Associations between multiple neurological biomarkers and distal sensorimotor polyneuropathy: KORA F4/FF4 study.

AIMS: The aim of this study was to assess associations between neurological biomarkers and distal sensorimotor polyneuropathy (DSPN). MATERIALS AND METHODS: Cross-sectional analyses were based on 1032 participants aged 61-82 years from the population-based KORA F4 survey, 177 of whom had DSPN at baseline. The prevalence of type 2 diabetes was 20%. Prospective analyses used data from 505 participants without DSPN at baseline, of whom 125 had developed DSPN until the KORA FF4 survey. DSPN was defined based on the examination part of the Michigan Neuropathy Screening Instrument. Serum levels of neurological biomarkers were measured using proximity extension assay technology. Associations between 88 biomarkers and prevalent or incident DSPN were estimated using Poisson regression with robust error variance and are expressed as risk ratios (RR) and 95% CI per 1-SD increase. Results were adjusted for multiple confounders and multiple testing using the Benjamini-Hochberg procedure. RESULTS: Higher serum levels of CTSC (cathepsin C; RR [95% CI] 1.23 (1.08; 1.39), pB-H = 0.044) and PDGFRα (platelet-derived growth factor receptor A; RR [95% CI] 1.21 (1.08; 1.35), pB-H = 0.044) were associated with prevalent DSPN in the total study sample. CDH3, JAM-B, LAYN, RGMA and SCARA5 were positively associated with DSPN in the diabetes subgroup, whereas GCP5 was positively associated with DSPN in people without diabetes (all pB-H for interaction <0.05). None of the biomarkers showed an association with incident DSPN (all pB-H>0.05). CONCLUSIONS: This study identified multiple novel associations between neurological biomarkers and prevalent DSPN, which may be attributable to functions of these proteins in neuroinflammation, neural development and myelination.

Association of transketolase polymorphisms with diabetic polyneuropathy in the general population: The KORA F4 study.

AIMS: We recently reported that genetic variability in the TKT gene encoding transketolase, a key enzyme in the pentose phosphate pathway, is associated with measures of diabetic sensorimotor polyneuropathy (DSPN) in recent-onset diabetes. Here, we aimed to substantiate these findings in a population-based KORA F4 study. MATERIALS AND METHODS: In this cross-sectional study, we assessed seven single nucleotide polymorphisms (SNPs) in the transketolase gene in 952 participants from the KORA F4 study with normal glucose tolerance (NGT; n = 394), prediabetes (n = 411), and type 2 diabetes (n = 147). DSPN was defined by the examination part of the Michigan Neuropathy Screening Instrument (MNSI) using the original MNSI > 2 cut-off and two alternative versions extended by touch/pressure perception (TPP) (MNSI > 3) and by TPP plus cold perception (MNSI > 4). RESULTS: After adjustment for sex, age, BMI, and HbA1c, in type 2 diabetes participants, four out of seven transketolase SNPs were associated with DSPN for all three MNSI versions (all p ≤ 0.004). The odds ratios of these associations increased with extending the MNSI score, for example, OR (95% CI) for SNP rs62255988 with MNSI > 2: 1.99 (1.16-3.41), MNSI > 3: 2.27 (1.26-4.09), and MNSI > 4: 4.78 (2.22-10.26); SNP rs9284890 with MNSI > 2: 2.43 (1.42-4.16), MNSI > 3: 3.46 (1.82-6.59), and MNSI > 4: 4.75 (2.15-10.51). In contrast, no associations were found between transketolase SNPs and the three MNSI versions in the NGT and prediabetes groups. CONCLUSIONS: The link of genetic variation in transketolase enzyme to diabetic polyneuropathy corroborated at the population level strengthens the concept suggesting an important role of pathways metabolising glycolytic intermediates in the evolution of diabetic polyneuropathy.

Association of dietary patterns with diabetes-related comorbidities varies among diabetes endotypes.

