Perceived health status after mid-urethral sling revision in 287 women from the VIGI-MESH registry: A cross-sectional study.

OBJECTIVE: To evaluate the health status and recovery of women after mid-urethral sling (MUS) revision in response to complications. DESIGN: Cross-sectional study using a questionnaire sent to women from a registry. SETTING: Twenty-two French surgical centres. POPULATION: A total of 287 women from the VIGI-MESH registry responded, having undergone MUS revision for complications. METHODS: Our sample of women were compared against a representative set of French women taken from the Eurostat database. Multivariate analysis was performed to identify clinical predictors for successful MUS revision. A qualitative analysis was carried out on free-text comments. MAIN OUTCOME MEASURES: Health status, defined by the Minimum European Health Module, and recovery, assessed by Patient Global Impression of Improvement. RESULTS: The response rate was 76% (287/378), with 49% of the women (141/287, 95% CI 43%-55%) reporting good health status, which was 8 points lower than that expected from the comparator French set (57%, 95% CI 55%-58%). Overall, 53% (147/275, 95% CI 47%-59%) of the women reported feeling much better after MUS revision. Just over one-third (35%, 95/275, 95% CI 29%-40%) of respondents reported poor health with little or no improvement. Multivariate analysis showed that being operated on for pain at revision was associated with worse self-perceived health than being operated on for exposure (OR 0.6, 95% CI 0.14-0.95); women with pre-existing comorbidity reported a poorer health status following MUS revision (OR 0.22, 95% CI 0.13-0.38). CONCLUSIONS: Our results suggest that half of the women recovered good health status after MUS revision, whereas a proportion appeared to be seriously affected by an MUS complication despite the revision.

QRS-T angle: is it a specific parameter associated with sudden cardiac death in type 2 diabetes? Results from the SURDIAGENE and the Mini-Finland prospective cohorts.

AIMS/HYPOTHESIS: Type 2 diabetes is associated with a high risk of sudden cardiac death (SCD), but the risk of dying from another cause (non-SCD) is proportionally even higher. The aim of the study was to identify easily available ECG-derived features associated with SCD, while considering the competing risk of dying from non-SCD causes. METHODS: In the SURDIAGENE (Survie, Diabete de type 2 et Genetique) French prospective cohort of individuals with type 2 diabetes, 15 baseline ECG parameters were interpreted among 1362 participants (mean age 65 years; HbA1c 62±17 mmol/mol [7.8±1.5%]; 58% male). Competing risk models assessed the prognostic value of clinical and ECG parameters for SCD after adjusting for age, sex, history of myocardial infarction, N-terminal pro b-type natriuretic peptide (NT-proBNP), HbA1c and eGFR. The prospective Mini-Finland cohort study was used to externally validate our findings. RESULTS: During median follow-up of 7.4 years, 494 deaths occurred including 94 SCDs. After adjustment, frontal QRS-T angle ≥90° (sub-distribution HR [sHR] 1.68 [95% CI 1.04, 2.69], p=0.032) and NT-proBNP level (sHR 1.26 [95% CI 1.06, 1.50] per 1 log, p=0.009) were significantly associated with a higher risk of SCD. Nevertheless, frontal QRS-T angle was the only marker not to be associated with causes of death other than SCD (sHR 1.08 [95% CI 0.84, 1.39], p=0.553 ). These findings were replicated in the Mini-Finland study subset of participants with diabetes (sHR 2.22 [95% CI 1.05, 4.71], p=0.04 for SCD and no association for other causes of death). CONCLUSIONS/INTERPRETATION: QRS-T angle was specifically associated with SCD risk and not with other causes of death, opening an avenue for refining SCD risk stratification in individuals with type 2 diabetes.

Renal function decline and heart failure hospitalisation in patients with type 2 diabetes: Dynamic predictions from the prospective SURDIAGENE cohort.

AIMS: For type 2 diabetes persons, we assessed the association between renal function decline and heart failure hospitalisation (HFH) and validated dynamic HFH predictions (DynHFH) based on repeated estimated Glomerular Filtration Rate (eGFR) values. METHODS: We studied 1413 patients from the SURDIAGENE cohort. From a joint model for longitudinal CKD-EPI measures and HFH risk, we calculated the probability of being HFH-free in the next five years. RESULTS: The mean eGFR decline was estimated at 1.48 ml/min/1.73 m2 per year (95 % CI from 1.23 to 1.74). We observed that eGFR decline was significantly associated with the HFH risk (adjHR = 1.15 for an increase in yearly decline of 1 ml/min/1.73 m2, 95 % CI from 1.03 to 1.26) independently of 7 baseline variables (from clinical, biological and ECG domains). Discrimination was good along the prediction times: AUC at 0.87 (95 %CI from 0.84 to 0.91) at patient inclusion and 0.77 (95 %CI from 0.67 to 0.87) at seven years' follow-up. CONCLUSIONS: Renal function decline was significantly associated with the HFH risk. In the era of computer-assisted medical decisions, the DynHFH, a tool that dynamically predicts HFH in type 2 diabetes persons (https://shiny.idbc.fr/DynHFH), might be helpful for precision medicine and the implementation of stratified medical decision-making.

