Pollution Monitoring System. TyG index was calculated by fasting triglyceride and glucose concentrations. The associations of short-term PM exposure and rs10830963 polymorphism of the MTNR1B gene with the TyG index were assessed using mixed linear models, in which covariates such as age, sex, and lifestyles were adjusted for. Gene-environment inter-action analysis was furtherly performed using the maximum likelihood methods to explore the potential effect modifier role of rs10830963 polymorphism in the association of PM with TyG index. RESULTS: A total of 4 395 participants from 2 084 families were included in the study, and the mean age of the study participants was (58.98±8.68) years, with 53. 90% females. The results of association analyses showed that for every 10 µg/m3 increase in PM2.5 concentration, TyG index increased by 0.017 (95%CI: 0.007-0.027), while for per 10 µg/m3 increment in PM10, TyG index increased by 0.010 (95%CI: 0.003-0.017). And the associations all had lagged effects. In addition, there was a positive association between the rs10830963 polymorphism and the TyG index. For per increase in risk allele G, TyG index was elevated by 0.040 (95%CI: 0.004-0.076). The TyG index was 0.079 (95%CI: 0.005-0.152) higher in carriers of the GG genotype compared with carriers of the CC genotype. The interaction of rs10830963 polymorphism with PM exposure had not been found to be statistically significant in the present study. CONCLUSION: Short-term exposure to PM2.5 and PM10 were associated with higher TyG index. The G allele of rs10830963 polymorphism in the MTNR1B gene was associated with the elevated TyG index.

Nanoformulations for the diagnosis and treatment of metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive phase of metabolic dysfunction-associated steatotic liver disease (MASLD) that develops into irreversible liver cirrhosis and hepatocellular carcinoma, ultimately necessitating liver transplantation as the sole life-saving option. However, given the drawbacks of liver transplantation, including invasiveness, chronic immunosuppression, and a lack of donor livers, prompt diagnosis and effective treatment are indispensable. Due to the limitations of liver biopsy and conventional imaging modalities in diagnosing MASH, as well as the potential hazards associated with liver-protecting medicines, numerous nanoformulations have been created for MASH theranostics. Particularly, there has been significant study interest in artificial nanoparticles, natural biomaterials, and bionic nanoparticles that exhibit exceptional biocompatibility and bioavailability. In this review, we summarized extracellular vesicles (EVs)-based omics analysis and Fe3O4-based functional magnetic nanoparticles as magnetic resonance imaging (MRI) contrast agents for MASH diagnosis. Additionally, artificial nanoparticles such as organic and inorganic nanoparticles, as well as natural biomaterials such as cells and cell-derived EVs and bionic nanoparticles including cell membrane-coated nanoparticles, have also been reported for MASH treatment owing to their specific targeting and superior therapeutic effect. This review has the potential to stimulate advancements in nanoformulation fabrication techniques. By exploring their compatibility with cell biology, it could lead to the creation of innovative material systems for efficient theragnostic uses for MASH. STATEMENT OF SIGNIFICANCE: People with metabolic dysfunction-associated steatohepatitis (MASH) will progress to fibrosis, cirrhosis, or even liver cancer. It is imperative to establish effective theragnostic techniques to stop MASH from progressing into a lethal condition. In our review, we summarize the advancement of artificial, natural, and bionic nanoparticles applied in MASH theragnosis. Furthermore, the issues that need to be resolved for these cutting-edge techniques are summarized to realize a more significant clinical impact. We forecast the key fields that will advance further as nanotechnology and MASH research progress. Generally, our discovery has significant implications for the advancement of nanoformulation fabrication techniques, and their potential to be compatible with cell biology could lead to the creation of innovative materials systems for effective MASH theragnostic.

Association of Life's Essential 8 with all-cause mortality and risk of cancer: a prospective cohort study.