BACKGROUND AND AIMS: Differences of dietary pattern adherence across the novel diabetes endotypes are unknown. This study assessed adherence to pre-specified dietary patterns and their associations with cardiovascular risk factors, kidney function, and neuropathy among diabetes endotypes. METHODS AND RESULTS: The cross-sectional analysis included 765 individuals with recent-onset (67 %) and prevalent diabetes (33 %) from the German Diabetes Study (GDS) allocated into severe autoimmune diabetes (SAID, 35 %), severe insulin-deficient diabetes (SIDD, 3 %), severe insulin-resistant diabetes (SIRD, 5 %), mild obesity-related diabetes (MOD, 28 %), and mild age-related diabetes (MARD, 29 %). Adherence to a Mediterranean diet score (MDS), Dietary Approaches to Stop Hypertension (DASH) score, overall plant-based diet (PDI), healthful (hPDI) and unhealthful plant-based diet index (uPDI) was derived from a food frequency questionnaire and associated with cardiovascular risk factors, kidney function, and neuropathy using multivariable linear regression analysis. Differences in dietary pattern adherence between endotypes were assessed using generalized mixed models. People with MARD showed the highest, those with SIDD and MOD the lowest adherence to the hPDI. Adherence to the MDS, DASH, overall PDI, and hPDI was inversely associated with high-sensitivity C-reactive protein (hsCRP) among people with MARD (ß (95%CI): -9.18 % (-15.61; -2.26); -13.61 % (-24.17; -1.58); -19.15 % (-34.28; -0.53); -16.10 % (-28.81; -1.12), respectively). Adherence to the PDIs was associated with LDL cholesterol among people with SAID, SIRD, and MOD. CONCLUSIONS: Minor differences in dietary pattern adherence (in particular for hPDI) and associations with markers of diabetes-related complications (e.g. hsCRP) were observed between endotypes. So far, evidence is insufficient to derive endotype-specific dietary recommendations. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01055093.

Serum neurofilament light chain: a novel biomarker for early diabetic sensorimotor polyneuropathy.

AIMS/HYPOTHESIS: No established blood-based biomarker exists to monitor diabetic sensorimotor polyneuropathy (DSPN) and evaluate treatment response. The neurofilament light chain (NFL), a blood biomarker of neuroaxonal damage in several neurodegenerative diseases, represents a potential biomarker for DSPN. We hypothesised that higher serum NFL levels are associated with prevalent DSPN and nerve dysfunction in individuals recently diagnosed with diabetes. METHODS: This cross-sectional study included 423 adults with type 1 and type 2 diabetes and known diabetes duration of less than 1 year from the prospective observational German Diabetes Study cohort. NFL was measured in serum samples of fasting participants in a multiplex approach using proximity extension assay technology. DSPN was assessed by neurological examination, nerve conduction studies and quantitative sensory testing. Associations of serum NFL with DSPN (defined according to the Toronto Consensus criteria) were estimated using Poisson regression, while multivariable linear and quantile regression models were used to assess associations with nerve function measures. In exploratory analyses, other biomarkers in the multiplex panel were also analysed similarly to NFL. RESULTS: DSPN was found in 16% of the study sample. Serum NFL levels increased with age. After adjustment for age, sex, waist circumference, height, HbA1c, known diabetes duration, diabetes type, cholesterol, eGFR, hypertension, CVD, use of lipid-lowering drugs and use of non-steroidal anti-inflammatory drugs, higher serum NFL levels were associated with DSPN (RR [95% CI] per 1-normalised protein expression increase, 1.92 [1.50, 2.45], p<0.0001), slower motor (all p<0.0001) and sensory (all p≤0.03) nerve conduction velocities, lower sural sensory nerve action potential (p=0.0004) and higher thermal detection threshold to warm stimuli (p=0.023 and p=0.004 for hand and foot, respectively). There was no evidence for associations between other neurological biomarkers and DSPN or nerve function measures. CONCLUSIONS/INTERPRETATION: Our findings in individuals recently diagnosed with diabetes provide new evidence associating higher serum NFL levels with DSPN and peripheral nerve dysfunction. The present study advocates NFL as a potential biomarker for DSPN.

Prediabetes and risk of mortality, diabetes-related complications and comorbidities: umbrella review of meta-analyses of prospective studies.

AIMS/HYPOTHESIS: The term prediabetes is used for individuals who have impaired glucose metabolism whose glucose or HbA1c levels are not yet high enough to be diagnosed as diabetes. Prediabetes may already be associated with an increased risk of chronic 'diabetes-related' complications. This umbrella review aimed to provide a systematic overview of the available evidence from meta-analyses of prospective observational studies on the associations between prediabetes and incident diabetes-related complications in adults and to evaluate their strength and certainty. METHODS: For this umbrella review, systematic reviews with meta-analyses reporting summary risk estimates for the associations between prediabetes (based on fasting or 2 h postload glucose or on HbA1c) and incidence of diabetes-related complications, comorbidities and mortality risk were included. PubMed, Web of Science, the Cochrane Library and Epistemonikos were searched up to 17 June 2021. Summary risk estimates were recalculated using a random effects model. The certainty of evidence was evaluated by applying the GRADE tool. This study is registered with PROSPERO, CRD42020153227. RESULTS: Ninety-five meta-analyses from 16 publications were identified. In the general population, prediabetes was associated with a 6-101% increased risk for all-cause mortality and the incidence of cardiovascular outcomes, CHD, stroke, heart failure, atrial fibrillation and chronic kidney disease, as well as total cancer, total liver cancer, hepatocellular carcinoma, breast cancer and all-cause dementia with moderate certainty of evidence. No associations between prediabetes and incident depressive symptoms and cognitive impairment were observed (with low or very low certainty of evidence). The association with all-cause mortality was stronger for prediabetes defined by impaired glucose tolerance than for prediabetes defined by HbA1c. CONCLUSIONS/INTERPRETATION: Prediabetes was positively associated with risk of all-cause mortality and the incidence of cardiovascular outcomes, CHD, stroke, chronic kidney disease, cancer and dementia. Further high-quality studies, particularly on HbA1c-defined prediabetes and other relevant health outcomes (e. g. neuropathy) are required to support the evidence.