The Added Value of Point-Light Display Observation in Total Knee Arthroplasty Rehabilitation Program: A Prospective Randomized Controlled Pilot Study.

Background and Objectives: The present study aimed to assess the potential benefit of the observation of rehabilitation-related point-light display in addition to a conventional 3-week rehabilitation program, the objective being to improve functional capacity in patients having undergone total knee arthroplasty. Materials and Methods: Patients randomized in the control group had conventional rehabilitation treatment with two sessions per day 5 days a week of physical therapy (90 min), whereas patients in the experimental group had a program of conventional rehabilitation combined with a point-light display observation two times per day (5 min) and 3 days a week. Results: The patients of both groups had improved their performances by the end of the program, and the pre- and post-test improvement were superior for the experimental group over the control group concerning the total WOMAC score (p = 0.04), the functional WOMAC score (p = 0.03), and correct recognition of point-light displays (p = 0.003). Conclusions: These findings provide new insight favoring systematic point-light display observation to improve functional recovery in patients with total knee arthroplasty.

Nutritional biomarkers and heart failure requiring hospitalization in patients with type 2 diabetes: the SURDIAGENE cohort.

BACKGROUND: Heart failure (HF) is a growing complication and one of the leading causes of mortality in people living with type 2 diabetes (T2D). Among the possible causes, the excess of red meat and the insufficiency of vegetables consumption are suspected. Such an alimentation is associated with nutritional biomarkers, including trimethylamine N-oxide (TMAO) and its precursors. Here, we aimed to study these biomarkers as potential prognostic factors for HF in patients with T2D. METHODS: We used the SURDIAGENE (SURvival DIAbetes and GENEtics) study, a large, prospective, monocentric cohort study including 1468 patients with T2D between 2001 and 2012. TMAO and its precursors (trimethylamine [TMA], betaine, choline, and carnitine) as well as thio-amino-acids (cysteine, homocysteine and methionine) were measured by liquid chromatography-tandem mass spectrometry. The main outcome was HF requiring Hospitalization (HFrH) defined as the first occurrence of acute HF leading to hospitalization and/or death, established by an adjudication committee, based on hospital records until 31st December 2015. The secondary outcomes were the composite event HFrH and/or cardiovascular death and all-cause death. The association between the biomarkers and the outcomes was studied using cause-specific hazard-models, adjusted for age, sex, history of coronary artery disease, NT-proBNP, CKD-EPI-derived eGFR and the urine albumin/creatinine ratio. Hazard-ratios (HR) are expressed for one standard deviation. RESULTS: The data of interest were available for 1349/1468 of SURDIAGENE participants (91.9%), including 569 (42.2%) women, with a mean age of 64.3 ± 10.7 years and a median follow-up of 7.3 years [25th-75th percentile, 4.7-10.8]. HFrH was reported in 209 patients (15.5%), HFrH and/or cardiovascular death in 341 (25.3%) and all-cause death in 447 (33.1%). In unadjusted hazard-models, carnitine (HR = 1.20, 95% CI [1.05; 1.37]), betaine (HR = 1.34, [1.20; 1.50]), choline (HR = 1.35, [1.20; 1.52]), TMAO (HR = 1.32, [1.16; 1.50]), cysteine (HR = 1.38, [1.21; 1.58]) and homocysteine (HR = 1.28, [1.17; 1.39]) were associated with HFrH, but not TMA and methionine. In the fully adjusted models, none of these associations was significant, neither for HFrH nor for HFrH and/or CV death, when homocysteine only was positively associated with all-cause death (HR = 1.16, [1.06; 1.27]). CONCLUSIONS: TMAO and its precursors do not appear to be substantial prognosis factors for HFrH, beyond usual cardiac- and kidney-related risk factors, whereas homocysteine is an independent risk factor for all-cause death in patients with T2D.

Differential prognostic burden of cardiovascular disease and lower-limb amputation on the risk of all-cause death in people with long-standing type 1 diabetes.