BACKGROUND: No study has concentrated on the association of LE8 with cancer risk and death. We aim to examine the association of LE8 with death and cancer. METHODS: A total of 94733 adults aged 51.42 ± 12.46 years and 77551 participants aged 54.09±12.06 years were enrolled in longitudinal and trajectory analysis respectively. Baseline LE8 was divided into three groups based on the American Heart Association criteria and three trajectory patterns by latent mixture models. We reviewed medical records and clinical examinations to confirm incident cancer during the period from 2006 to 2020. Death information was collected from provincial vital statistics offices. Cox models were used. RESULTS: 12807 all-cause deaths and 5060 cancers were documented during a 14-year follow-up. Relative to participants with high LE8 at baseline, participants with lower levels of LE8 have a significantly increased risk of mortality and incident cancer. All these risks have an increasing trend with LE8 level decreasing. Meanwhile, the trajectory analysis recorded 7483 all-cause deaths and 3037 incident cancers after approximately 10 years. The associations of LE8 with death and cancer were identical to the longitudinal study. In the subtype cancer analysis, LE8 has a strong effect on colorectal cancer risk. Moreover, the cut point is 56.67 in the association between LE8 and death, while the cut point altered to 64.79 in the association between LE8 and incident cancers. These associations were enhanced among younger adults. CONCLUSIONS: There was a significant association of LE8 with death and cancer risk, especially for the young population.

Corr-Track: Category-Level 6D Pose Tracking with Soft-Correspondence Matrix Estimation.

Category-level pose tracking methods can continuously track the pose of objects without requiring any prior knowledge of the specific shape of the tracked instance. This makes them advantageous in augmented reality and virtual reality applications. The key challenge is how to train neural networks to accurately predict the poses of objects they have never seen before and exhibit strong generalization performance. We propose a novel category-level 6D pose tracking method Corr-Track, which is capable of accurately tracking objects belonging to the same category from depth video streams. Our approach utilizes direct soft correspondence constraints to train a neural network, which estimates bidirectional soft correspondences between sparsely sampled point clouds of objects in two frames. We first introduce a soft correspondence matrix for pose tracking tasks and establish effective constraints through direct spatial point-to-point correspondence representations in the sparse point cloud correspondence matrix. We propose the "point cloud expansion" strategy to address the "point cloud shrinkage" problem resulting from soft correspondences. This strategy ensures that the corresponding point cloud accurately reproduces the shape of the target point cloud, leading to precise pose tracking results. We evaluated our approach on the NOCS-REAL275 and Wild6D dataset and observed superior performance compared to previous methods. Additionally, we conducted cross-category experiments that further demonstrated its generalization capability.

Detecting Gene-Gene Interaction among DNA Repair Genes in Chinese non-Syndromic Cleft lip with or Without Palate Trios.

OBJECTIVE: The objective of this study is to investigate the gene-gene interactions associated with NSCL/P among DNA repair genes. DESIGN: This study included 806 NSCL/P case-parent trios from China. Quality control process was conducted for genotyped single nucleotide polymorphisms (SNPs) located in six DNA repair genes (ATR, ERCC4, RFC1, TYMS, XRCC1 and XRCC3). We tested gene-gene interactions with Cordell's method using statistical package TRIO in R software. Bonferroni corrected significance level was set as P = 4.24 × 10-4. We also test the robustness of the interactions by permutation tests. SETTING: Not applicable. PATIENTS/PARTICIPANTS: A total of 806 NSCL/P case-parent trios (complete trios: 682, incomplete trios: 124) with Chinese ancestry. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE(S): Not applicable. RESULTS: A total of 118 SNPs were extracted for the interaction tests. Fourteen pairs of significant interactions were identified after Bonferroni correction, which were confirmed in permutation tests. Twelve pairs were between ATR and ERCC4 or XRCC3. The most significant interaction occurred between rs2244500 in TYMS and rs3213403 in XRCC1(P = 8.16 × 10-15). CONCLUSIONS: The current study identified gene-gene interactions among DNA repair genes in 806 Chinese NSCL/P trios, providing additional evidence for the complicated genetic structure underlying NSCL/P. ATR, ERCC4, XRCC3, TYMS and RFC1 were suggested to be possible candidate genes for NSCL/P.

Effect of statin therapy patterns on readmission and mortality in patients with intracerebral hemorrhage.

