The absence of preexisting neutralizing antibodies specific for the novel A (H7N9) influenza virus indicates a lack of prior human exposure. As influenza A virus–specific CD8 ⁺ T lymphocytes (CTLs) ...can be broadly cross-reactive, we tested whether immunogenic peptides derived from H7N9 might be recognized by memory CTLs established following infection with other influenza strains. Probing across multiple ethnicities, we identified 32 conserved epitopes derived from the nucleoprotein (NP) and matrix-1 (M1) proteins. These NP and M1 peptides are presented by HLAs prevalent in 16–57% of individuals. Remarkably, some HLA alleles (A*0201, A*0301, B*5701 , B*1801, and B*0801) elicit robust CTL responses against any human influenza A virus, including H7N9, whereas ethnicities where HLA-A*0101, A*6801, B*1501, and A*2402 are prominent, show limited CTL response profiles. By this criterion, some groups, especially the Alaskan and Australian Indigenous peoples, would be particularly vulnerable to H7N9 infection. This dissection of CTL-mediated immunity to H7N9 thus suggests strategies for both vaccine delivery and development.
Diabetes and obesity are complex diseases associated with insulin resistance and fatty liver. The latter is characterized by dysregulation of the Akt, AMP-activated protein kinase (AMPK), and IGF-I ...pathways and expression of microRNAs (miRNAs). In China, multicomponent traditional Chinese medicine (TCM) has been used to treat diabetes for centuries. In this study, we used a three-herb, berberine-containing TCM to treat male Zucker diabetic fatty rats. TCM showed sustained glucose-lowering effects for 1 week after a single-dose treatment. Two-week treatment attenuated insulin resistance and fatty degeneration, with hepatocyte regeneration lasting for 1 month posttreatment. These beneficial effects persisted for 1 year after 1-month treatment. Two-week treatment with TCM was associated with activation of AMPK, Akt, and insulin-like growth factor-binding protein (IGFBP)1 pathways, with downregulation of miR29-b and expression of a gene network implicated in cell cycle, intermediary, and NADPH metabolism with normalization of CYP7a1 and IGFBP1 expression. These concerted changes in mRNA, miRNA, and proteins may explain the sustained effects of TCM in favor of cell survival, increased glucose uptake, and lipid oxidation/catabolism with improved insulin sensitivity and liver regeneration. These novel findings suggest that multicomponent TCM may be a useful tool to unravel genome regulation and expression in complex diseases.
Memory CD8⁺ T lymphocytes (CTLs) specific for antigenic peptides derived from internal viral proteins confer broad protection against distinct strains of influenza A virus (IAV). However, immune ...efficacy can be undermined by the emergence of escape mutants. To determine how T-cell receptor (TCR) composition relates to IAV epitope variability, we used ex vivo peptide–HLA tetramer enrichment and single-cell multiplex analysis to compare TCRs targeted to the largely conserved HLA-A*0201-M158 and the hypervariable HLA-B*3501-NP418 antigens. The TCRαβs for HLA-B*3501-NP418⁺ CTLs varied among individuals and across IAV strains, indicating that a range of mutated peptides will prime different NP418-specific CTL sets. Conversely, a dominant public TRAV27/TRBV19⁺ TCRαβ was selected in HLA-A*0201⁺ donors responding to M158. This public TCR cross-recognized naturally occurring M158 variants complexed with HLA-A*0201. Ternary structures showed that induced-fit molecular mimicry underpins TRAV27/TRBV19⁺ TCR specificity for the WT and mutant M158 peptides, suggesting the possibility of universal CTL immunity in HLA-A*0201⁺ individuals. Combined with the high population frequency of HLA-A*0201, these data potentially explain the relative conservation of M158. Moreover, our results suggest that vaccination strategies aimed at generating broad protection should incorporate variant peptides to elicit cross-reactive responses against other specificities, especially those that may be relatively infrequent among IAV-primed memory CTLs.
OBJECTIVE Insulin has mitogenic effects, although hyperglycemia may be a risk factor for cancer in type 2 diabetes. It remains uncertain whether use of insulin increases cancer risk because of its ...effect on cell growth and proliferation or decreases cancer risk because of its glucose-lowering effect. RESEARCH DESIGN AND METHODS A 1:2-matched new insulin user cohort on age (+/-3 years), smoking status, and likelihood of initiating insulin therapy (+/-0.05) was selected from a cohort of 4,623 Chinese patients with type 2 diabetes, free of cancer, and naive to insulin at enrollment. Stratified Cox regression analysis on the matched pairs was used to obtain hazard ratios (HRs) of insulin therapy and A1C for cancer risk. A structured adjustment scheme was used to adjust for covariates. RESULTS Of 973 new insulin users, 971 had matched nonusers (n = 1935). The cancer incidence in insulin nonusers was much higher than that in insulin users (49.2 vs. 10.2, per 1,000 person-years, P < 0.0001). After further adjustment for all other covariates with a P value less than 0.3 and nonlinear associations with cancer, A1C was associated with an increased cancer risk (HR per percentage 1.26, 95% CI 1.03-1.55), whereas use of insulin was associated with a decreased cancer risk (HR of insulin users vs. nonusers: 0.17, 0.09-0.32). Consistent results were found in analyses including all 973 insulin users and 3,650 nonusers. CONCLUSIONS In Chinese patients with type 2 diabetes, hyperglycemia predicts cancer, whereas insulin usage was associated with a reduced cancer risk.
