Association of echocardiographic parameters with all-cause and cardiovascular mortality in patients with type 2 diabetes.

BACKGROUND: This study aimed to evaluate associations between echocardiography markers and mortality in patients with type 2 diabetes mellitus (T2DM). METHODS: Diabetes Care Management Program database of a medical center was used, including 5612 patients with T2DM aged 30 years and older and who underwent echocardiography assessment between 2001 and 2021. Cox proportional hazard regression models were used to evaluate associations of echocardiography abnormalities with all-cause and expanded cardiovascular disease (CVD) mortality. RESULTS: During a mean follow-up of 5.8 years, 1273 patients died. Hazard ratios (95% confidence intervals) of all-cause mortality for each standard deviation increase were presented for the cardiac systolic function indicator of left ventricular ejection fraction (0.77, 0.73-0.81), cardiac structural parameters of left ventricular mass index (1.25, 1.19-1.31) and left atrial volume index (1.31, 1.25-1.37), and cardiac diastolic function of E/A ratio (1.10, 1.07-1.13), E/e' ratio (1.37, 1.30-1.45), and TR velocity (1.25, 1.18-1.32); meanwhile, the values of expanded CVD mortality included left ventricular ejection fraction (0.67, 0.62-0.72), left ventricular mass index (1.35, 1.25-1.45), left atrial volume index (1.40, 1.31-1.50), E/A ratio (1.12, 1.08-1.16), E/e' ratio (1.57, 1.46-1.69), and TR velocity (1.29, 1.19-1.39), respectively. CONCLUSIONS: Cardiac systolic function indicator of left ventricular ejection fraction, cardiac structural parameters of left ventricular mass index and left atrial volume index, and cardiac diastolic function indicators of E/A ratio, E/e' ratio, and TR velocity are associated with all-cause and expanded CVD mortality in patients with T2DM.

Association of carotid atherosclerosis markers with all-cause and cardiovascular disease-specific mortality in persons with type 2 diabetes: a causal mediation analysis with glucose variation.

AIMS: Glucose variation (GV) is independently associated with mortality in patients with diabetes. However, no study has examined the effects of carotid atherosclerosis markers on mortality after considering GV. Our purpose is to investigate the independent effects of carotid atherosclerosis markers in persons with type 2 diabetes (T2DM) after considering GV and the mediation effects of carotid atherosclerosis markers on associations between GV with cardiovascular disease (CVD) mortality. MATERIALS AND METHODS: This study is a retrospective cohort study including 3628 persons with T2DM who were admitted to a medical center between January 01, 2001 and October 31, 2021. GV was defined as a coefficient of variation (CV) of repeated measurements within a year before the index date (date of first IMT assessment). Carotid atherosclerosis markers included intima-media thickness (IMT), plaque, and stenosis. The outcomes consisted of all-cause and expanded cardiovascular disease (CVD) mortality. Cox proportional hazards models were applied. RESULTS: Among the participants, 286 (7.9%) had IMT ≥ 2 mm, 2834 (78.1%) had carotid plaque, and 464 (12.8%) had carotid stenosis ≥ 50%. When GV was considered, IMT, carotid plaque, and carotid stenosis were significant factors for all-cause mortality (except IMT considering HbA1c-CV) and expanded CVD mortality. IMT was a significant mediator in the associations of fasting plasma glucose (FPG)-CV with all-cause and expanded CVD mortality (2 and 3.19%, respectively), and carotid stenosis was a significant mediator in the association between FPG-CV and expanded CVD mortality (3.83%). CONCLUSIONS: Our statistical evaluations show suggests that carotid atherosclerosis markers are important predictors of CVD mortality in persons with T2DM if GV is considered. In addition, IMT and carotid stenosis were significant mediators in the association between GV and mortality.

Mitochondrial DNA haplogroup D and brain microstructure regulate cognitive function among community-dwelling older adults.

