Association between Iron Deficiency and Survival in Older Patients with Cancer.

BACKGROUND: iron deficiency (ID) is frequent in older patients. PURPOSE: to evaluate the association between ID and survival in patients ≥ 75 years old with confirmed solid tumors. METHODS: a retrospective monocentric study including patients between 2009 and 2018. ID, absolute ID (AID) and functional ID (FID) were defined according to the European Society for Medical Oncology (ESMO) criteria. Severe ID was defined by a ferritin level < 30 µg/L. RESULTS: in total, 556 patients were included, the mean age was 82 (±4.6) years, 56% were male, the most frequent cancer was colon cancer (19%, n = 104), and metastatic cancers were found in 38% (n = 211). Median follow-up time: 484 [190-1377] days. In anemic patients, ID and FID were independently associated with an increased risk of mortality (respectively, HR 1.51; p = 0.0065 and HR 1.73; p = 0.0007). In non-anemic patients, FID was independently associated with better survival (HR 0.65; p = 0.0495). CONCLUSION: in our study, ID was significantly associated with survival, and with better survival for patients without anemia. These results suggest that attention should be paid to the iron status in older patients with tumors and raise questions about the prognostic value of iron supplementation for iron-deficient patients without anemia.

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.

Neuroblastoma suppressor of tumorigenicity 1 is a circulating protein associated with progression to end-stage kidney disease in diabetes.

Circulating proteins associated with transforming growth factor-ß (TGF-ß) signaling are implicated in the development of diabetic kidney disease (DKD). It remains to be comprehensively examined which of these proteins are involved in the pathogenesis of DKD and its progression to end-stage kidney disease (ESKD) in humans. Using the SOMAscan proteomic platform, we measured concentrations of 25 TGF-ß signaling family proteins in four different cohorts composed in total of 754 Caucasian or Pima Indian individuals with type 1 or type 2 diabetes. Of these 25 circulating proteins, we identified neuroblastoma suppressor of tumorigenicity 1 (NBL1, aliases DAN and DAND1), a small secreted protein known to inhibit members of the bone morphogenic protein family, to be most strongly and independently associated with progression to ESKD during 10-year follow-up in all cohorts. The extent of damage to podocytes and other glomerular structures measured morphometrically in 105 research kidney biopsies correlated strongly with circulating NBL1 concentrations. Also, in vitro exposure to NBL1 induced apoptosis in podocytes. In conclusion, circulating NBL1 may be involved in the disease process underlying progression to ESKD, and its concentration in circulation may identify subjects with diabetes at increased risk of progression to ESKD.

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.

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.

Comprehensive Search for Novel Circulating miRNAs and Axon Guidance Pathway Proteins Associated with Risk of ESKD in Diabetes.

BACKGROUND: Mechanisms underlying the pro gression of diabetic kidney disease to ESKD are not fully understood. METHODS: We performed global microRNA (miRNA) analysis on plasma from two cohorts consisting of 375 individuals with type 1 and type 2 diabetes with late diabetic kidney disease, and targeted proteomics analysis on plasma from four cohorts consisting of 746 individuals with late and early diabetic kidney disease. We examined structural lesions in kidney biopsy specimens from the 105 individuals with early diabetic kidney disease. Human umbilical vein endothelial cells were used to assess the effects of miRNA mimics or inhibitors on regulation of candidate proteins. RESULTS: In the late diabetic kidney disease cohorts, we identified 17 circulating miRNAs, represented by four exemplars (miR-1287-5p, miR-197-5p, miR-339-5p, and miR-328-3p), that were strongly associated with 10-year risk of ESKD. These miRNAs targeted proteins in the axon guidance pathway. Circulating levels of six of these proteins-most notably, EFNA4 and EPHA2-were strongly associated with 10-year risk of ESKD in all cohorts. Furthermore, circulating levels of these proteins correlated with severity of structural lesions in kidney biopsy specimens. In contrast, expression levels of genes encoding these proteins had no apparent effects on the lesions. In in vitro experiments, mimics of miR-1287-5p and miR-197-5p and inhibitors of miR-339-5p and miR-328-3p upregulated concentrations of EPHA2 in either cell lysate, supernatant, or both. CONCLUSIONS: This study reveals novel mechanisms involved in progression to ESKD and points to the importance of systemic factors in the development of diabetic kidney disease. Some circulating miRNAs and axon guidance pathway proteins represent potential targets for new therapies to prevent and treat this condition.

Correlates of premature pap test screening, under 25 years old: analysis of data from the CONSTANCES cohort study.

BACKGROUND: Many countries currently recommend that screening for cervical cancer begin at the age of 25 years. Premature screening (before that age) could lead to unnecessary follow-up examinations and procedures that turn out to be useless. Our objective is to ascertain if the use of particular contraceptive methods are associated with premature screening. METHODS: This cross-sectional study based on the CONSTANCES cohort enabled us to include 4297 women younger than 25 years. The factors associated with premature screening were modeled by logistic regression. Missing data were handled by multiple imputations. The multivariate analyses were adjusted for sex life, social and demographic characteristics, and health status. RESULTS: Nearly half (48.5%) the women younger than 25 years had already undergone premature screening. Women not using contraceptives (aOR 0.3, 95% CI 0.3-0.5) and those using nonmedicalized contraceptives (condom, spermicide, etc.) (aOR 0.5, 95% CI 0.4-0.6) had premature screening less often than women using birth control pills. Higher risks of premature screening were observed in 20-year-old women (aOR 2.7, 95% CI 2.2-3.3) and in those with more than 5 lifetime partners (aOR 2.5, 95% CI 2.0-3.1), compared respectively with women who were younger and those with 5 or fewer lifetime partners. CONCLUSION: Young women using contraceptives that require a doctor's prescription are exposed to premature screening more often than those not using contraception and those with nonmedicalized contraceptives.