BACKGROUND: Cardiovascular disease (CVD) and nontraumatic lower-limb amputation (LLA) each results in reduced life expectancy in patients with type 1 diabetes, but the differential burden between these conditions is unknown. We compared the effects of CVD and LLA on the risk of mortality in people with type 1 diabetes. METHODS: We used pooled data from the SURGENE, GENEDIAB, and GENESIS prospective cohorts. Data were divided into: 1/absence of CVD (myocardial infarction and/or stroke) nor LLA, 2/history of CVD alone without LLA, 3/LLA alone without CVD or 4/both conditions at baseline. Participants with baseline history of peripheral artery disease were excluded from groups 1 and 2. The study endpoint was any death occurring during follow-up, regardless of the causes. RESULTS: Among 1169 participants (male 55%, age 40 ± 13 years, diabetes duration 23 ± 11 years), CVD, LLA or both were present at baseline in 49 (4.2%), 62 (5.3%) and 20 (1.7%) subjects, respectively. All-cause death occurred in 304 (26%) participants during 17-year follow-up, corresponding to 18,426 person-years and an incidence rate of 16 (95%CI, 15-18) per 1000 person-years. The risk of death increased in individuals with baseline history of CVD (adjusted HR 2.00 [95% CI 1.34-3.01], p = 0.0008) or LLA (2.26 [1.56-3.28], p < 0.0001), versus no condition, with an additive effect in people with both conditions (5.32 [3.14-9.00], p < 0.0001). No incremental risk of death was observed in people with CVD versus LLA (0.87 [0.54-1.41]). Compared with no condition, CVD and LLA were similarly associated with reduced life expectancy during follow-up: 2.79 (95% CI 1.26-4.32) and 3.38 (1.87-4.88) years, respectively. Combined conditions expose to 7.04 (4.76-9.31) less years of life expectancy (all p < 0.0001). CONCLUSIONS: CVD and LLA conferred a similar burden regarding mortality in type 1 diabetes population. Our findings encourage a careful consideration of people with type 1 diabetes and LLA as usually recommended for those with CVD, in terms of management of risk factors, treatments and prevention.

Do diabetic complications influence cancer-related events in people with type 2 diabetes? A cohort approach.

AIM: To investigate whether diabetic micro- and macrovascular complications (mMVC) influence cancer-related events in people with type 2 diabetes. METHODS: People with type 2 diabetes from the SURDIAGENE cohort were characterized (duration of diabetes, HbA1c, mMVC, history of cancer) and prospectively followed-up for death and cancer-related events (occurrence, dissemination and cancer-related death). RESULTS: Between 2002 and 2012, 1468 participants (58% men, mean age 64.8 ± 10.7 years, mean duration of diabetes 14.5 ± 9.9 years at baseline) were enrolled. At baseline, 119 (8%) had a personal history of cancer. Incident cancer occurred in 207 (14%) patients during a mean follow-up of 7.3 ± 3.7 years and was associated with older age, smoking status and personal history of cancer. mMVC were not associated with cancer-related events, considering cancer occurrence, node/metastasis dissemination and cancer-specific death. Risk of all-cause mortality was increased in diabetic patients cumulating cancer history and mMVC (HR 1.73, 95%CI 1.25-2.38) compared to those with neither cancer nor mMVC. In our cohort, cancer-related death was not associated with mMVC (HR 1.05, 95%CI 0.67-1.64), but conversely history of cancer was significantly associated with cardiovascular-related death (HR 2.41, 95%CI 1.36-4.26). CONCLUSION: In our cohort, mMVC were not associated with cancer-related events, while history of cancer was significantly associated with cardiovascular death.

Increased serum S100A12 levels are associated with higher risk of acute heart failure in patients with type 2 diabetes.

AIMS: The hyperglycaemic stress induces the release of inflammatory proteins such as S100A12, one of the endogenous ligands of the receptors for advanced glycation end products (RAGE). Chronic activation of RAGE has multiple deleterious effects in target tissues such as the heart and the vessels by promoting oxidative stress, inflammation by the release of cytokines, macrophages infiltration, and vascular cell migration and proliferation, causing ultimately endothelial cell and cardiomyocyte dysfunction. The aim of our study was to investigate the prognostic value of circulating S100A12 beyond established cardiovascular risk factors (CVRF) for heart failure (HF) and major adverse cardiovascular events (MACE) in a cohort of patients with type 2 diabetes. METHODS AND RESULTS: Serum S100A12 concentrations were measured at baseline in 1345 type 2 diabetes patients (58% men, 64 ± 11 years) recruited in the SURDIAGENE prospective cohort. Endpoints were the occurrence of acute HF requiring hospitalization (HHF) and MACE. We used a proportional hazard model adjusted for established CVRF (age, sex, duration of diabetes, estimated glomerular filtration rate, albumin/creatinine ratio, history of coronary artery disease) and serum S100A12. During the median follow-up of 84 months, 210 (16%) and 505 (38%) patients developed HHF and MACE, respectively. Baseline serum S100A12 concentrations were associated with an increased risk of HHF [hazard ratio (HR) (95% confidence interval) 1.28 (1.01-1.62)], but not MACE [1.04 (0.90-1.20)]. After adjustment for CVRF, S100A12 concentrations remained significantly associated with an increased risk of HHF [1.29 (1.01-1.65)]. In a sub-analysis, patients with high probability of pre-existing HF [N terminal pro brain natriuretic peptide (NT-proBNP) >1000 pg/mL, n = 87] were excluded. In the remaining 1258 patients, the association of serum S100A12 with the risk of HHF tended to be more pronounced [1.39 (1.06-1.83)]. When including the gold standard HF marker NT-proBNP in the model, the prognostic value of S100A12 for HHF did not reach significance. Youden method performed at 7 years for HHF prediction yielded an optimal cut-off for S100A12 concentration of 49 ng/mL (sensitivity 53.3, specificity 52.2). Compared with those with S100A12 ≤ 49 ng/mL, patients with S100A12 > 49 ng/mL had a significantly increased risk of HHF in the univariate model [HR = 1.58 (1.19-2.09), P = 0.0015] but also in the multivariate model [HR = 1.63 (1.23-2.16), P = 0.0008]. After addition of NT-proBNP to the multivariate model, S100A12 > 49 ng/mL remained associated with an increased risk of HHF [HR = 1.42 (1.07-1.90), P = 0.0160]. However, the addition of S100A12 categories on top of multivariate model enriched by NT-pro BNP did not improve the ability of the model to predict HHF (relative integrated discrimination improvement = 1.9%, P = 0.1500). CONCLUSIONS: In patients with type 2 diabetes, increased serum S100A12 concentration is independently associated with risk of HHF, but not with risk of MACE. Compared with NT-proBNP, the potential clinical interest of S100A12 for the prediction of HF events remains limited. However, S100A12 could be a candidate for a multimarker approach for HF risk assessment in diabetic patients.