Differences in the prevalence of erectile dysfunction between novel subgroups of recent-onset diabetes.

AIMS/HYPOTHESIS: In men with diabetes, the prevalence of erectile dysfunction increases with advanced age and longer diabetes duration and is substantially higher in men with type 2 diabetes than those with type 1 diabetes. This study aimed to evaluate the prevalence of erectile dysfunction among the five novel subgroups of recent-onset diabetes and determine the strength of associations between diabetes subgroups and erectile dysfunction. METHODS: A total of 351 men with recent-onset diabetes (<1 year) from the German Diabetes Study baseline cohort and 124 men without diabetes were included in this cross-sectional study. Erectile dysfunction was assessed with the International Index of Erectile Function (IIEF) questionnaire. Poisson regression models were used to estimate associations between diabetes subgroups (each subgroup tested against the four other subgroups as reference) and erectile dysfunction (dependent binary variable), adjusting for variables used to define diabetes subgroups, high-sensitivity C-reactive protein and depression. RESULTS: The prevalence of erectile dysfunction was markedly higher in men with diabetes than in men without diabetes (23% vs 11%, p = 0.004). Among men with diabetes, the prevalence of erectile dysfunction was highest in men with severe insulin-resistant diabetes (SIRD) (52%), lowest in men with severe autoimmune diabetes (SAID) (7%), and intermediate in men with severe insulin-deficient diabetes (SIDD), mild obesity-related diabetes (MOD) and mild age-related diabetes (MARD) (31%, 18% and 29%, respectively). Men with SIRD had an adjusted RR of 1.93 (95% CI 1.04, 3.58) for prevalent erectile dysfunction (p = 0.038). Similarly, men with SIDD had an adjusted RR of 3.27 (95% CI 1.18, 9.10) (p = 0.023). In contrast, men with SAID and those with MARD had unadjusted RRs of 0.26 (95% CI 0.11, 0.58) (p = 0.001) and 1.52 (95% CI 1.04, 2.22) (p = 0.027), respectively. However, these associations did not remain statistically significant after adjustment. CONCLUSIONS/INTERPRETATION: The high RRs for erectile dysfunction in men with recent-onset SIRD and SIDD point to both insulin resistance and insulin deficiency as major contributing factors to this complication, suggesting different mechanisms underlying erectile dysfunction in these subgroups.

Effect of obesity on the associations of 25-hydroxyvitamin D with prevalent and incident distal sensorimotor polyneuropathy: population-based KORA F4/FF4 study.

BACKGROUND/OBJECTIVES: The association between vitamin D and DSPN has been investigated in cross-sectional studies in individuals with diabetes. However, evidence from prospective and population-based studies is still lacking. Also, the potential modifying effect of obesity and glucose tolerance has not been investigated. Therefore, we examined the cross-sectional and prospective associations of serum 25(OH)D with DSPN and assessed possible effect modifications. SUBJECTS/METHODS: The study included individuals aged 62-81 years who participated in the German KORA F4 (2006-2008) and FF4 (2013-2014) studies. DSPN was assessed using the Michigan Neuropathy Screening Instrument. Cross-sectional analyses (n = 1065; 33% of the participants had obesity) assessed the associations of baseline 25(OH)D with prevalent DSPN, while prospective analyses (n = 422) assessed the associations of 25(OH)D with incident DSPN. RESULTS: No association was found between 25(OH)D and prevalent DSPN in the total sample after adjustment for age, sex, season of blood sampling, BMI, metabolic variables, lifestyle factors, and comorbidities. However, a decrease by 10 nmol/L in 25(OH)D was associated with prevalent DSPN (RR (95% CI) 1.08 (1.01, 1.16)) in individuals with obesity but not in normal-weight individuals (RR (95% CI) 0.97 (0.92, 1.02), pinteraction = 0.002). No evidence for effect modification by glucose tolerance was found (p > 0.05). In the prospective analysis, 25(OH)D levels in the first and second tertiles were associated with higher risk of DSPN (RR (95% CI) 1.18 (1.02; 1.38) and 1.40 (1.04; 1.90)) compared to the third tertile after adjustment for age, sex, season of blood sampling, and BMI. There was no evidence for effect modification by obesity or glucose tolerance categories. CONCLUSIONS: Our study did not show consistent evidence for cross-sectional and prospective associations between serum 25(OH)D levels and DSPN in the total study population of older individuals. However, there was evidence for an association between lower serum 25(OH)D levels and higher prevalence of DSPN in individuals with obesity.