INTRODUCTION: Maintaining physical and cognitive function among older adults is important. These functional states are affected by mitochondria through various mechanisms, such as cellular energy production and oxidative stress control. Owing to its involvement in the relations among the brain, cognition, and physical function, mitochondrial function may be affected by mitochondrial DNA (mtDNA) haplogroups. This study explored the effect of mtDNA haplogroups and brain microstructure on physical and cognitive functions among community-dwelling older adults. METHODS: This study was a community-based cross-sectional research. A total of 128 subjects aged 65 years and older without dementia completed several assessments, including mtDNA sequencing, physical and cognitive function tests, and magnetic resonance imaging (MRI) scans. Cognitive function and impairment were assessed by the MMSE and AD8 questionnaires. mtDNA haplogroups were classified by HaploGrep 2 software, and white matter microstructural integrity was scanned by 3T MRI. RESULTS: The mean age of the subjects was 77.3 years. After the adjustment for covariates, the mtDNA haplogroup D carriers showed significantly lower mini-mental state examination (MMSE) scores than other carriers (p = 0.047). Further considering the brain microstructure, the mtDNA haplogroup D (p = 0.002) and white matter volumes in the left precuneus corrected for total intracranial volumes (p = 0.014) were found to be independently influencing factors of the MMSE scores. CONCLUSIONS: The mtDNA haplogroup D and white matter microstructure regulated the cognitive function among community-dwelling older adults. The findings provide new insights into the research gap. Scientists must further venture into this field.

Association of time-varying sleep duration and cognitive function with mortality in the elderly: a 12-year community-based cohort study.

BACKGROUND: Sleeping problems and cognitive impairment are common in elders. Baseline sleep duration and cognitive status are predictors of mortality. But few studies have explored whether longitudinal changes in sleep duration and cognitive function are related to mortality in older adults. The present study investigated the time-varying relationships of sleep duration and cognitive function with subsequent mortality among community-dwelling elders by using 12 years of repeated-measure data. METHODS: Taichung Community Health Study for Elders (TCHS-E) is a retrospective, population-based cohort that started in 2009 (wave 1) with a total of 912 elders aged 65 years or above. Follow up was conducted in 2010 (wave 2), 2018 (wave 3), and 2020 (wave 4). Sleep duration and Mini-Mental State Examination (MMSE) forms were executed at baseline and three visits during follow-up. Time-varying Cox proportional hazards regression estimated adjusted hazard ratios (HRs) of mortality with 95% confidence intervals (CIs). RESULTS: During about 12 years (9,396 person-years) follow-up, 329 deaths from all causes were documented, including 102 deaths due to expanded cardiovascular disease (CVD). In the multivariable-adjusted, time-varying Cox proportional hazard model, the adjusted HR values of all-cause mortality were 1.47 (1.02-2.12) for sleep duration > 9 h/day (vs. 7 h/day) and 1.81 (1.26-2.59) for MMSE < 27 (vs. 30). The adjusted HR values of the expanded CVD mortality were 2.91 (1.24-6.83) for MMSE of 29; 2.69 (1.20-6.05) for MMSE of 27-28; and 4.32 (95% CI: 1.92-9.74) for MMSE < 27. The dose-dependent relationship was significant (p < 0.001). The combinations of sleep duration longer than 9 h/day and MMSE < 27 were linked with the highest risks for expanded CVD and all-cause mortality. CONCLUSIONS: Long sleep duration and low cognitive function were jointly and independently linked with higher risk of mortality in elders residing in community.

A non-invasive mouse model that recapitulates disuse-induced muscle atrophy in immobilized patients.

Disuse muscle atrophy occurs consequent to prolonged limb immobility or bed rest, which represents an unmet medical need. As existing animal models of limb immobilization often cause skin erosion, edema, and other untoward effects, we here report an alternative method via thermoplastic immobilization of hindlimbs in mice. While significant decreases in the weight and fiber size were noted after 7 days of immobilization, no apparent skin erosion or edema was found. To shed light onto the molecular mechanism underlying this muscle wasting, we performed the next-generation sequencing analysis of gastrocnemius muscles from immobilized versus non-mobilized legs. Among a total of 55,487 genes analyzed, 787 genes were differentially expressed (> fourfold; 454 and 333 genes up- and down-regulated, respectively), which included genes associated with muscle tissue development, muscle system process, protein digestion and absorption, and inflammation-related signaling. From a clinical perspective, this model may help understand the molecular/cellular mechanism that drives muscle disuse and identify therapeutic strategies for this debilitating disease.

Three-year trajectories of sleep duration and mortality in patients with type 2 diabetes-a hospital-based retrospective cohort study.