Intraglomerular Dysfunction Predicts Kidney Failure in Type 2 Diabetes.

No longitudinal data link intraglomerular hemodynamic dysfunction with end-stage kidney disease (ESKD) in people with type 2 diabetes (T2D). Afferent (RA) and efferent (RE) arteriolar resistance and intraglomerular pressure (PGLO) are not directly measurable in humans but are estimable from glomerular filtration rate (GFR), renal plasma flow (RPF), blood pressure, hematocrit, and plasma oncotic pressure. We examined the association of the RA-to-RE ratio and PGLO with ESKD incidence in 237 Pima Indian individuals with T2D who underwent serial measures of GFR (iothalamate) and RPF (p-aminohippurate). Their association with kidney structural lesions was also examined in a subset of 111 participants. Of the 237 participants (mean age 42 years, diabetes duration 11 years, and GFR 153 mL/min and median urine albumin-to-creatinine ratio 36 mg/g), 69 progressed to ESKD during a median follow-up of 17.5 years. In latent class analysis, distinct trajectories characterized by increasing RA-to-RE ratio (HR 4.60, 95% CI 2.55-8.31) or elevated PGLO followed by a rapid decline (HR 2.96, 95% CI 1.45-6.02) strongly predicted incident ESKD. PGLO (R 2 = 21%, P < 0.0001) and RA-to-RE ratio (R 2 = 15%, P < 0.0001) also correlated with mesangial fractional volume, a structural predictor of DKD progression. In conclusion, intraglomerular hemodynamic parameters associated strongly with incident ESKD and correlated with structural lesions of DKD.

Plasma concentrations of lipoproteins and risk of lower-limb peripheral artery disease in people with type 2 diabetes: the SURDIAGENE study.

AIMS/HYPOTHESIS: The lipid profile has not been fully investigated in individuals with peripheral artery disease (PAD). We aimed to evaluate the relationship between plasma concentrations of lipoproteins and the prevalence of lower-limb PAD at baseline and its incidence during follow-up in people with type 2 diabetes. METHODS: Plasma concentrations of total cholesterol, HDL-cholesterol, triacylglycerol and apolipoprotein (Apo) A-I, ApoA-II, ApoB-100 and Apo(a) were measured at baseline using colorimetric or MS methods in the SURDIAGENE cohort. Total cholesterol/HDL-cholesterol ratio, non-HDL-cholesterol and LDL-cholesterol were estimated using computation formulas. Logistic and Cox proportional hazard regression models were fitted to estimate OR or HR, with related 95% CI, for baseline prevalence or incidence of major PAD (lower-limb amputation or requirement of revascularisation) during follow-up by increasing lipoprotein tertiles, after adjustment for key confounders. RESULTS: Among 1468 participants (women 42%, mean ± SD age 65 ± 11 years, duration of diabetes 14 ± 10 years at baseline), 129 (8.8%) had a baseline history of major PAD. Major PAD was less prevalent at baseline in the highest (vs lowest) tertile of HDL-cholesterol (OR 0.42 [95% CI 0.26, 0.71], p = 0.001) and ApoA-I (OR 0.39 [95% CI 0.23, 0.67], p = 0.0007), and more frequent in the highest tertile of total cholesterol/HDL-cholesterol ratio (OR 1.95 [95% CI 1.18, 3.24], p = 0.01). Among 1339 participants without a history of PAD at baseline, incident PAD occurred in 97 (7.2%) during a median (25th-75th percentile) duration of follow-up of 7.1 (4.4-10.7) years, corresponding to 9685 person-years and an incidence rate of 9.8 (95% CI 8.0, 12.0) per 1000 person-years. The risk of incident PAD was lower in the top (vs bottom) tertile of HDL-cholesterol (HR 0.54 [95% CI 0.30, 0.95], p = 0.03) or ApoA-I (HR 0.50 [95% CI 0.28, 0.86], p = 0.01) and higher in the top tertile of total cholesterol/HDL-cholesterol ratio (HR 2.81 [95% CI 1.61, 5.04], p = 0.0002) and non-HDL-cholesterol (HR 1.80 [95% CI 1.06, 3.12], p = 0.03). CONCLUSIONS/INTERPRETATION: We reported independent associations between HDL-cholesterol, ApoA-I, total cholesterol/HDL-cholesterol ratio or non-HDL-cholesterol and the prevalence or the incidence of major PAD in people with type 2 diabetes. Our findings provide a picture of lipoprotein profile in people with type 2 diabetes. Graphical abstract.