There is limited and inconsistent evidence for the association of statin therapy and statin treatment patterns with the risk of recurrent intracerebral hemorrhage (ICH) in patients with prior ICH. To assess the association of statin therapy and its intensity, type, initiation time, and discontinuation with the risk of recurrent ICH and mortality in Chinese patients with ICH. Patients with newly diagnosed ICH in the Beijing Employee Medical Claims Data database from 2010 to 2017 were included. Post-ICH statin users (post-diagnosis only) and nonusers (never), statin discontinuers (pre-diagnosis only) and continuers (pre- and post-diagnosis) were matched on a 1:1 propensity score, respectively. Adjusted Cox proportional risk models were used to estimate the risk ratios for ICH readmission and mortality under various statin patterns. A total of 2668 post-ICH statin users and 2668 nonusers without a history of statin use were enrolled. Post-ICH statin users had a lower risk of ICH readmission (HR, 0.57; 95% CI 0.48, 0.69) and all-cause death (0.56: 0.49, 0.63) than nonusers. Low/moderate-intensity treatment was associated with a 63% lower risk of recurrent ICH compared with nonusers (0.37: 0.29, 0.46), whereas high-intensity treatment did not reduce the risk (0.93: 0.74, 1.16). Both low/moderate-intensity (0.42: 0.36, 0.48) and high-intensity statins (0.57: 0.48, 0.69) were associated with a lower risk of all-cause mortality. The risk of ICH readmission was 53% (0.47: 0.30, 0.74) lower with adherence to rosuvastatin than with atorvastatin. Only starting medication within 30 days of the first diagnosis of ICH reduced the risk of ICH readmission (0.49: 0.40, 0.60). Among patients with a history of statin use, 1807 discontinuing and 1,807 continuing users of statins were included. The risk of ICH readmission (4.00: 3.32, 4.80) and the risk of all-cause death (4.01: 3.57, 4.50) were substantially increased in statin discontinuation compared with continued statin use. Statin therapy after ICH was associated with lower risks for ICH readmission and all-cause mortality compared with non-statin therapy, especially at low/moderate intensity and early initiation of statins after ICH. Adherence to rosuvastatin was associated with a lower risk of recurrence of ICH than atorvastatin. Among patients with a statin history prior to ICH, discontinuation of statins after ICH was associated with increased risk of ICH recurrence and death.

The combined effects of arteriosclerosis and diabetes on cardiovascular disease risk.

The morbidity and mortality of cardiovascular disease (CVD) rank first among common diseases. Arteriosclerosis and diabetes are risk factors for CVDs, which influence each other. However, their combined effects on CVDs are still unclear. In this study, people who participated in brachial-ankle pulse wave velocity (baPWV) testing and the annual physical examination of the Kailuan Group Finance Co., Ltd., from January 1, 2010, to December 31, 2020, were selected, and their anthropometric, biochemical and epidemiological data were collected. The participants were divided into four groups according to diabetes and arteriosclerosis diagnosis and follow-up. Cox proportional hazards regression and subdistribution hazard models were used to analyse the combined effects of arteriosclerosis and diabetes on CVDs. Multiple sensitivity analyses were also performed. A total of 59,268 Asian populations were selected, including 14,425 females (28.11%) with an average age of 48.10 (± 12.72) years. During follow-up, 1830 subjects developed CVDs (mean follow-up period, 4.72 years). The cumulative incidence rates of the healthy control, diabetes, arteriosclerosis, and comorbidity groups were 5.04% (807/38781), 15.17% (253/3860), 17.04% (465/5987), and 25.59% (305/2684), respectively. The results of multivariate Cox regression analysis showed that compared with the healthy control group, the risk of CVD in the diabetes, arteriosclerosis, and comorbidity groups was significantly increased. Their HR values were 1.88 (95% CI 1.62-2.18), 1.40 (95% CI 1.23-1.60), and 2.10 (95% CI 1.80-2.45), respectively. The results of the sensitivity analysis were robust. For each one standard increase in fasting blood glucose or baPWV, the HR values for CVDs were 1.16 (95% CI 1.12-1.20) and 1.22 (95% CI 1.16-1.28), respectively. The results indicated that both arteriosclerosis and diabetes lead to an increased risk of CVDs. The risk of CVDs, coronary atherosclerotic heart disease, heart failure, stroke, coronary artery bypass grafting and ischemic stroke in patients with arteriosclerosis and diabetes was significantly higher than that in patients with arteriosclerosis or diabetes alone. Therefore, the primary prevention of CVDs in patients with arteriosclerosis complicated with diabetes needs more attention.

Identification of genetic loci jointly influencing COVID-19 and coronary heart diseases.