OBJECTIVES: Most studies have shown that a single item of self-reported sleep duration is related to mortality risk. However, the long-term effect of sleep duration on mortality remains unclear in patients with diabetes. This study aimed to examine the associations of 3-year trajectory patterns of sleep duration with all-cause and expanded cardiovascular disease mortality in patients with type 2 diabetes. METHODS: Patients with type 2 diabetes and self-reported sleep duration during a 3-year interval were included. Expanded cardiovascular disease was defined as death due to cardiovascular disease, diabetes, and kidney diseases. Cox's proportional hazards models were employed to examine the associations between sleep duration patterns and mortality after controlling for sociodemographic factors, lifestyle behaviors, diabetes-related variables, diabetic complications, and medication use. RESULTS: A total of 7591 patients were included for analysis, and 995 deaths (13.11%) and 424 expanded cardiovascular disease deaths (5.59%) were observed during a mean follow-up of 8.51 years. Five trajectory patterns of sleep duration were identified: cluster 1: "constant 7- to 8-hour group" (50.03%); cluster 2: "constant low group" (19.68%); cluster 3: "high with decreasing trend group" (3.08%); cluster 4: "low with fluctuation group" (1.28%); and cluster 5: "constant high group" (25.93%). Compared with cluster 1, clusters 3 and 4 were associated with increased risks of all-cause mortality (1.41, 1.08-1.84; 1.44, 1.01-2.05), and cluster 5 was associated with high risks of all-cause and expanded cardiovascular disease mortality (1.26, 1.08-1.46; 1.42, 1.12-1.79). CONCLUSIONS: Sleep duration trajectories with constant high or unstable patterns may be associated with higher mortality.

Association of body indices and risk of mortality in patients with type 2 diabetes.

INTRODUCTION: A body shape index (ABSI) is independently associated with mortality in general population, but studies on the predictability of ABSI in the risk of mortality in patients with type 2 diabetes (T2D) are limited. We aimed to examine the independent and joint association of ABSI, body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), and body roundness index (BRI) with mortality in patients with T2D. RESEARCH DESIGN AND METHODS: The study included 11 872 patients (46.5% women) aged 30 years and older and who took part in diabetes care management program of a medical center in Taiwan. Body indices were evaluated by anthropometric measurements at baseline between 2001 and 2016, and their death status was followed up through 2021. Multivariate Cox regression models were used to assess the effect of body indices on mortality. RESULTS: During a mean follow-up of 10.2 years, 560 cardiovascular disease (CVD) deaths and 3043 deaths were recorded. For ABSI, WC, WHR, WHtR and BRI, all-cause mortality rates were statistically significantly greater in Q4 versus Q2. For BMI and WHtR, all-cause mortality rates were also statistically significantly greater in Q1 versus Q2. The combination of BMI and ABSI exhibited a superiority in identifying risks of all-cause mortality and CVD mortality (HRs: 1.45 and 1.37, both p<0.01). CONCLUSIONS: Combined use of ABSI and BMI can contribute to the significant explanation of the variation in death risk in comparison with the independent use of BMI or other indices.

Longitudinal changes in swallowing function after surgery and proactive swallowing therapy for oral cancer.

BACKGROUND: This study aimed to describe and explore the longitudinal changes in swallowing function among patients with oral cancer who underwent surgery and proactive swallowing therapy from baseline to 1-year postoperation. METHODS: We retrospectively studied 118 patients over a 4.5-year duration. Swallowing functional assessment including 10-item Eating Assessment Tool (EAT-10), Functional Oral Intake Scale (FOIS), M. D. Anderson Dysphagia Inventory, and Modified Barium Swallow Impairment Profile (MBSImP™) was performed at baseline, 1-month, 6-month, and 1-year postoperatively. RESULTS: All swallowing parameters worsened 1-month postoperation. EAT-10, FOIS, and MBSImP™ oral and pharyngeal impairment scores improved significantly compared with 1-month postoperation at 6 months. Other swallowing parameters, except for weight, did not differ significantly from baseline at 6 months. The rate of tube-feeding dependency was 11.5% and 5.6% at 1 and 6 months postoperation, respectively. CONCLUSIONS: Periodic swallowing functional assessments help delineate the longitudinal changes in swallowing functional outcomes.

Trends in energy and macronutrient intake among Taiwanese older adults in 1999-2000, 2005-2008 and 2013-2016 periods.