Association of serum uromodulin with adipokines in dependence of type 2 diabetes.

BACKGROUND: The renal tubular glycoprotein uromodulin is associated with obesity and type 2 diabetes, but the underlying mechanisms are elusive. We investigated the association of serum uromodulin with adipokines and tested the effect modification by diabetes status. METHODS: The associations of serum uromodulin with eight adipokines were assessed in 795-1080 participants of the KORA F4 study aged 62-81 years using linear regression models adjusted for sex, age, BMI, estimated glomerular filtration rate and diabetes. Significant associations were assessed for effect modification by diabetes status. We further tested using logistic regression whether adjustment for the significant adipokines affected the association of uromodulin with type 2 diabetes. RESULTS: Serum uromodulin was inversely associated with chemerin and retinol-binding protein-4 after multivariable adjustment (p < 0.001) and Bonferroni correction for multiple testing. No significant association was observed between uromodulin and the other adipokines (leptin, adiponectin, secreted frizzled-related protein 5, progranulin, omentin-1 and vaspin) after correcting for multiple testing. The association of uromodulin with chemerin and retinol-binding protein-4 was stronger in participants with type 2 diabetes than in participants without diabetes (p for interaction < 0.05). However, inclusion of chemerin and retinol-binding protein-4 in logistic regression models did not attenuate the association of serum uromodulin with diabetes. CONCLUSIONS: Serum uromodulin was inversely associated with the predominantly pro-inflammatory adipokines chemerin and retinol-binding protein-4. The associations were stronger in participants with type 2 diabetes compared to participants without diabetes. However, the association of serum uromodulin with type 2 diabetes was independent of chemerin and retinol-binding protein-4.

Novel biomarkers of inflammation, kidney function and chronic kidney disease in the general population.

BACKGROUND: Inflammatory processes have been implicated in the development of chronic kidney disease (CKD). We investigated the association of a large panel of inflammatory biomarkers reflecting aspects of immunity with kidney function and CKD incidence. METHODS: We used data from two independent population-based studies, KORA F4 (discovery, n = 1110, mean age 70.3 years, 48.7% male) and ESTHER (replication, n = 1672, mean age 61.9 years, 43.6% male). Serum levels of biomarkers were measured using proximity extension assay technology. The association of biomarkers with estimated glomerular filtration rate (eGFR) at baseline and with incident CKD was investigated using linear and logistic regression models adjusted for cardiorenal risk factors. Independent results from prospective analyses of both studies were pooled. The significance level was corrected for multiple testing by false-discovery rate (PFDR < 0.05). RESULTS: In the KORA F4 discovery study, 52 of 71 inflammatory biomarkers were inversely associated with eGFR based on serum creatinine. Top biomarkers included CD40, TNFRSF9 and IL10RB. Forty-two of these 52 biomarkers were replicated in the ESTHER study. Nine of the 42 biomarkers were associated with incident CKD independent of cardiorenal risk factors in the meta-analysis of the KORA (n = 142, mean follow-up 6.5 years) and ESTHER (n = 103, mean follow-up 8 years) studies. Pathway analysis revealed the involvement of inflammatory and immunomodulatory processes reflecting cross-communication of innate and adaptive immune cells. CONCLUSIONS: Novel and known biomarkers of inflammation were reproducibly associated with kidney function. Future studies should investigate their clinical utility and underlying molecular mechanisms in independent cohorts.

Plasma Proteomics of Renal Function: A Transethnic Meta-Analysis and Mendelian Randomization Study.

BACKGROUND: Studies on the relationship between renal function and the human plasma proteome have identified several potential biomarkers. However, investigations have been conducted largely in European populations, and causality of the associations between plasma proteins and kidney function has never been addressed. METHODS: A cross-sectional study of 993 plasma proteins among 2882 participants in four studies of European and admixed ancestries (KORA, INTERVAL, HUNT, QMDiab) identified transethnic associations between eGFR/CKD and proteomic biomarkers. For the replicated associations, two-sample bidirectional Mendelian randomization (MR) was used to investigate potential causal relationships. Publicly available datasets and transcriptomic data from independent studies were used to examine the association between gene expression in kidney tissue and eGFR. RESULTS: In total, 57 plasma proteins were associated with eGFR, including one novel protein. Of these, 23 were additionally associated with CKD. The strongest inferred causal effect was the positive effect of eGFR on testican-2, in line with the known biological role of this protein and the expression of its protein-coding gene (SPOCK2) in renal tissue. We also observed suggestive evidence of an effect of melanoma inhibitory activity (MIA), carbonic anhydrase III, and cystatin-M on eGFR. CONCLUSIONS: In a discovery-replication setting, we identified 57 proteins transethnically associated with eGFR. The revealed causal relationships are an important stepping stone in establishing testican-2 as a clinically relevant physiological marker of kidney disease progression, and point to additional proteins warranting further investigation.