BACKGROUND: Comorbidities of coronavirus disease 2019 (COVID-19)/coronary heart disease (CHD) pose great threats to disease outcomes, yet little is known about their shared pathology. The study aimed to examine whether comorbidities of COVID-19/CHD involved shared genetic pathology, as well as to clarify the shared genetic variants predisposing risks common to COVID-19 severity and CHD risks. METHODS: By leveraging publicly available summary statistics, we assessed the genetically determined causality between COVID-19 and CHD with bidirectional Mendelian randomization. To further quantify the causality contributed by shared genetic variants, we interrogated their genetic correlation with the linkage disequilibrium score regression method. Bayesian colocalization analysis coupled with conditional/conjunctional false discovery rate analysis was applied to decipher the shared causal single nucleotide polymorphisms (SNPs). FINDINGS: Briefly, we observed that the incident CHD risks post COVID-19 infection were partially determined by shared genetic variants. The shared genetic variants contributed to the causality at a proportion of 0.18 (95% CI 0.18-0.19) to 0.23 (95% CI 0.23-0.24). The SNP (rs10490770) located near LZTFL1 suggested direct causality (SNPs → COVID-19 → CHD), and SNPs in ABO (rs579459, rs495828), ILRUN(rs2744961), and CACFD1(rs4962153, rs3094379) may simultaneously influence COVID-19 severity and CHD risks. INTERPRETATION: Five SNPs located near LZTFL1 (rs10490770), ABO (rs579459, rs495828), ILRUN (rs2744961), and CACFD1 (rs4962153, rs3094379) may simultaneously influence their risks. The current study suggested that there may be shared mechanisms predisposing to both COVID-19 severity and CHD risks. Genetic predisposition to COVID-19 is a causal risk factor for CHD, supporting that reducing the COVID-19 infection risk or alleviating COVID-19 severity among those with specific genotypes might reduce their subsequent CHD adverse outcomes. Meanwhile, the shared genetic variants identified may be of clinical implications for identifying the target population who are more vulnerable to adverse CHD outcomes post COVID-19 and may also advance treatments of 'Long COVID-19.'

Better Life's Essential 8 Is Associated With Lower Risk of Diabetic Kidney Disease: A Community-Based Study.

Background Diabetic kidney disease (DKD) is a common diabetic complication and increases the complexity of diabetes management. No prospective study has focused on the association between DKD and Life's Essential 8 (LE8). Our study aims to examine the association between LE8 and DKD risk. Methods and Results A total of 7605 participants, aged 54.32±9.77 years, and 4688 participants, aged 56.11±10.38 years, were included in the longitudinal and trajectory analyses, respectively, from 2006 to 2020. The DKD was confirmed using data collected during each follow-up. LE8 was based on 4 health behaviors and 4 health factors. The range of each metric was 0 to 100, and the overall LE8 score was calculated as the unweighted average of all 8 component metric scores. The trajectories of LE8 during 2006 to 2010 were classified using latent mixture models. Cox models and restricted cubic splines were applied. After a median follow-up of 12.41 and 6.71 years in longitudinal and trajectory analyses, respectively, the DKD incidence decreased, with the LE8 level increasing (P-trend<0.05), and the linearity assumption for this relationship (P-nonlinear=0.685) had been satisfied. Adjusted hazard ratios (HRs) for the highest tertile were 0.77 (95% CI, 0.69-0.87) and 0.70 (95% CI, 0.62-0.78) in baseline and time-updated LE8 scores, respectively, compared with the lowest tertile. Adjusted HR was 0.53 (95% CI, 0.41-0.69) for the stable-high pattern compared with the stable-low pattern. Conclusions Although LE8 is an indicator of cardiovascular health, the beneficial impact of a high LE8 score is also evident in the protection of renal health among patients with diabetes.

Association of Metformin Use with Iron Deficiency Anemia in Urban Chinese Patients with Type 2 Diabetes.