Diabetes outcomes are influenced by host factors, settings, and care processes. We examined the association of data-driven integrated care assisted by information and communications technology (ICT) ...with clinical outcomes in type 2 diabetes in public and private healthcare settings.
The web-based Joint Asia Diabetes Evaluation (JADE) platform provides a protocol to guide data collection for issuing a personalized JADE report including risk categories (1-4, low-high), 5-year probabilities of cardiovascular-renal events, and trends and targets of 4 risk factors with tailored decision support. The JADE program is a prospective cohort study implemented in a naturalistic environment where patients underwent nurse-led structured evaluation (blood/urine/eye/feet) in public and private outpatient clinics and diabetes centers in Hong Kong. We retrospectively analyzed the data of 16,624 Han Chinese patients with type 2 diabetes who were enrolled in 2007-2015. In the public setting, the non-JADE group (n = 3,587) underwent structured evaluation for risk factors and complications only, while the JADE (n = 9,601) group received a JADE report with group empowerment by nurses. In a community-based, nurse-led, university-affiliated diabetes center (UDC), the JADE-Personalized (JADE-P) group (n = 3,436) received a JADE report, personalized empowerment, and annual telephone reminder for reevaluation and engagement. The primary composite outcome was time to the first occurrence of cardiovascular-renal diseases, all-site cancer, and/or death, based on hospitalization data censored on 30 June 2017. During 94,311 person-years of follow-up in 2007-2017, 7,779 primary events occurred. Compared with the JADE group (136.22 cases per 1,000 patient-years 95% CI 132.35-140.18), the non-JADE group had higher (145.32 95% CI 138.68-152.20; P = 0.020) while the JADE-P group had lower event rates (70.94 95% CI 67.12-74.91; P < 0.001). The adjusted hazard ratios (aHRs) for the primary composite outcome were 1.22 (95% CI 1.15-1.30) and 0.70 (95% CI 0.66-0.75), respectively, independent of risk profiles, education levels, drug usage, self-care, and comorbidities at baseline. We reported consistent results in propensity-score-matched analyses and after accounting for loss to follow-up. Potential limitations include its nonrandomized design that precludes causal inference, residual confounding, and participation bias.
ICT-assisted integrated care was associated with a reduction in clinical events, including death in type 2 diabetes in public and private healthcare settings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There are no validated risk scores for predicting coronary heart disease (CHD) in Chinese patients with type 2 diabetes mellitus. This study aimed to validate the UKPDS risk engine and, if indicated, ...develop CHD risk scores. A total of 7,067 patients without CHD at baseline were analyzed. Data were randomly assigned to a training data set and a test data set. Cox models were used to develop risk scores to predict total CHD in the training data set. Calibration was assessed using the Hosmer-Lemeshow test, and discrimination was examined using the area under the receiver-operating characteristic curve in the test data set. During a median follow-up of 5.40 years, 4.97% of patients (n = 351) developed incident CHD. The UKPDS CHD risk engine overestimated the risk of CHD with suboptimal discrimination, and a new total CHD risk score was developed. The developed total CHD risk score was 0.0267 × age (years) − 0.3536 × sex (1 if female) + 0.4373 × current smoking status (1 if yes) + 0.0403 × duration of diabetes (years) − 0.4808 × Log10 (estimated glomerular filtration rate ml/min/1.73 m2 ) + 0.1232 × Log10 (1 + spot urinary albumin-creatinine ratio mg/mmol) + 0.2644 × non–high-density lipoprotein cholesterol (mmol/L). The 5-year probability of CHD = 1 − 0.9616EXP(0.9440 × RISK SCORE − 0.7082) . Predicted CHD probability was not significantly different from observed total CHD probability, and the adjusted area under the receiver-operating characteristic curve was 0.74 during 5 years of follow-up. In conclusion, the UKPDS CHD risk engine overestimated the risk of Chinese patients with type 2 diabetes mellitus and the newly developed total CHD risk score performed well in the test data set. External validations are required in other Chinese populations.