Relationship Between Diabetic Retinopathy Stages and Risk of Major Lower-Extremity Arterial Disease in Patients With Type 2 Diabetes.

OBJECTIVE: We evaluated the association between diabetic retinopathy stages and lower-extremity arterial disease (LEAD), its prognostic value, and the influence of potential contributors to this relationship in a prospective cohort of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Diabetic retinopathy was staged at baseline as absent, nonproliferative, or proliferative. A Cox regression model was fitted in order to compute the hazard ratio (HR) (95% CI) for major LEAD (lower-limb amputation or revascularization) during follow-up by baseline retinopathy stages. The retinopathy-LEAD association was assessed in subgroups by age, sex, diabetes duration, HbA1c, systolic blood pressure, diabetic kidney disease, smoking, and macrovascular disease at baseline. The performance of retinopathy in stratifying LEAD risk was assessed by using the C statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI). RESULTS: Among 1,320 participants without a history of LEAD at baseline, 94 (7.1%) developed a major LEAD during a 7.1-year median follow-up (incidence rate 9.6 per 1,000 person-years [95% CI 7.8-11.7]). The LEAD incidence rate (per 1,000 person-years) increased as retinopathy worsened: it was 5.5 (95% CI 3.9-7.8) in participants in whom retinopathy was absent, 14.6 (11.1-19.3) in those with nonproliferative retinopathy, and 20.1 (11.1-36.3) in those with proliferative retinopathy. Nonproliferative retinopathy (adjusted HR 2.31 [95% CI 1.43-3.81], P = 0.0006) and proliferative retinopathy (3.14 [1.40-6.15], P = 0.007) remained associated with major LEAD. No heterogeneity was observed across subgroups. Retinopathy enhanced the C statistic (+0.023 [95% CI 0.003-0.044], P = 0.02), IDI (0.209 [0.130-0.321], P < 0.001), and NRI (0.562 [0.382-0.799], P < 0.001) values for risk of LEAD, beyond traditional risk factors. CONCLUSIONS: An independent dose-response relationship was identified between diabetic retinopathy stages and major LEAD. Retinopathy yielded incremental prognostic information for stratifying risk of LEAD, suggesting its usefulness as a predictor of LEAD.

Comparison of a new versus standard removable offloading device in patients with neuropathic diabetic foot ulcers: a French national, multicentre, open-label randomized, controlled trial.

INTRODUCTION: The offloading is crucial to heal neuropathic diabetic foot ulcer (DFU). Removable offloading are the most used devices. Orthèse diabète is a new customized removable knee-high offloading device immobilizing foot and ankle joints, with some specific and innovative features that may improve offloading. We aimed to evaluate the efficiency of this device in DFU healing. RESEARCH, DESIGN AND METHODS: The evaluation of Offloading using a new removable ORTHOsis in DIABetic foot study is a French multicenter (13 centers) randomized controlled trial with blinded end points evaluation. Adults with neuropathic DFU were randomly assigned to either Orthèse Diabète (experimental device), or any type of conventional (usually used in France) removable offloading devices (control group). The primary outcome was the 3-month proportion of patients with fully healed DFU. RESULTS: Among 112 randomized patients (men 78%, age 62±10 years), the primary outcome occurred in 19 (33%) participants using conventional device vs 19 (35%) Orthèse Diabète users (p=0.79). Study groups were also comparable in terms of prespecified secondary end points including occurrence of new DFU (25% vs 27% in conventional and experimental groups), ipsilateral lower-limb amputation (4% vs 10%) or infectious complications (14% vs 13%) (p>0.05 for all). Adverse events were comparable between groups, including 4 deaths unrelated to study allocation (1 sudden death, 2 ventricular arrhythmias and 1 pancreatic cancer). Adverse events believed to be related to the device were higher in the Orthèse Diabète group than in the control group (15% vs 4%). Orthèse Diabète was less frequently worn than conventional devices (46% vs 66%, p=0.04). CONCLUSIONS: Orthèse Diabète, a new removable offloading orthosis immobilizing foot and ankle joints did not show superiority compared with conventional removable devices in neuropathic DFU healing and cannot be recommended to heal DFU. TRIAL REGISTRATION NUMBER: NCT01956162.

Plasma Trimethylamine N-Oxide and Risk of Cardiovascular Events in Patients With Type 2 Diabetes.