BACKGROUND: Previous evidence yielded contradictory findings on the relationship between metformin and anemia. This study aims to assess whether metformin use is associated with iron-deficiency anemia (IDA) risk in patients with type 2 diabetes (T2D) in Beijing, China. METHODS: Overall, 60,327 newly diagnosed T2D patients were included based on a historical cohort study design. The information pertaining to these patients was gathered from the Beijing Medical Claim Data for Employees Database. These patients were then categorized into the metformin and non-metformin groups and matched on a 1:1 propensity score based on their initial antidiabetic prescription. The Cox proportional hazards models were utilized to calculate the incidences and the hazard ratios (HRs). RESULTS: The study enrolled 27,960 patients with type 2 diabetes, with 13,980 patients in each of the initial glucose-lowering prescription groups: metformin and non-metformin. During a median follow-up period of 4.84 years, 4832 patients developed IDA. The incidence of IDA was significantly lower in the metformin group (26.08/1000 person-years) than in the non-metformin group (43.20/1000 person-years). Among the three groups divided by the proportion of days covered by metformin, we found a negative correlation between the proportion of days covered by metformin and the risk of IDA. The risk of IDA in patients with a proportion of days covered by metformin of <20%, 20-79%, and ≥80% was 0.43 (0.38, 0.48), 0.37 (0.34, 0.42), and 0.91 (0.85, 0.98), respectively, compared to the non-metformin group. We also performed subgroup analyses and sensitivity analyses: the incidence of IDA in the metformin group was lower than that in the non-metformin group in all subgroups, and the protective effect was more significant in subgroups of patients aged ≥65, with Charlson comorbidity index (CCI) ≥2, and with gastric acid inhibitor use. CONCLUSIONS: In Chinese patients with T2DM, metformin treatment was associated with a decreased risk of IDA admission, and this risk responded positively to the proportion of days covered by metformin. These findings suggest that metformin may have a pleiotropic effect on IDA in patients with type 2 diabetes. Our study has important clinical implications for the management of patients with diabetes and other conditions that increase the risk of IDA.

Identifying Risk Factors for Aspiration in Patients Hospitalized with Community-Acquired Pneumonia.

Background: Aspiration pneumonia (AP) is difficult to diagnose and has poor outcomes. This case-control study aimed to explore the risk factors and delineate the antibiotic usage for AP. Methods: Inpatients diagnosed with community-acquired pneumonia (CAP) from 2013 to 2017, enrolled in the urban employee basic medical insurance program in Beijing, were included and classified into the AP (N = 2,885) and non-AP (N = 53,825) groups. Risk factors were identified by logistic regression. Results: Older age (compared to 18-64 years, OR for 65-79 years: 4.3, 95% CI: 3.8-4.9; OR for >80 years: 6.3, 95% CI: 5.6-7.2), male (OR: 1.4, 95% CI: 1.3-1.5), cerebrovascular disease (OR: 3.1, 95% CI: 2.8-3.5), dementia (OR: 2.0, 95% CI: 1.8-2.1), vomiting (OR: 1.4, 95% CI: 1.2-1.7), Parkinson's disease (OR: 2.1, 95% CI: 1.8-2.4), and epilepsy (OR: 3.2, 95% CI: 2.8-3.7) were associated with an increased risk of AP. 92.8% of the AP patients received antibiotic therapy. Among them, patients treated with broad-spectrum antibiotics, antibiotics for injection, and combined antibiotics accounted for 93.3%, 97.9%, and 81.7%, respectively. Conclusions: Older age, male, and several comorbidities were independent risk factors for AP, and combined antibiotics treatments are common, which merits attention in accurate detection of AP in a high-risk population.

Is statin therapy after ischaemic stroke associated with increased intracerebral hemorrhage? The association may be dependent on intensity of statin therapy.

BACKGROUND: There has been concern that statin therapy may be associated with an increased risk of intracerebral hemorrhage (ICH). We investigated whether the intensity and type of statin therapy instituted after ischemic stroke (IS) were associated with risk of future ICH in a region of northern China with a high incidence of stroke. METHODS: Newly diagnosed IS patients who were not treated with lipid-lowering drugs in the Beijing Employee Medical Claims Data database from 2010 to 2017 were included. The primary exposure variable was any statin prescription within 1 month of the first documented stroke diagnosis. High-intensity statin therapy was defined as atorvastatin ⩾ 80 mg, simvastatin ⩾ 80 mg, pravastatin ⩾ 40 mg, and rosuvastatin ⩾ 20 mg per day or equivalent combination. An adjusted Cox proportional hazards model was used to estimate the hazard ratio (HR) for ICH during follow-up in groups exposed and not exposed to statins. RESULTS: Of 62,252 participants with IS and 628 ICH readmissions were recorded during a median follow-up of 3.17 years. The risk of ICH among statin users (N = 43,434) was similar to that among nonusers (N = 18,818) with an adjusted HR and 95% confidence interval (CI) of 0.86 (0.73, 1.02). Compared with non-statin therapy, patients with low/moderate-intensity therapy had a lower risk of ICH (0.62: 0.52, 0.75), while patients with high-intensity therapy had a substantially higher risk (2.12: 1.72, 2.62). For patients with different types of statin therapy, adherence to rosuvastatin had the lowest risk of ICH compared to adherence to atorvastatin (0.46: 0.34, 0.63), followed by simvastatin (0.60: 0.45, 0.81). CONCLUSION: In patients with IS, any statin therapy was not associated with an increased risk of ICH. However there appeared to be differential risk according to the dose of statin with high-intensity statin therapy being associated with an increased risk of ICH, while low/moderate-intensity therapy was associated with a lower risk.