BACKGROUND: This study aimed to explore trends, in 3 periods, in the intake of energy and macronutrients among Taiwanese older adults. METHODS: Study subjects were those aged ≥65 years in the Nutrition and Health Survey in Taiwan 1999-2000 as well as the surveys in 2005-2008 and 2013-2016. Twenty-four-hour dietary recall data were obtained. This study used the 3 nutrition survey datasets for 1999-2000, 2005-2008, and 2013-2016, including data on the questionnaire, physical examination, and dietary intakes. Each nutrition survey involved the face-to-face household interview, and individual's dietary intake of carbohydrate, fat, and protein (% of energy) was estimated. Subsequently, intake statuses of the three macronutrients were classified into below, meeting, and above intake categories. RESULTS: In the 2013-2016 survey, approximately 40% of the older adults had a low intake of energy. The prevalence of older adults with a meeting intake of carbohydrate, fat, and protein have increased from the 1999-2000 to 2013-2016 periods. The prevalence of people having a low intake of carbohydrate declined from the 1999-2000 period to the 2013-2016 period. The prevalence of high fat intake in 2013-2016 was approximately 5% higher than that in 1999-2000. In the 2013-2016 period, the prevalence of low intake of carbohydrate, fat, and protein were 25.9, 24.5, and 4.9%, respectively; moreover, the prevalence of high intake of the aforementioned macronutrients were 38.7, 36.2, and 17.6%, respectively. CONCLUSIONS: Our study provides important evidence on the dietary patterns, as well as their changes over time among Taiwanese older adults. Such information would be useful for health policy makers about the burden of unbalanced diet and for nutrition educators on planning nutrition promotion interventions about well-balanced dietary for the older persons.

TCM as adjunctive therapy improves risks of respiratory hospitalizations in persons with type 2 diabetes: A retrospective cohort study.

Patients with type 2 diabetes are at a higher risk of chronic obstructive pulmonary disease (COPD) and asthma than the general population. In addition, emerging evidence suggests that traditional Chinese medicine (TCM) might be beneficial for patients with type 2 diabetes. We investigated whether TCM use was associated with a reduced risk of respiratory hospitalizations in patients with type 2 diabetes. Conducting a retrospective cohort study, we used data retrieved from the NDCMP database. Among 56,035 patients, 5226 were classified as TCM users; 50,809 were classified as TCM nonusers. Both groups were analyzed until the end of 2011 to examine the incidence of respiratory hospitalizations by using a Cox proportional hazards model to evaluate effects of TCM use on respiratory hospitalizations. During the 6-year study follow-up period, the incidence density rates of COPD- and asthma-related hospitalization were estimated to be 13.03 and 4.47 per 10,000 patient-years for TCM nonusers and 10.08 and 3.28 per 10,000 patient-years for TCM users, respectively. The HR of COPD-related hospitalization in TCM users was 0.88 (95% CI = 0.79-0.99); and the HR of asthma-related hospitalization in TCM users was 0.81 (95% CI = 0.66-1.00). Stratified analyses revealed that effects of TCM use were stronger among individuals who had diabetes for <3 years. As a part of Integrative Medicine, our study results demonstrate that TCM use was associated with a significant reduced risk of respiratory hospitalizations, especially in patients with diabetes for <3 years.

Association of high-sensitivity C-reactive protein and diabetic nephropathy in patients with type 2 diabetes: a Mendelian randomization study.

INTRODUCTION: Observational studies support the relationship between C-reactive protein (CRP) level and diabetic nephropathy (DN) in patients with diabetes. The research question regarding whether the relationship between serum high-sensitivity C-reactive protein (hsCRP) level and DN is causal lacks experimental evidence. Therefore, this study aimed to evaluate the causality between hsCRP and DN based on Mendelian randomization (MR) analysis. RESEARCH DESIGN AND METHODS: A total of 2332 participants with type 2 diabetes from the Taiwan Biobank database was analyzed. Genetic risk scores (GRSs), which comprise four validated CRP loci as two instrumental variables, were calculated as unweighted and weighted scores to evaluate the causal relationship of hsCRP with DN risk. The two-stage regression model was used to estimate OR and 95% CI. RESULTS: The analyses of the observational study showed that the hsCRP level was significantly associated with DN after multivariate adjustment (adjusted OR 1.15; 95% CI 1.01 to 1.32). Unweighted/weighted GRSs for log-transformed hsCRP satisfied MR assumptions 1 and 3, respectively; that is, a significant association with hsCRP was observed but that with DN was absent (adjusted OR 1.00, 95% CI 0.92 to 1.09; 1.00, 0.72 to 1.39, respectively). The MR analyses demonstrated that a 1-unit increase in the log-transformed genetically predicted hsCRP by unweighted and weighted GRSs was associated with DN, demonstrating ORs of 1.80 (95% CI 1.51 to 2.14) and 1.67 (95% CI 1.40 to 1.98), respectively. CONCLUSIONS: The current study provided experimental evidence that hsCRP level was causally related to DN. These findings suggest that the elevated hsCRP may be a causal risk factor for DN in patients with type 2 diabetes.

Risk prediction of nephropathy by integrating clinical and genetic information among adult patients with type 2 diabetes.