OBJECTIVE:--Type 2 diabetes is the leading cause of end-stage renal disease worldwide. Aside from hyperglycemia and hypertension, other metabolic factors may determine renal outcome. We examined risk ...associations of metabolic syndrome with new onset of chronic kidney disease (CKD) in 5,829 Chinese patients with type 2 diabetes enrolled between 1995 and 2005. RESEARCH DESIGN AND METHODS--Metabolic syndrome was defined by National Cholesterol Education Program Adult Treatment Panel III criteria with the Asian definition of obesity. Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease formula modified for the Chinese population. New onset of CKD was defined as eGFR <60 ml/min per 1.73 m² at the time of censor. Subjects with CKD at baseline were excluded from the analysis. RESULTS:--After a median follow-up duration of 4.6 years (interquartile range: 1.9-7.3 years), 741 patients developed CKD. The multivariable-adjusted hazard ratio (HR) of CKD was 1.31 (95% CI 1.12-1.54, P = 0.001) for subjects with metabolic syndrome compared with those without metabolic syndrome. Relative to subjects with no other components of metabolic syndrome except for diabetes, those with two, three, four, and five metabolic syndrome components had HRs of an increased risk of CKD of 1.15 (0.83-1.60, P = 0.407) 1.32 (0.94-1.86, P = 0.112), 1.64 (1.17-2.32, P = 0.004), and 2.34 (1.54-3.54, P < 0.001), respectively. The metabolic syndrome traits of central obesity, hypertriglyceridemia, hypertension, and low BMI were independent predictors for CKD. CONCLUSIONS:--The presence of metabolic syndrome independently predicts the development of CKD in subjects with type 2 diabetes.
Low total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations have been associated with the metabolic syndrome (MetS) in men, but the reported strength of association varies ...considerably.
We aimed to investigate whether associations differ across specific subgroups (according to age and body mass index (BMI)) and individual MetS components.
Two previously published meta-analyses including an updated systematic search in PubMed and EMBASE.
Cross-sectional or prospective observational studies with data on TT and/or SHBG concentrations in combination with MetS in men.
We conducted an individual participant data meta-analysis of 20 observational studies. Mixed effects models were used to assess cross-sectional and prospective associations of TT, SHBG and free testosterone (FT) with MetS and its individual components. Multivariable adjusted odds ratios (ORs) and hazard ratios (HRs) were calculated and effect modification by age and BMI was studied.
Men with low concentrations of TT, SHBG or FT were more likely to have prevalent MetS (ORs per quartile decrease were 1.69 (95% CI 1.60-1.77), 1.73 (95% CI 1.62-1.85) and 1.46 (95% CI 1.36-1.57) for TT, SHBG and FT, respectively) and incident MetS (HRs per quartile decrease were 1.25 (95% CI 1.16-1.36), 1.44 (95% 1.30-1.60) and 1.14 (95% 1.01-1.28) for TT, SHBG and FT, respectively). Overall, the magnitude of associations was largest in non-overweight men and varied across individual components: stronger associations were observed with hypertriglyceridemia, abdominal obesity and hyperglycaemia and associations were weakest for hypertension.
Associations of testosterone and SHBG with MetS vary according to BMI and individual MetS components. These findings provide further insights into the pathophysiological mechanisms linking low testosterone and SHBG concentrations to cardiometabolic risk.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Vancomycin area under the concentration curve (AUC) is known to predict vancomycin-induced acute kidney injury (AKI). Data were analyzed from a rat model (
= 48) and two prospective clinical studies ...(PROVIDE
= 263 and CAMERA2
= 291). A logit-link model was used to calculate the multiplicative factors between the probability of AKI from clinical studies and in the rat. The rat was 2.7 to 4.2 times more sensitive to AKI between AUCs of 199.5 and 794.3 mg·h/liter, respectively.
OBJECTIVE:--Chronic kidney disease (CKD) predicts cardiovascular disease (CVD) in the general population. We investigated the effects of stages of renal function using the estimated glomerular ...filtration rate (eGFR) on all-cause mortality and cardiovascular end points in a prospective cohort of Chinese type 2 diabetic patients. RESEARCH DESIGN AND METHODS--Between 1995 and 2000, 4,421 patients without macrovascular disease or end-stage renal disease were recruited. Renal function was assessed by eGFR, as calculated by the abbreviated Modification of Diet in Renal Disease Study Group formula. Clinical end points included all-cause mortality, cardiovascular end point (cardiovascular death, new admissions due to angina, myocardial infarction, stroke, revascularization, or heart failure), and renal end point (reduction in eGFR by >50%, progression of eGFR to stage 5, or dialysis or renal death). RESULTS:--After a median follow-up period of 39.4 months (interquartile range 20.3-55), all-cause mortality rate increased from 1.2% (95% CI 0.8-1.7) to 18.3% (9.1-27.5) (P for trend <0.001) as renal function deteriorated from stage 1 (eGFR >=90 ml/min per 1.73 m²) to stage 4 (15-29 ml/min per 1.73 m²). The respective rate of new cardiovascular end points also increased from 2.6% (2.0-3.3) to 25.3% (15.0-35.7) (P for trend <0.001). After adjustment for covariates (age, sex, albuminuria, use of renin-angiotensin-aldosterone system RAAS inhibitors, lipids, blood pressure, and glycemic control), hazard ratios across different stages of eGFR (>=90, 60-89, 30-59, and 15-29 ml/min per 1.73 m²) for all-cause mortality were 1.00, 1.27, 2.34, and 9.82 (P for trend <0.001), for cardiovascular end points were 1.00, 1.04, 1.05, and 3.23 (P for trend <0.001), and for renal end points were 1.00, 1.36, 3.34, and 27.3 (P for trend <0.001), respectively. CONCLUSIONS:--Chinese type 2 diabetic patients with reduced eGFR were at high risk of developing cardiovascular end points and all-cause mortality, independent of albuminuria and metabolic control.
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