OBJECTIVE: Even though trimethylamine N-oxide (TMAO) has been demonstrated to interfere with atherosclerosis and diabetes pathophysiology, the association between TMAO and major adverse cardiovascular events (MACE) has not been specifically established in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We examined the association of plasma TMAO concentrations with MACE and all-cause mortality in a single-center prospective cohort of consecutively recruited patients with T2D. RESULTS: The study population consisted in 1463 SURDIENE participants (58% men), aged 65 ±â€…10 years. TMAO concentrations were significantly associated with diabetes duration, renal function, high-density lipoprotein cholesterol, soluble tumor necrosis factor receptor 1 (sTNFR1) concentrations (R2 = 0.27) and were significantly higher in patients on metformin, even after adjustment for estimated glomerular filtration rate (eGFR): 6.7 (8.5) vs 8.5 (13.6) µmol/L, respectively (PeGFR-adjusted = 0.0207). During follow-up (median duration [interquartile range], 85 [75] months), 403 MACE and 538 deaths were registered. MACE-free survival and all-cause mortality were significantly associated with the quartile distribution of TMAO concentrations, patients with the highest TMAO levels displaying the greatest risk of outcomes (P < 0.0001). In multivariate Cox models, compared with patients from the first 3 quartiles, those from the fourth quartile of TMAO concentration had an independently increased risk for MACE: adjusted hazard ratio (adjHR) 1.32 (1.02-1.70); P = 0.0325. Similarly, TMAO was significantly associated with mortality in multivariate analysis: adjHR 1.75 (1.17-2.09); P = 0.0124, but not when sTNFR1 and angiopoietin like 2 were considered: adjHR 1.16 (0.95-1.42); P = 0.1514. CONCLUSIONS: We revealed an association between higher TMAO concentrations and increased risk of MACE and all-cause mortality, thereby opening some avenues on the role of dysbiosis in cardiovascular risk, in T2D patients.

Serum tenascin-C is independently associated with increased major adverse cardiovascular events and death in individuals with type 2 diabetes: a French prospective cohort.

AIMS/HYPOTHESIS: Tenascin-C (TN-C) is an extracellular matrix glycoprotein highly expressed in inflammatory and cardiovascular (CV) diseases. Serum TN-C has not yet been specifically studied in individuals with type 2 diabetes, a condition associated with chronic low-grade inflammation and increased CV disease risk. In this study, we hypothesised that elevated serum TN-C at enrolment in participants with type 2 diabetes would be associated with increased risk of death and major adverse CV events (MACE) during follow-up. METHODS: We used a prospective, monocentric cohort of consecutive type 2 diabetes participants (the SURDIAGENE [SUivi Rénal, DIAbète de type 2 et GENEtique] cohort) with all-cause death as a primary endpoint and MACE (CV death, non-fatal myocardial infarction or stroke) as a secondary endpoint. We used a proportional hazard model after adjustment for traditional risk factors and the relative integrated discrimination improvement (rIDI) to assess the incremental predictive value of TN-C for these risk factors. RESULTS: We monitored 1321 individuals (58% men, mean age 64 ± 11 years) for a median of 89 months. During follow-up, 442 individuals died and 497 had MACE. Multivariate Cox analysis showed that serum TN-C concentrations were associated with an increased risk of death (HR per 1 SD: 1.27 [95% CI 1.17, 1.38]; p < 0.0001) and MACE (HR per 1 SD: 1.23 [95% CI 1.13, 1.34]; p < 0.0001). Using TN-C concentrations on top of traditional risk factors, prediction of the risk of all-cause death (rIDI: 8.2%; p = 0.0006) and MACE (rIDI: 6.7%; p = 0.0014) improved significantly, but modestly. CONCLUSIONS/INTERPRETATION: In individuals with type 2 diabetes, increased serum TN-C concentrations were independently associated with death and MACE. Therefore, including TN-C as a prognostic biomarker could improve risk stratification in these individuals.

Frailty and diabetes status in older patients with cancer: impact on mortality in the ANCRAGE cohort.

BACKGROUND: Frailty, diabetes and cancer are associated with aging, but the relationship between these conditions is not well defined. AIMS: We studied older patients with cancer from the prospective single-center cohort ANCRAGE (ANalyses of CanceR in AGEd) aiming to determine the impact of type 2 diabetes (T2D) and its vascular complications (VC) on frailty and adverse outcomes (mortality, unplanned readmission) during follow-up. METHODS: Analysis of cohort patients ≥ 75 years, included between 2009 and 2017, who underwent a comprehensive geriatric assessment (CGA). Variables of interest were history of T2D and VC, tumor site and metastatic status, CGA including eight domains (social environment, functional status, mobility, nutrition, mood, cognition, polypharmacy and comorbidities) and frailty. RESULTS: Among 1092 patients (47% female, mean age 82 ± 5 years), 219 (20%) had a reported diagnosis of T2D at baseline including 152 (69%) with VC. The most common tumor sites were prostate (15%), breast (15%), skin (12%), and colorectum (11%); 29% of patients had a metastatic disease. Frailty was highly prevalent (84%). During follow-up (median of 15.3 months), 653 (60%) patients died (60% no T2D, 43% T2D without VC, 66% with VC). After adjustment for age, gender and metastatic status, diabetics with VC had a higher risk of all-cause death (aHR1.89, 1.24-2.86, p = 0.004). Death was more frequently due to a non-cancer cause (p < 0.001). No difference in unplanned readmissions was observed in the three groups. Frailty was an independent risk factor for mortality and unplanned readmissions (p < 0.001 both). CONCLUSION: In older cancer patients from the prospective ANCRAGE cohort, all-cause mortality was significantly higher in frail patients and those with complicated T2D, a finding questioning the quality of care management in such vulnerable patients, and stimulating further research in this multidisciplinary field.