Metformin treatment and risk of diabetic peripheral neuropathy in patients with type 2 diabetes mellitus in Beijing, China.

Background: Metformin treatment is associated with vitamin B12 deficiency, which is a risk factor for neuropathy. However, few studies have examined the relationship between metformin treatment and diabetic peripheral neuropathy (DPN), and the available findings are contradictory. We aimed to assess whether metformin treatment is associated with DPN in patients with type 2 diabetes mellitus (T2DM) in Beijing, China. Methods: All patients with newly diagnosed T2DM between January 2010 and September 2012 in the Medical Claim Data for Employees database were included. Metformin treatment was defined as any record of metformin prescription. The average daily dose of metformin during follow-up was calculated. DPN was defined as DPN admissions occurring after a diagnosis of T2DM in the database. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. Results: Among 49,705 T2DM patients, 1,933 DPN events were recorded during a median follow-up of 6.36 years. The crude incidence rates were 7.12 and 3.91 per 1000 person-years for patients treated with metformin (N=37,052) versus those not treated (N=12,653). Patients treated with metformin had an 84% increased risk of DPN compared with patients not using metformin (HR, 1.84; 95% CI, 1.62, 2.10). The daily dose was positively associated with DPN risk (HR, 1.48; 95% CI, 1.46, 1.51; P for trend <0.001). The risk of DPN was 1.53-fold (1.30, 1.81) and 4.31-fold (3.76, 4.94) higher in patients with daily doses of 1.0-2.0 g and >2.0 g, respectively, than in patients who did not receive treatment. Patients aged less than 60 years had a higher risk of DPN (P<0.05 for interaction test). Among patients taking vitamin B12 at baseline, there was no increased risk of DPN in the metformin group (1.92: 0.79, 4.69). Conclusions: In Chinese patients with T2DM, metformin treatment was associated with an increased risk of DPN admission and this risk responds positively to the daily dose of metformin. In particular, metformin use was a major risk factor for DPN in younger patients. Concomitant use of vitamin B12 may avoid the increased risk of DPN associated with metformin use.

KCNQ1 rs2237892 polymorphism modify the association between short-term ambient particulate matter exposure and fasting blood glucose: A family-based study.

BACKGROUND: The association between particulate matter and fasting blood glucose (FBG) has shown conflicting results. Genome-wide association studies have shown that KCNQ1 rs2237892 polymorphism is associated with the risk of diabetes. Whether KCNQ1 rs2237892 polymorphism might modify the association between particulate matter and FBG is still uncertain. METHODS: Data collected from a family-based cohort study in Northern China, were used to perform the analysis. A generalized additive Gaussian model was used to examine the short-term effects of air pollutants on FBG. We further conducted interaction analyses by including a cross-product term of air pollutants by rs2237892 within KCNQ1 gene. RESULTS: A total of 4418 participants were included in the study. In the single pollutant model, the FBG level increased 0.0031 mmol/L with per 10 µg/m3 elevation in fine particular matter (PM2.5) for lag 0 day. After additional adjustments for nitrogen dioxide (NO2) and sulfur dioxide (SO2), similar results were observed for lag 0-2 days. As for particulate matter with particle size below 10 µm (PM10), the significant association between the daily average concentration of the pollutant and FBG level was observed for lag 0-3 days. Additionally, rs2237892 in KCNQ1 gene modified the association between PM and FBG level. The higher risk of FBG levels associated with elevations in PM10 and PM2.5 were more evident as the number of risk allele C increased. Individuals with a CC genotype had the highest risk of elevation in FBG levels. CONCLUSION: Short-term exposures to PM2.5 and PM10 were associated with higher FBG levels. Additionally, rs2237892 in KCNQ1 gene might modify the association between the air pollutants and FBG levels.

The Effectiveness of a Self-management Program of Bowel Dysfunction in Patients With Mid and Low Rectal Cancer After Sphincter-Preserving Surgery: A Pilot Randomized Controlled Trial.