Epidemiology of herpes simplex virus type 2 in Latin America and the Caribbean: systematic review, meta-analyses and metaregressions.

OBJECTIVE: To characterise epidemiology of herpes simplex virus type 2 (HSV-2) in Latin America and the Caribbean. METHODS: HSV-2 reports were systematically reviewed and synthesised, and findings were reported following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analyses and metaregressions were conducted. FINDING: 102 relevant reports were identified including 13 overall incidence measures, 163 overall (and 402 stratified) seroprevalence measures, and 7 and 10 proportions of virus detection in genital ulcer disease and in genital herpes, respectively. Pooled mean seroprevalence was 20.6% (95% CI 18.7% to 22.5%) in general populations, 33.3% (95% CI 26.0% to 41.0%) in intermediate-risk populations, 74.8% (95% CI 70.6% to 78.8%) in female sex workers, and 54.6% (95% CI 47.4% to 61.7%) in male sex workers, men who have sex with men and transgender people. In general populations, seroprevalence increased from 9.6% (95% CI 7.1% to 12.4%) in those aged <20 years to 17.9% (95% CI 13.6% to 22.5%) in those aged 20-30, 27.6% (95% CI 21.4% to 34.2%) in those aged 30-40 and 38.4% (95% CI 32.8% to 44.2%) in those aged >40. Compared with women, men had lower seroprevalence with an adjusted risk ratio (ARR) of 0.68 (95% CI 0.60 to 0.76). Seroprevalence declined by 2% per year over the last three decades (ARR of 0.98, 95% CI 0.97 to 0.99). Pooled mean proportions of HSV-2 detection in GUD and genital herpes were 41.4% (95% CI 18.9% to 67.0%) and 91.1% (95% CI 82.7% to 97.2%), respectively. CONCLUSIONS: One in five adults is HSV-2 infected, a higher level than other world regions, but seroprevalence is declining. Despite this decline, HSV-2 persists as the aetiological cause of nearly half of GUD cases and almost all of genital herpes cases.

Higher circulating omentin is associated with increased risk of primary cardiovascular events in individuals with diabetes.

AIMS/HYPOTHESIS: Higher concentrations of the adipokine omentin are associated with lower levels of cardiometabolic risk factors in experimental and cross-sectional studies, but with higher risk of type 2 diabetes and cardiovascular diseases in population-based cohort studies. However, it is unknown whether high omentin concentrations are associated with increased risk of cardiovascular events in people with established diabetes. Therefore, the present study investigated the association between serum omentin concentrations and the risk of cardiovascular events in individuals with diabetes. METHODS: This prospective study was based on participants of the German ESTHER cohort with diabetes and without previous cardiovascular event. The ESTHER cohort consists of individuals aged 50-75 years at baseline who were recruited by their general practitioners. After exclusion of individuals with serum C-reactive protein ≥10 mg/l (≥95.24 nmol/l), the final analysis population consisted of 933 individuals. At baseline, serum omentin concentrations were measured by ELISA. Cox regression models were fitted to estimate HRs and their corresponding 95% CIs for associations of omentin tertiles with a composite endpoint of cardiovascular events and separately with incident myocardial infarction, stroke and cardiovascular death. RESULTS: During 14 years of follow-up, 228 individuals experienced a primary cardiovascular event (myocardial infarction, stroke or cardiovascular death). After comprehensive adjustment for age, sex, BMI, metabolic and lifestyle factors and medication use, HRs (95% CIs) for the 2nd and 3rd tertile of omentin compared with the 1st tertile were: 1.24 (95% CI 0.86, 1.79) and 1.63 (1.15, 2.32) (ptrend = 0.005) for the composite cardiovascular endpoint; 1.39 (0.78, 2.47) and 1.71 (0.98, 2.99) (ptrend = 0.065) for incident myocardial infarction; 1.40 (0.78, 2.53) and 2.05 (1.17, 3.58) (ptrend = 0.010) for incident stroke; and 1.43 (0.85, 2.40) and 1.72 (1.04, 2.83) (ptrend = 0.040) for cardiovascular death. Effect estimates and p values were almost unaltered after additional adjustment for adiponectin. CONCLUSIONS/INTERPRETATION: Higher omentin concentrations are associated with an increased risk for cardiovascular events in individuals with diabetes after adjustment for multiple cardiovascular risk factors. Given data from preclinical studies, it appears possible that this association reflects a compensatory, but insufficient upregulation of omentin concentrations as a response to stimuli that increase cardiovascular risk.

Meta-analysis of predictive models to assess the clinical validity and utility for patient-centered medical decision making: application to the CAncer of the Prostate Risk Assessment (CAPRA).