Comparison of the removal of uraemic toxins with medium cut-off and high-flux dialysers: a randomized clinical trial.

BACKGROUND: Accumulation of middle-weight uraemic toxins in haemodialysis (HD) patients results in increased morbidity and mortality. Whether medium cut-off HD (MCO-HD) improves removal of middle-weight uraemic toxins remains to be demonstrated. METHODS: This cross-over prospective study included 40 patients randomly assigned to receive either 3 months of MCO-HD followed by 3 months of high-flux HD (HF-HD), or vice versa. The primary endpoint was myoglobin reduction ratio (RR) after 3 months of MCO-HD. Secondary endpoints were the effect of MCO-HD on other middle-weight toxins and protein-bound toxins, and on parameters of nutrition, inflammation, anaemia and oxidative stress. RESULTS: Compared with HF-HD, MCO-HD provided higher mean RR of myoglobin (36 ± 8 versus 57 ± 13%, P < 0.0001), beta2-microglobulin (68 ± 6 versus 73 ± 15%, P = 0.04), prolactin (32 ± 13 versus 59 ± 11%, P < 0.0001), fibroblast growth factor 23 (20 ± 21 versus 41 ± 22%, P = 0.0002), homocysteine (43 ± 7 versus 46 ± 9%, P = 0.03) and higher median RR of kappa [54 (48-58) versus 70 (63-74)%, P < 0.0001] and lambda free light chain (FLC) [15 (9-22) versus 44 (38-49)%, P < 0.0001]. Mean ± SD pre-dialysis levels of beta2-microglobulin (28.4 ± 5.6 versus 26.9 ± 5.1 mg/L, P = 0.01) and oxidized low-density lipoprote (6.9 ± 4.4 versus 5.5 ± 2.5 pg/mL, P = 0.04), and median (interquartile range) kappa FLC [145 (104-203) versus 129 (109-190) mg/L, P < 0.03] and lambda FLC [106 (77-132) versus 89 (62-125) mg/L, P = 0.002] were significantly lower. Mean albumin levels decreased significantly (38.2 ± 4.1 versus 36.9 ± 4.3 g/L, P = 0.004), without an effect on nutritional status as suggested by unchanged normalized protein catabolic rate and transthyretin level. CONCLUSIONS: Compared with HF-HD, MCO-HD provides higher myoglobin and other middle molecules RR and is associated with moderate hypoalbuminemia. The potential benefits of this strategy on long-term clinical outcomes deserve further evaluation.

Association of Urine Haptoglobin With Risk of All-Cause and Cause-Specific Mortality in Individuals With Type 2 Diabetes: A Transethnic Collaborative Work.

OBJECTIVE: Haptoglobin is an acute-phase reactant with pleiotropic functions. We aimed to study whether urine haptoglobin may predict risk of mortality in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: We employed a transethnic approach with a cohort of Asian origin (Singapore) (N = 2,061) and a cohort of European origin (France) (N = 1,438) included in the study. We used survival analyses to study the association of urine haptoglobin with risk of all-cause and cause-specific mortality. RESULTS: A total of 365 and 525 deaths were registered in the Singapore cohort (median follow-up 7.5 years [interquartile range 3.5-12.8]) and French SURDIAGENE cohort (median follow-up 6.8 years [interquartile range 4.3-10.5], respectively. Singapore participants with urine haptoglobin in quartiles 2 to 4 had higher risk for all-cause mortality compared with quartile 1 (unadjusted hazard ratio [HR] 1.47 [95% CI 1.02-2.11], 2.28 [1.62-3.21], and 4.64 [3.39-6.35], respectively). The association remained significant in quartile 4 after multiple adjustments (1.68 [1.15-2.45]). Similarly, participants in the French cohort with haptoglobin in quartile 4 had significantly higher hazards for all-cause mortality compared with quartile 1 (unadjusted HR 2.67 [2.09-3.42] and adjusted HR 1.49 [1.14-1.96]). In both cohorts, participants in quartile 4 had a higher risk of mortality attributable to cardiovascular disease and infection but not malignant tumor. CONCLUSIONS: Urine haptoglobin predicts risk of mortality independent of traditional risk factors, suggesting that it may potentially be a novel biomarker for risk of mortality in patients with type 2 diabetes.

Association between sleep disturbances, fear of hypoglycemia and psychological well-being in adults with type 1 diabetes mellitus, data from cross-sectional VARDIA study.