BACKGROUND: Most patients with mid and low rectal cancer passively react to bowel symptoms after sphincter-preserving surgery (SPS), and their self-management behaviors are scarce in the Chinese patient population. OBJECTIVE: The aim of this study was to evaluate the effect of a self-management program for bowel symptoms in patients with mid and low rectal cancer after SPS. METHODS: A convenient sampling method was used to recruit patients with mid and low rectal cancer after SPS in gastric wards from 2 tertiary hospitals in Beijing, China. Ninety-five patients (intervention, n = 47; control, n = 48) were recruited. The intervention group received a predetermined self-management program plus routine postoperative care; the control group received only routine care in the ward. Data on patients' bowel symptoms, quality of life, and bowel symptom self-management behaviors were collected at baseline and at 3 and 6 months postoperatively using questionnaires. A generalized estimating equation was adopted to examine group effect and time effect. RESULTS: Bowel symptoms and quality of life in both the intervention and control groups of patients improved significantly 6 months after SPS compared with baseline (time effect, P < .001). The total score of patients' bowel symptom self-management behaviors and the score of the therapeutic domain increased significantly in the intervention group compared with those in the control group (group effect, P = .009). CONCLUSIONS: Self-management programs could help prompt patients' self-management behaviors, but the extent to which they impact patients' bowel symptoms requires further investigation. IMPLICATIONS FOR PRACTICE: The bowel dysfunction self-management program could alter the behavior of patients. It also effectively improves self-management strategies for bowel symptoms.

Synergism of cell adhesion regulatory genes and instant air pollutants on blood pressure elevation.

Accumulating evidence suggests that an instant exposure to particulate matter (PM) may elevate blood pressure (BP), where cell-adhesion regulatory genes may be involved in the interplay. However, few studies to date critically examined their interaction, and it remained unclear whether these genes modified the association. To assess the association between instant PM exposure and BP, and to examine whether single-nucleotide polymorphisms (SNPs) mapped in four cell adhesion regulatory genes modify the relationship, a cross-sectional study was performed, based on the baseline of an ongoing family-based cohort in Beijing, China. A total of 4418 persons from 2089 families in Northern China were included in the analysis. Four tagged SNPs in cell adhesion regulatory genes were selected among ZFHX3, CXCL12, RASGRP1 and MIR146A. A generalized additive model (GAM) with a Gaussian link was adopted to estimate the change in blood pressure after instant PM2.5 or PM10 exposure. A cross-product term of PM2.5/PM10 and genotype was incorporated into the GAM model to test for interaction. The study observed that an instant exposure to either PM2.5 or PM10 was found to be associated with elevated systolic blood pressure (SBP). On average, a 10 µg/m3 increase in instant exposure to PM2.5 and PM10 concentration corresponded to 0.140% (95% CI: 0.014%-0.265%, P = 0.029) and 0.173% (95% CI: 0.080%-0.266%, P < 0.001) higher SBP. However, diastolic blood pressure (DBP) was not elevated as the PM2.5 or PM10 concentration increased (P > 0.05). A synergetic interaction on SBP was observed between SNPs in four cell adhesion regulatory genes (rs2910164 in MIR146A, rs2297630 in CXCL12, rs7403531 in RASGRP1, and rs7193343 in ZFHX3) and instant PM2.5 exposure (Pfor interaction <0.05). Briefly, as carriers of risk alleles in each of these four genes increased, an enhanced association was found between instant PM2.5 exposure and SBP.

Dynamic patterns of blood lipids and DNA methylation in response to statin therapy.

INTRODUCTION: Statins are lipid-lowering drugs and starting treatment has been associated with DNA methylation changes at genes related to lipid metabolism. However, the longitudinal pattern of how statins affect DNA methylation in relation to lipid levels has not been well investigated. METHODS: We conducted an epigenetic association study in a longitudinal Swedish twin sample in previously reported lipid-related CpGs (cg10177197, cg17901584 and cg27243685). First, we applied a mixed-effect model to assess the association between blood lipids (total cholesterol (TC), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), total triglyceride (TG)) and DNA methylation. Then, we performed a piecewise latent linear-linear growth curve model (LGCM) to explore the long-term changing pattern of lipids and methylation in response to statin treatment. Finally, we used a bivariate autoregressive latent trajectory model with structured residuals (ALT-SR) to analyze the cross-lagged effects in different lipid-CpG pairs in statin users and non-users. RESULTS: We replicated the associations between TC, LDL, HDL and DNA methylation level in cg17901584 and cg27243685 (P values ranged from 4.70E-12 to 1.84E-04). From the piecewise LGCM, we showed that TC and LDL significantly decreased in statin users before treatment started and then remained stable. For non-statin users, we only found a slightly significant decreasing trend for TC and TG. We observed a similar dynamic pattern for methylation levels at cg27243685 and cg17901584. Before statin initiation, cg27243685 showed a significantly increasing trend and cg17901584 a decreasing trend, but post-treatment, there were no additional changes. From the ALT-SR model, we found TG levels to be significantly associated with the DNA methylation level of cg27243685 at the next measurement in statin users (estimate = 0.383, 95% CI: 0.173, 0.594, P value < 0.001). CONCLUSIONS: Longitudinal blood lipid and DNA methylation levels change after statin treatment initiation, where the latter is mostly a response to alterations in lipid levels and not vice versa.