BACKGROUND: The Cancer of the Prostate Risk Assessment (CAPRA) score was designed and validated several times to predict the biochemical recurrence-free survival after a radical prostatectomy. Our objectives were, first, to study the clinical validity of the CAPRA score, and, second, to assess its clinical utility for stratified medicine from an original patient-centered approach. METHODS: We proposed a meta-analysis based on a literature search using MEDLINE. Observed and predicted biochemical-recurrence-free survivals were compared to assess the calibration of the CAPRA score. Discriminative capacities were evaluated by estimating the summary time-dependent ROC curve. The clinical utility of the CAPRA score was evaluated according to the following stratified decisions: active monitoring for low-risk patients, prostatectomy for intermediate-risk patients, or radio-hormonal therapy for high risk patients. For this purpose, we assessed CAPRA's clinical utility in terms of its ability to maximize time-dependent utility functions (i.e. Quality-Adjusted Life-Years - QALYs). RESULTS: We identified 683 manuscripts and finally retained 9 studies. We reported good discriminative capacities with an area under the SROCt curve at 0.73 [95%CI from 0.67 to 0.79], while graphical calibration seemed acceptable. Nevertheless, we also described that the CAPRA score was unable to discriminate between the three medical alternatives, i.e. it did not allow an increase in the number of life years in perfect health (QALYs) of patients with prostate cancer. CONCLUSIONS: We confirmed the prognostic capacities of the CAPRA score. In contrast, we were not able to demonstrate its clinical usefulness for stratified medicine from a patient-centered perspective. Our results also highlighted the confusion between clinical validity and utility. This distinction should be better considered in order to develop predictive tools useful in practice.

Relationship of very low serum 25-hydroxyvitamin D3 levels with long-term survival in a large cohort of colorectal cancer patients from Germany.

To investigate the association of serum 25-hydroxyvitamin D (25(OH)D3) with survival in a large prospective cohort study of colorectal cancer (CRC) patients. The study population consisted of 2,910 patients diagnosed with CRC between 2003 and 2010 who participated in the DACHS study, a multicenter study from Germany with comprehensive long-term follow-up. 25(OH)D3 was determined in serum samples collected shortly after cancer diagnosis by High Performance Liquid Chromatography-Electro Spray Ionization-Mass Spectrometry. Analyses of survival outcomes were performed using Cox regression with comprehensive adjustment for relevant confounders. The majority (59%) of CRC patients were vitamin D deficient (serum 25(OH)D3 levels <30 nmol/L). During a median follow-up of 4.8 years, 787 deaths occurred, 573 of which were due to CRC. Compared to patients in the highest 25(OH)D3 quintile (>45.20 nmol/L), those in the lowest 25(OH)D3 quintile (<11.83 nmol/L) had a strongly increased mortality. Adjusted hazard ratios (95% Confidence Interval) were 1.78 (1.39-2.27), 1.65 (1.24-2.21), 1.32 (1.03-1.71) and 1.48 (1.18-1.85) for all-cause mortality, CRC-specific mortality, recurrence-free and disease-free survival, respectively. Subgroup analyses did not show any significant effect modification across strata defined by sex, age, stage, body mass index, or the late entry. Dose-response analyses showed a strong inverse relationship between serum 25(OH)D3 levels and survival endpoints at 25(OH)D3 levels <30 nmol/L, and no association with mortality at higher 25(OH)D3 levels. Vitamin D deficiency is highly prevalent in CRC patients and a strong independent predictor of poor prognosis. The possibility of enhancing CRC prognosis by vitamin D supplementation, ideally combined with outdoor physical activity, should be evaluated by randomized controlled trials focusing on patients with vitamin D deficiency.

IL-17A and IL-17F genes variants and susceptibility to childhood asthma in Tunisia.

OBJECTIVES: IL-17A and IL-17F are new pro-inflammatory cytokines implicated in neutrophilic inflammation and thus, involved in the pathogenesis of asthma. We investigated the possible association among asthma and IL-17A -197G/A (rs2275913), IL-17F 7488A/G (rs763780) and IL-17F 7383A/G (rs2397084). METHODS: The study was performed in 171 patients with asthma (mean age 9.5 years, 105 boys, and 66 girls) and 171 healthy individuals matched with patients in age and sex. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to detect genes' polymorphisms. RESULTS: IL-17A -197G/A and IL-17F 7383A/G were associated with asthma in children (p = 0.008, p = 0.001, respectively). No association was found with IL-17F 7488A/G polymorphism. Haplotype analysis revealed a significant association between GA and AG haplotypes and asthma (p = 0.004, p = 0.02). When patients were stratified according to the atopic status, no significant association was detected with any of the three studied variants. CONCLUSION: Our results suggested that SNPs in IL-17A and IL-17F confer susceptibility to childhood asthma in Tunisia.

Correlates of Skeletal Muscle Mass and Differences Between Novel Subtypes in Recent-Onset Diabetes.