AIM: To assess the relationship between sleep quality, fear of hypoglycemia, glycemic variability and psychological well-being in type 1 diabetes mellitus. METHODS: Our data were provided by the VARDIA Study, a multicentric cross-sectional study conducted between June and December 2015. Sleep characteristics were assessed by the Pittsburgh Sleep Quality Index (PSQI). Fear of hypoglycemia and psychological well-being were measured with the Hypoglycemia Fear Survey version II (HFS-II) and the Hospital Anxiety and Depression Scale (HADS), respectively. Glycemic variability (GV) was determined using the CV of three 7-point self-monitoring blood glucose profiles and the mean amplitude of glycemic excursion (MAGE). RESULTS: 315 patients were eligible for PSQI questionnaire analysis: 54% women, mean age 47 ± 15, mean diabetes duration of 24 ± 13 years, HbA1c of 7.6 ± 0.9% (60 ± 7,5mmol/mol). Average PSQI score was 6.0 ± 3.3 and 59.8% of the patients had a PSQI score > 5. HFS-II score and HADS were significantly higher among "poor" sleepers (p < 0.0001) and PSQI score was positively associated with HADS (ß = 0.22; 95% CI = 0.08;0.35). GV evaluated by CV or MAGE did not differ between "poor" and "good" sleepers (p = 0.28 and 0.54, respectively). CONCLUSIONS: Adult patients with type 1 diabetes have sleep disturbances which correlate with psychological well-being. This study suggests that psychological management can be a target to improve sleep quality in adults with type 1 diabetes mellitus.

[Interest of the multidimensional prognostic index (MPI) as an assessment tool in hospitalized patients in geriatrics]. / Intérêt de l'indice pronostique multidimensionnel (MPI) comme outil d'évaluation chez des patients hospitalisés en gériatrie.

The collection of prognostic information in the elderly is essential. The main objective was to perform a replication of the multidimensional prognostic index (MPI), to predict mortality at one-year in patients hospitalized in geriatric wards. Secondary objectives were to evaluate if the MPI was predictive of the length of hospital stay, and of rehospitalization in the following year. METHODS: Prospective study conducted from February 2015 to November 2016 at the University Hospital of Poitiers (Geriatrics department). A comprehensive geriatric assessment (number of treatment, lifestyle, autonomy, comorbidities, risk of pressure sore, nutritional and cognitive status) was used to calculate the MPI score and to categorize patients into three groups: low (MPI-1), moderate (MPI-2) and high (MPI-3) risk of mortality. RESULTS: 153 patients were included, with mean age 85.9 ± 5.4 years. Twenty-one patients (13.7%) belonged to MPI-1 group, 98 (64.1%) to MPI-2 group, and 34 (22.2%) to MPI-3 group. The number of deaths at one-year according to the MPI group was different (p < 0.01). The one-year prognostic performance of MPI was good (AUC at 0.76). MPI was also predictive of hospital length stay (p < 0.05). CONCLUSION: MPI appears to be a relevant prognostic tool in the stratification of one-year mortality risk in elderly patients hospitalized in geriatrics.

No association between fear of hypoglycemia and blood glucose variability in type 1 diabetes: The cross-sectional VARDIA study.

AIMS: In type 1 diabetes (T1D), treatment efficacy is limited by the unpredictability of blood glucose results and glycemic variability (GV). Fear of Hypoglycemia (FOH) remains a major brake for insulin treatment optimization. We aimed to assess the association of GV with FOH in participants with T1D in an observational cross-sectional study performed in 9 French Diabetes Centres (NCT02790060). METHODS: Participants were T1D for ≥5 years, aged 18-75 years, on stable insulin therapy for ≥3 months. The coefficient of variation (CV) of blood glucose and mean amplitude of glycemic excursions (MAGE) were used to assess GV from 7-point self-monitoring of blood glucose (SMBG). FOH was assessed using the validated French version of the Hypoglycemia Fear Survey-II (HFS-II) questionnaire. RESULTS: Among a total of 570 recruited participants, 298 were suitable for analysis: 46% women, 58% on continuous subcutaneous insulin infusion [CSII], mean age 49 ±â€¯16 years, HbA1c 7.5 ±â€¯0.9%, HFS-II score 67 ±â€¯18 and 12% with recent history of severe hypoglycemia during the previous 6 months, mean CV 39.8 ±â€¯9.7% and MAGE 119 ±â€¯42 mg/dL. CV and MAGE did not significantly correlate with HFS-II score (R = -0.05;P = 0.457 and R = 0.08;P = 0.170). Participants with severe hypoglycemia in the previous 6 months had higher HFS scores. Participants with higher HFS scores presented more hypoglycemias during follow-up. CONCLUSIONS: FOH as determined using the HFS-II questionnaire was not associated with 7-point SMBG variability in participants with T1D, but was associated with a positive history of severe hypoglycemia. Higher FOH was associated with higher frequency of hypoglycemia during follow-up.