Association of metformin and depression in patients with type 2 diabetes.

BACKGROUND: Emerging evidence showed metformin may have pleiotropic effects on ameliorating depression. However, whether metformin was associated with decreased risk of depression remains unclear. METHODS: A historical cohort study was conducted based on a medical claim database from 2010 to 2017 in Beijing, China. Patients newly diagnosed with T2D were classified into the metformin and non-metformin groups according to their initial antidiabetic prescription. The incidences of depression between the groups were compared using Cox proportional regression model. RESULTS: There were 193,624 (37.4 %) and 323,930 (62.6 %) T2D patients in the metformin and non-metformin groups. The mean age was 54.9 (SD: 13.1) years and 53.9% were females. With a median follow-up of 3.2 years, 64,963 patients developed depression. The adjusted incidence of depression in the metformin group (30.6, 95 % CI: 30.1, 31.0 per 1000 person-years) was significantly lower than in the non-metformin group (39.6, 95 % CI: 39.3, 40.0 per 1000 person-years, P < 0.001). The metformin group was significantly associated with a lower risk of depression compared with the overall non-metformin group (HR: 0.77, 95% CI: 0.75, 0.78), as well as compared with α-glucosidase inhibitors (HR: 0.73, 95 % CI: 0.71, 0.74), sulfonylureas (HR: 0.84, 95 % CI: 0.82, 0.86), and glinides (HR: 0.85, 95 % CI: 0.82, 0.88), except for thiazolidinediones (HR: 0.96, 95 % CI: 0.91, 1.01). The association between metformin and lower depression risk was significant in all the age and sex subgroups. CONCLUSIONS: Metformin was associated with a lower risk of depression compared with other oral hypoglycemic agents, indicating a potential pleiotropic effect on depression.

Glucosamine Use Is Associated with a Higher Risk of Cardiovascular Diseases in Patients with Osteoarthritis: Results from a Large Study in 685,778 Subjects.

Glucosamine is widely used around the world and as a popular dietary supplement and treatment in patients with osteoarthritis in China; however, the real-world cardiovascular risk of glucosamine in long-term use is still unclear. A retrospective, population-based cohort study was performed, based on the Beijing Medical Claim Data for Employees from 1 January 2010 to 31 December 2017. Patients newly diagnosed with osteoarthritis were selected and divided into glucosamine users and non- glucosamine users. The glucosamine users group was further divided into adherent, partially adherent, and non-adherent groups according to the medication adherence. New-onset cardiovascular diseases (CVD) events, coronary heart diseases (CHD), and stroke, were identified during the observational period. COX proportional regression models were used to estimate the risks. Of the 685,778 patients newly diagnosed with osteoarthritis including 240,419 glucosamine users and 445,359 non-users, the mean age was 56.49 (SD: 14.45) years and 59.35% were females. During a median follow-up of 6.13 years, 64,600 new-onset CVD, 26,530 CHD, and 17,832 stroke events occurred. Glucosamine usage was significantly associated with CVD (HR: 1.10; 95% CI: 1.08−1.11) and CHD (HR: 1.12; 95% CI: 1.09−1.15), but not with stroke (HR: 1.03; 95% CI: 0.99−1.06). The highest CVD risk was shown in the adherent group (HR: 1.68; 95% CI: 1.59−1.78), followed by the partially adherent group (HR: 1.26, 95% CI: 1.22−1.30), and the non-adherent group (HR: 1.03; 95% CI: 1.02−1.05), with a significant dose−response relationship (p-trend < 0.001). In this longitudinal study, adherent usage of glucosamine was significantly associated with a higher risk for cardiovascular diseases in patients with osteoarthritis.