AIMS: Diabetic nephropathy (DN) is a major healthcare challenge. We developed and internally and externally validated a risk prediction model of DN by integrating clinical factors and SNPs from genes of multiple CKD-related pathways in the Han Chinese population. MATERIALS AND METHODS: A total of 1526 patients with type 2 diabetes were randomly allocated into derivation (n = 1019) or validation (n = 507) sets. External validation was performed with 3899 participants from the Taiwan Biobank. We selected 66 SNPs identified from literature review for building our weighted genetic risk score (wGRS). The steps for prediction model development integrating clinical and genetic information were based on the Framingham Heart Study. RESULTS: The AUROC (95% CI) for this DN prediction model with combined clinical factors and wGRS was 0.81 (0.78, 0.84) in the derivation set. Furthermore, by directly using the information of these 66 SNPs, our final prediction model had AUROC values of 0.85 (0.82, 0.87), 0.89 (0.86, 0.91), and 0.77 (0.74, 0.80) in the derivation, internal validation, and external validation sets, respectively. Under the combined model, the results with a cutoff point of 30% showed 70.91% sensitivity, 67.84% specificity, 51.54% positive predictive value, and 82.86% negative predictive value. CONCLUSIONS: We developed and internally and externally validated a model with clinical factors and SNPs from genes of multiple CKD-related pathways to predict DN in Taiwan. This model can be used in clinical risk management practice as a screening tool to identify persons who are genetically predisposed to DN for early intervention and prevention.

Obesity marker trajectories and cognitive impairment in older adults: a 10-year follow-up in Taichung community health study for elders.

BACKGROUND: Obesity and cognitive impairment prevalence increases as age increases. Recent growing evidence finds links between obesity and cognitive impairment in older adults. However, the association between the two is controversial. This study aims to identify obesity marker trajectory patterns, and to assess whether these patterns are associated with cognitive impairment and cognitive decline during a 10-year follow-up period among community-dwelling older adults. METHODS: A total of 626 older adults aged 65 and older were involved in the study, with at least two repeated measurements at baseline, one-year or 10-year follow-up. Cognitive function was measured through the Mini Mental State Examination. Obesity markers included body mass index, waist circumference, waist-to-hip (WHR), fat mass (FM), and abdominal fat (AF) measured by dual-energy X-ray absorptiometry. Multivariate logistic regression analyses were performed to estimate the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of cognitive impairment and cognitive decline for obesity marker trajectory patterns. RESULTS: After a 10-year follow-up, 168 older adults with incident cognitive impairment and 156 with rapid cognitive decline were defined as the top 25th percentile of cognitive decline. Four distinct trajectory groups of obesity markers were identified. In multivariate logistic regression analyses, a low likelihood of cognitive impairment was observed in the consistently high-level group from FM trajectory (ORs = 0.41, 95% CI = 0.20-0.85); the high-level U-shaped group from WHR trajectory (0.43, 0.22-0.84); and the median-level flat inverse U-shaped, consistently high-level, and low-level flat U-shaped groups from AF trajectory (0.44, 0.26-0.77; 0.33, 0.18-0.61; 0.39, 0.18-0.82). In addition, a low likelihood of rapid decline was found in the low-level, slightly increasing trend group from WHR trajectory (0.43, 0.22-0.85). CONCLUSION: FM and AF trajectories with consistent high levels and WHR trajectory with high level with U-shaped group are associated with low risks of incident cognitive impairment in older adults. Similarly, WHR trajectory with a low but slowly increasing trend is associated with a decreased risk of cognitive decline.

Joint effect of blood pressure and glycemic variation on the risk of cardiovascular morbidity and mortality in persons with type 2 diabetes.

OBJECTIVE: Few studies have explored the association of visit-to-visit variation in blood pressure (BP) and glycemic factors with cardiovascular disease (CVD) morbidity and mortality. This study aimed to examine the independent and joint effect of visit-to-visit BP and glycemic variation on CVD morbidity and mortality in persons with T2DM. METHODS: The present study consisted of two retrospective cohort studies. The Taiwan Diabetes Study was based on a database of the National Diabetes Care Management Program (DCMP) and linked with cardiovascular morbidity incidence. The Taichung Diabetes Study was based on the DCMP database of a medical center, which can be linked with the National Death Registry dataset. The outcomes were analyzed by using Cox's proportional hazard models. RESULTS: A total of 13,280 and 10,894 persons with T2DM in Taiwan and Taichung Diabetes Study, respectively, were included. SBP-CV, FPG-CV, and HbA1c-CV were significant predictors of stroke, CVD event or death, all-cause mortality, and expanded CVD mortality, whereas DBP-CV was a significant predictor of all-cause mortality and expanded and non-expanded CVD mortality. The joint effect of SBP, FPG, and HbA1c predicted the incidence of stroke and CVD event or death with increased risks of 16 %-35 %. In addition, the joint effect of SBP, DBP, FPG, and HbA1c was associated with all-cause and expanded CVD mortality with increased risks of 29 %-81 %. CONCLUSIONS: The joint effect of BP and glucose variation improved the prediction of cardiovascular morbidity and mortality. Moreover, simultaneous measurement of visit-to-visit BP and glycemic variation may stratify persons with cardiovascular risks and may be regarded as important therapeutic goals in the care of T2DM.