CONTEXT: Low skeletal muscle mass (SMM) is associated with long-standing diabetes but little is known about SMM in newly diagnosed diabetes. OBJECTIVE: We aimed to identify correlates of SMM in recent-onset diabetes and to compare SMM between novel diabetes subtypes. METHODS: SMM was normalized to body mass index (SMM/BMI) in 842 participants with known diabetes duration of less than 1 year from the German Diabetes Study (GDS). Cross-sectional associations between clinical variables, 79 biomarkers of inflammation, and SMM/BMI were assessed, and differences in SMM/BMI between novel diabetes subtypes were analyzed with different degrees of adjustment for confounders. RESULTS: Male sex and physical activity were positively associated with SMM/BMI, whereas associations of age, BMI, glycated hemoglobin A1c, homeostatic model assessment for ß-cell function, and estimated glomerular filtration rate with SMM/BMI were inverse (all P < .05; model r2 = 0.82). Twenty-three biomarkers of inflammation showed correlations with SMM/BMI after adjustment for sex and multiple testing (all P < .0006), but BMI largely explained these correlations. In a sex-adjusted analysis, individuals with severe autoimmune diabetes had a higher SMM/BMI whereas individuals with severe insulin-resistant diabetes and mild obesity-related diabetes had a lower SMM/BMI than all other subtypes combined. However, differences were attenuated after adjustment for the clustering variables. CONCLUSION: SMM/BMI differs between diabetes subtypes and may contribute to subtype differences in disease progression. Of note, clinical variables rather than biomarkers of inflammation explain most of the variation in SMM/BMI.

Differential associations between selenoprotein P and distal sensorimotor polyneuropathy in people with and without diabetes: KORA F4/FF4 study.

BACKGROUND: Oxidative stress is a risk factor for distal sensorimotor polyneuropathy (DSPN). Selenoprotein P is a protein with antioxidant properties but has not been investigated in the context of DSPN. This study aimed to assess the associations between selenoprotein P and DSPN in people without and with type 2 diabetes (T2D). METHODS: Cross-sectional and prospective analyses were based on 1053 (including 217 with T2D) and 513 participants (including 79 with T2D), respectively, aged 61-82 years from the population-based KORA F4 survey. DSPN at baseline (KORA F4) and in the follow-up survey KORA FF4 was defined based on the Michigan Neuropathy Screening Instrument. Serum levels of full-length selenoprotein P were quantified by ELISA. Associations between selenoprotein P and prevalent or incident DSPN were estimated using logistic regression analysis adjusting for multiple confounders. RESULTS: Selenoprotein P levels were not associated with prevalent DSPN in the total sample. However, there was a significant interaction by diabetes status. Higher levels of selenoprotein P were associated with lower odds of prevalent DSPN in individuals without T2D (fully adjusted model: OR 0.825 [95 % CI 0.682, 0.998], p = 0.0476), but not in those with T2D (OR [95 % CI] 1.098 [0.829, 1.454], p = 0.5132; pinteraction = 0.0488). Selenoprotein P levels were not associated with incident DSPN over a follow-up of 6.5 years. CONCLUSION: In individuals without T2D from the older general population, lower selenoprotein P levels were associated with a higher prevalence of DSPN. Whether the antioxidant properties of selenoprotein P are responsible for the observed associations remains to be elucidated in future research.

Environmental risk factors of incident distal sensorimotor polyneuropathy: Results from the prospective population-based KORA F4/FF4 study.

Distal sensorimotor polyneuropathy (DSPN) is a common condition in older populations with high prevalence of obesity and type 2 diabetes. We hypothesised that the risk of DSPN is increased by multiple ubiquitous environmental risk factors, particularly in people with obesity. This study was based on 423 individuals aged 62-81 years without DSPN who participated in the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 survey (2006-2008) in Southern Germany. During 6.5 years of follow-up, 188 participants developed clinical DSPN as assessed by the Michigan Neuropathy Screening Instrument. Environmental exposures, including air temperature, surrounding greenness (assessed with the normalized difference vegetation index [NDVI]), long-term road traffic noise and air pollution, were assessed at participants' residences. The cumulative risk index (CRI) evaluated the joint effects of co-occurring exposures on DSPN risk based on effect estimates from multi-exposure Poisson regression models. The models were adjusted for age, sex, height, waist circumference, smoking, alcohol consumption, physical activity, education and neighbourhood socioeconomic status. In the entire cohort, the co-occurrence of an interquartile range (IQR) decrease in temperature of the warm season and NDVI in a 100-m buffer and of an IQR increase in night-time average traffic noise and in annual average particle number concentration (PNC) was positively associated with incident DSPN (CRI [95 % CI] 1.39 [1.02, 1.91]). Effect estimates for exposure combinations were generally higher in individuals with obesity (CRI 1.34-2.01) than in those without obesity (CRI 0.90-1.33). The four-exposure model showed a twofold increased risk of DSPN among obese (CRI [95 % CI] 2.01 [1.10, 3.67]), but not among non-obese individuals (CRI [95 % CI] 1.18 [0.83, 1.67]). Thus, ubiquitous environmental exposures jointly augment the risk of DSPN in the older population. Lower air temperature in the warm season, less greenness, and higher noise levels and ultrafine particle concentrations identified people with obesity as a particularly vulnerable subgroup.