Independent and joint associations of skeletal muscle mass and physical performance with all-cause mortality among older adults: a 12-year prospective cohort study.

BACKGROUND: Decreased skeletal muscle mass and low physical performance are independently associated with increased mortality in elderly individuals. However, little is known about the effects of skeletal muscle mass combined with physical performance on the prediction of mortality risk among community-dwelling older adults. This study aimed to determine the combined effects of skeletal muscle mass and physical performance on total mortality. METHODS: A community-based prospective cohort study was conducted among 641 participants aged 65 and older in 2009. The height-adjusted skeletal muscle index (hSMI) and the weight-adjusted SMI (wSMI) were determined by dual-energy X-ray absorptiometry examination. Physical performance tests measured at baseline included gait speed (GS), timed up-and-go (TUG) test, timed chair stand (TCS), weight-adjusted leg press (WaLP), and handgrip strength (HS). Cox proportional hazards regression models were applied to determine the adjusted hazard ratios (HRs) of mortality with 95% confidence intervals (95% CIs) for baseline skeletal muscle mass, physical performance, and traditional risk factors. RESULTS: During the follow-up of 12 years, 198 (30.89%) participants died. Low hSMI, low GS, high TUG, high TCS, low WaLP, and low HS were associated with high risks of mortality after the adjustment for confounders. The results of receiver operating characteristic (ROC) curve analyses revealed the values of ROC for models with additional consideration for TUG or all indicators significantly improved the discriminatory ability of mortality compared with the model with traditional factors (all P < 0.05). Elders with low hSMI and low GS (HRs = 4.33, 95% CI: 2.76-6.78), high TUG (4.11, 2.60-6.48), high TCS (2.97, 1.92-4.59), low WaLP (3.19, 2.13-4.79), and low HS (4.08, 2.70-6.17) were associated with high risks of mortality compared with those with high hSMI and their corresponding counterparts. CONCLUSION: The hSMI and physical performance are significantly associated with increased risks of all-cause mortality. The combined use of hSMI and physical performance can provide improved risk stratification, which may be appropriately used as a screening tool targeting high-risk elders for the effective prevention of sarcopenia-related mortality.

Development of a traditional Chinese medicine-based agent for the treatment of cancer cachexia.

BACKGROUND: Despite recent advances in understanding the pathophysiology of cancer cachexia, prevention/treatment of this debilitating disease remains an unmet medical need. METHODS: We developed an integrated, multi-tiered strategy involving both in vitro and in vivo muscle atrophy platforms to identify traditional Chinese medicine (TCM)-based anti-cachectic agents. In the initial screening, we used inflammatory cytokine-induced atrophy of C2C12 myotubes as a phenotypic screening platform to assess the protective effects of TCMs. The selected TCMs were then evaluated for their abilities to protect Caenorhabditis elegans from age-related reduction of mobility and contractility, followed by the C-26 colon adenocarcinoma mouse model of cachexia to confirm the anti-muscle atrophy effects (body/skeletal muscle weights, fibre size distribution, grip strengths, and serum IL-6). Transcriptome analysis, quantitative real-time polymerase chain reaction, and immunoblotting were performed to gain understanding of the potential mechanism(s) by which effective TCM protected against C26 tumour-induced muscle atrophy. RESULTS: Of 29 widely used TCMs, Dioscorea radix (DR) and Mu Dan Pi (MDP) showed a complete protection (all P values, 0.0002) vis-à-vis C26 conditioned medium control in the myotube atrophy platform. MDP exhibited a unique ability to ameliorate age-associated decreases in worm mobility, accompanied by improved total body contractions, relative to control (P < 0.0001 and <0.01, respectively), which, however, was not noted with DR. This differential in vivo protective effect between MDP and DR was also confirmed in the C-26 mouse model. MDP at 1000 mg/kg (MDP-H) was effective in protecting body weight loss (P < 0.05) in C-26 tumour-bearing mice without changing food or water intake, accompanied by the restoration of the fibre size distribution of hindleg skeletal muscles (P < 0.0001) and the forelimb grip strength (P < 0.05). MDP-treated C-26-tumour-bearing mice were alert, showed normal posture and better body conditions, and exhibited lower serum IL-6 levels (P = 0.06) relative to vehicle control. This decreased serum IL-6 was associated with the in vitro suppressive effect of MDP (25 and 50 µg/mL) on IL-6 secretion into culture medium by C26 cells. RNA-seq analysis, followed by quantitative real-time polymerase chain reaction and/or immunoblotting, shows that MDP's anti-cachectic effect was attributable to its ability to reverse the C-26 tumour-induced re-programming of muscle homoeostasis-associated gene expression, including that of two cachexia drivers (MuRF1 and Atrogin-1), in skeletal muscles. CONCLUSIONS: All these findings suggest the translational potential of MDP to foster new strategies for the prevention and/or treatment of cachexia. The protective effect of MDP on other types of muscle atrophy such as sarcopenia might warrant investigations.

Prediction of all-cause and cardiovascular mortality using ankle-brachial index and brachial-ankle pulse wave velocity in patients with type 2 diabetes.

Ankle-brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV) are used as non-invasive indicators for detecting atherosclerosis and arterial stiffness, two well-known predictors of mortality in patients with type 2 diabetes mellitus (T2DM). ABI and baPWV have independent associations with mortality; however, their joint and interactive effects on mortality have not been assessed in patients with T2DM. This work aims to evaluate the independent, joint, and interactive associations of ABI and baPWV with all-cause and expanded cardiovascular disease (CVD) mortality in patients with T2DM. This observational study included 2160 patients with T2DM enlisted in the Diabetes Care Management Program database of China Medical University Hospital from 2001 to 2016 and then followed their death status until August 2021. Cox proportional hazard models were used to evaluate the independent, joint, and interactive effects of ABI and baPWV on the risk of all-cause and expanded CVD mortality. A total of 474 patient deaths occurred after a mean follow-up of 8.4 years, and 268 of which were attributed to cardiovascular events. Abnormal ABI (≤ 0.9) and highest baPWV quartile were independently associated with increased risks of all-cause [ABI: hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.30-2.11; baPWV: 1.63, 1.16-2.27] and expanded CVD mortality (ABI: 2.21, 1.62-3.02; baPWV: 1.75, 1.09-2.83). The combination of abnormal ABI (≤ 0.9) and highest baPWV quartile was associated with a significantly higher risk of all-cause (4.51, 2.50-8.11) and expanded CVD mortality (9.74, 4.21-22.51) compared with that of the combination of normal ABI and lowest baPWV quartile. Significant interactions were observed between ABI and baPWV in relation to all-cause and expand CVD mortality (both p for interaction < 0.001). Through their independent, joint, and interactive effects, ABI and baPWV are significant parameters that can improve the prediction of all-cause and expanded CVD mortality in patients with T2DM and help identify high-risk patients who may benefit from diabetes care.

Sleep duration predicts subsequent long-term mortality in patients with type 2 diabetes: a large single-center cohort study.

BACKGROUND: Sleep duration is associated with mortality. However, prior studies exploring whether sleep duration predicts subsequent long-term mortality in patients with diabetes are limited. This study aims to examine whether metabolic factors affect the associations between baseline sleep duration and subsequent risks of all-cause, expanded, and non-expanded cardiovascular disease (CVD) mortalities among patients with type 2 diabetes (T2D). METHODS: A total of 12,526 T2D patients aged 30 years and older, with a follow-up period ≥ 3 years, were identified from the Diabetes Case Management Program of a medical center in Taiwan. Sleep duration was measured using computerized questionnaires by case managers, and the time frame for this question was 1 month prior to the interview date. Sleep duration in relation to subsequent mortality from all causes, expanded CVD, and non-expanded CVD was examined using Cox proportional hazard models. RESULTS: Within 10 years of follow-up, 2918 deaths (1328 CVD deaths and 1590 non-CVD deaths) were recorded. A J-shaped association was observed for all-cause, expanded CVD, and non-expanded CVD mortalities, and the lowest risks were observed for patients with 5-7 h of sleep. The significant joint effects included sleep duration of more or less than 7 h with age ≥ 65 years [adjusted HRs: 4.00 (3.49-4.60)], diabetes duration ≥ 5 years [1.60 (1.40-1.84)], age at diabetes diagnosis ≤ 45 years [1.69 (1.38-2.07)], insulin use [1.76 (1.54-2.03)], systolic blood pressure/diastolic blood pressure > 130/85 mmHg [1.24 (1.07-1.43)], triglyceride ≥ 150 mg/dL [1.38 (1.22-1.56)], HbA1c ≥ 7% [1.31 (1.13-1.52)], and body mass index < 27 kg/m2 [1.31 (1.17-1.45)] for all-cause mortality. CONCLUSION: A J-shaped association was observed between sleep duration and all-cause and expanded CVD mortality, and a sleep duration of 5-7 h had the lowest mortality risk. Sleep duration also showed significant synergistic interactions with diabetes duration but shared an antagonistic interaction with age and obesity.