Association of renin and aldosterone with glucose metabolism in a Western European population: the KORA F4/FF4 study.

INTRODUCTION: Primary aldosteronism is associated with impaired glucose tolerance. Whether plasma aldosterone and/or renin concentrations are associated with type 2 diabetes and continuous measures of glucose metabolism in the general population is still under debate. RESEARCH DESIGN AND METHODS: The analyses included 2931 participants of the KORA F4 study at baseline and 2010 participants of the KORA FF4 study after a median follow-up of 6.5 years. The associations of active plasma renin and aldosterone concentrations with type 2 diabetes and continuous measures of glucose metabolism were assessed using logistic and linear regression models. Results were adjusted for sex, age, body mass index (BMI), estimated glomerular filtration rate, potassium, use of ACE inhibitors, angiotensin receptor blockers, beta blockers, diuretics and calcium channel blockers. RESULTS: Cross-sectionally, renin was associated with type 2 diabetes (OR per SD: 1.25, 95% CI 1.10 to 1.43, p<0.001), fasting glucose, 2-hour glucose, insulin, proinsulin, HOMA-B (homeostasis model assessment of beta cell function) and HOMA-IR (homeostasis model assessment of insulin resistance) (all p values <0.001). Aldosterone was not associated with type 2 diabetes (OR: 1.04, 95% CI 0.91 to 1.19; p=0.547) but with insulin, proinsulin and HOMA-IR (all p values <0.001). The aldosterone-renin ratio was inversely associated with type 2 diabetes and several measures of glucose metabolism. Longitudinally, neither renin (OR: 1.12, 95% CI 0.92 to 1.36) nor aldosterone (OR: 0.91, 95% CI 0.74 to 1.11) were associated with incident type 2 diabetes. Renin was inversely associated with changes of insulin concentrations. CONCLUSIONS: In the KORA F4/FF4 study, renin and aldosterone were not associated with incident type 2 diabetes and largely unrelated to changes of measures of glucose metabolism. Cross-sectionally, aldosterone was associated with surrogate parameters of insulin resistance. However, these associations were not independent of renin.

Association of circulating MR-proADM with all-cause and cardiovascular mortality in the general population: Results from the KORA F4 cohort study.

BACKGROUND AND AIM: Despite its vasodilatory effect, adrenomedullin and its surrogate mid-regional pro-adrenomedullin (MR-proADM) have been found to be positively associated with all-cause and cardiovascular mortality. However, the underlying mechanisms thereof remain unclear and the associations were mostly shown in geriatric cohorts or in patients with chronic diseases. Therefore, we aimed to investigate the possible involvement of abdominal obesity, selected adipokines, and biomarkers of subclinical inflammation in the association of MR-proADM with mortality in a population based study cohort. METHODS: Prospective analysis of the KORA F4 study; median follow-up 9.1 (8.8-9.4) years. Complete data on MR-proADM and mortality was available for 1551 participants, aged 56.9±12.9 years (mean±SD). Correlation and regression analyses of MR-proADM with overall (BMI) and abdominal obesity (waist circumference), selected adipokines and biomarkers of subclinical inflammation. Cox proportional hazard models on the association of MR-proADM with all-cause and cardiovascular mortality with adjustment for cardiovascular risk factors and selected biomarkers in study subgroups (n = 603-1551). RESULTS: MR-proADM associated with all-cause (HR (95%CI): 2.37 (1.72-3.26) and 2.31 (1.67-3.20)) and cardiovascular mortality (4.28 (2.19-8.39) and 4.44 (2.25-8.76)) after adjustment for traditional cardiovascular risk factors including BMI or waist circumference, respectively. MR-proADM was further associated with four out of seven examined adipokines (leptin, retinol-binding protein-4, chemerin, and adiponectin) and with five out of eleven examined biomarkers of subclinical inflammation (high-sensitivity C-reactive protein, interleukin-6, myeloperoxidase, interleukin-22, and interleukin-1 receptor antagonist) after multivariable adjustment and correction for multiple testing. However, only IL-6 substantially attenuated the association of MR-proADM with all-cause mortality. CONCLUSIONS: We found an association of MR-proADM with (abdominal) obesity, selected adipokines, and biomarkers of subclinical inflammation. However, the association of MR-proADM with mortality was independent of these parameters. Future studies should investigate the role of IL-6 and further characteristics of subclinical inflammation in the association between MR-proADM and all-cause mortality.