Development and validation of a risk prediction model for chronic kidney disease among individuals with type 2 diabetes.

Many studies had established the chronic kidney disease (CKD) prediction models, but most of them were conducted on the general population and not on patients with type 2 diabetes, especially in Asian populations. This study aimed to develop a risk prediction model for CKD in patients with type 2 diabetes from the Diabetes Care Management Program (DCMP) in Taiwan. This research was a retrospective cohort study. We used the DCMP database to set up a cohort of 4,601 patients with type 2 diabetes without CKD aged 40-92 years enrolled in the DCMP program of a Taichung medical center in 2002-2016. All patients were followed up until incidences of CKD, death, and loss to follow-up or 2016. The dataset for participants of national DCMP in 2002-2004 was used as external validation. The incident CKD cases were defined as having one of the following three conditions: ACR data greater than or equal to 300 (mg/g); both eGFR data less than 60 (ml/min/1.73 m2) and ACR data greater than or equal to 30 (mg/g); and eGFR data less than 45 (ml/min/1.73 m2). The study subjects were randomly allocated to derivation and validation sets at a 2:1 ratio. Cox proportional hazards regression model was used to identify the risk factors of CKD in the derivation set. Time-varying area under receiver operating characteristics curve (AUC) was used to evaluate the performance of the risk model. After an average of 3.8 years of follow-up period, 3,067 study subjects were included in the derivation set, and 786 (25.63%) were newly diagnosed CKD cases. A total of 1,534 participants were designated to the validation set, and 378 (24.64%) were newly diagnosed CKD cases. The final CKD risk factors consisted of age, duration of diabetes, insulin use, estimated glomerular filtration rate, albumin-to-creatinine ratio, high-density lipoprotein cholesterol, triglyceride, diabetes retinopathy, variation in HbA1c, variation in FPG, and hypertension drug use. The AUC values of 1-, 3-, and 5-year CKD risks were 0.74, 0.76, and 0.77 in the validation set, respectively, and were 0.76, 0.77, and 0.76 in the sample for external validation, respectively. The value of Harrell's c-statistics was 0.76 (0.74, 0.78). The proposed model is the first CKD risk prediction model for type 2 diabetes patients in Taiwan. The 1-, 3-, and 5-year CKD risk prediction models showed good prediction accuracy. The model can be used as a guide for clinicians to develop medical plans for future CKD preventive intervention in Chinese patients with type 2 diabetes.

Effect of blood pressure trajectory and variability on new-onset chronic kidney disease in patients with type 2 diabetes.

This study aimed to evaluate the effects of BP trajectory and variability on chronic kidney disease (CKD) incidence in patients with type 2 diabetes. This retrospective longitudinal study included 4,560 participants with type 2 diabetes, aged ≥30 years, free of CKD, with ≥3 years of follow-up, and who attended the Diabetes Care Management Program in 2001-2013. The follow-up period ended in 2016. The adverse outcome was a new-onset CKD event, which was determined using eGFR and albuminuria. Cox proportional hazards models were used to assess the associations. At the end of the follow-up, 1255 participants had developed CKD, with a mean follow-up of 4.3 ± 3.2 years. Three trajectory subgroups of BP, i.e., Cluster 1: "moderate-stable" for SBP and "moderate-downward" for DBP, Cluster 2: "low-upward-downward" for both SBP and DBP, and Cluster 3: "high-downward-upward" for both SBP and DBP, were generated. The BP variability was grouped into three classes on the basis of tertiles. For the BP trajectory, patients in Cluster 3 of DBP had a higher CKD risk than those in Cluster 1 (HR = 1.24, 95% CI = 1.03-1.50). For the BP variability, patients in Tertile 3 had a significantly higher CKD risk than those in Tertile 1 (SBP: 1.28, 1.11-1.47; DBP: 1.17, 1.02-1.34). Persons with type 2 diabetes who achieved a small reduction in DBP after participating in the education program but rebounded and those who had the highest variation in both SBP and DBP faced the highest increase in CKD risk.