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.

Comprehensive geriatric assessment in older patients with cancer: an external validation of the multidimensional prognostic index in a French prospective cohort study.

BACKGROUND: Older patients with cancer require specific and individualized management. The 3-group Multidimensional Prognostic Index (MPI) based on the Comprehensive Geriatric Assessment (CGA) has shown a predictive interest in terms of mortality. The objective of our study was to assess the prognostic value of MPI for 1-year mortality in an external prospective French cohort of elderly patients with cancer. METHODS: From March 2015 to March 2017 a prospective single-center cohort study enrolled all patients with cancer, aged 75 years and older referred to the geriatric oncology clinic. We used a proportional hazard model for 1-year mortality adjusted for age, sex, tumor sites and metastatic status. C-statistics were used to assess the incremental predictive value of MPI index to these risk factors. RESULTS: overall, 433 patients underwent CGA with MPI (women 42%; mean age 82.8 ± 4.8 years). The most common tumor sites were prostate (23%), skin (17%), colorectum (15%) and breast (12%); 29% of patients had a metastatic disease; 231 patients (53%) belonged to the "MPI-1" group, 172 (40%) to the "MPI-2" group and 30 patients were classified in the "MPI-3" group. One-year mortality rate was 32% (23% in MPI-1, 41% in MPI-2 and 53% in MPI-3, p = 0.024). All domains of MPI except cognition and living status were significantly associated with mortality at one-year, as well as tumor sites and metastatic status. Higher MPI was associated with a higher mortality risk (adjusted HR 1.56 [95%CI 1.70-2.09] and 1.72 [1.33-2.22] for MPI groups 2 and 3 compared to 1; p < 0.0001). CONCLUSIONS: In addition to established risk factors, MPI improves risk prediction of 1-year mortality. This practical prognostic tool may help to optimize management of these vulnerable patients.

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.

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.

Circulating TNF receptors and risk of renal disease progression, cardiovascular disease events and mortality in patients with diabetes: a systematic review and meta-analysis.

PURPOSE: Inflammation plays an important role in the pathogenesis of diabetes complications. This study aims to assess the association between circulating inflammatory biomarkers TNF receptors (TNFRs) and the risk of renal disease progression, cardiovascular disease (CVD) events, and mortality in patients with diabetes. METHODS: PubMed and Embase databases were comprehensively searched up to March 2019. Data were extracted independently by two reviewers. A random effects model was performed for the pooled analyses. RESULTS: Five studies in 3316 subjects assessed TNFRs with renal disease in patients with type 1 diabetes and showed both TNFR-1 and TNFR-2 were consistently associated with the renal outcomes. Fourteen studies in 7696 subjects evaluated TNFRs in patients with type 2 diabetes. The pooled risk ratio per doubling increase in TNFR-1 and TNFR-2 for renal disease progression was more than two (2.64 [1.98, 3.52] and 2.23 [1.69, 2.94]). The subgroup analyses and sensitivity analyses further illustrated these results of renal outcome and its robustness. Moreover, higher TNFR-1 and TNFR-2 was also significantly associated with CVD events and mortality in patients with type 2 diabetes. CONCLUSIONS: Circulating TNFR-1 and TNFR-2 are independently associated with higher risk of renal disease progression, CVD events, and mortality in patients with diabetes and might contribute to the clinical risk assessment in the future.

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.

Changes in Albuminuria But Not GFR are Associated with Early Changes in Kidney Structure in Type 2 Diabetes.

BACKGROUND: In type 1 diabetes, changes in the GFR and urine albumin-to-creatinine ratio (ACR) are related to changes in kidney structure that reflect disease progression. However, such changes have not been studied in type 2 diabetes. METHODS: Participants were American Indians with type 2 diabetes enrolled in a clinical trial of losartan versus placebo. We followed a subset who underwent kidney biopsy at the end of the 6-year trial, with annual measurements of GFR (by urinary clearance of iothalamate) and ACR. Participants had a second kidney biopsy after a mean follow-up of 9.3 years. We used quantitative morphometric analyses to evaluate both biopsy specimens. RESULTS: Baseline measures for 48 participants (12 men and 36 women, mean age 45.6 years) who completed the study included diabetes duration (14.6 years), GFR (156 ml/min), and ACR (15 mg/g). During follow-up, glomerular basement membrane (GBM) width, mesangial fractional volume, and ACR increased, and surface density of peripheral GBM and GFR decreased. After adjustment for sex, age, ACR, and each morphometric variable at baseline, an increase in ACR during follow-up was significantly associated with increases in GBM width, mesangial fractional volume, and mean glomerular volume, and a decrease in surface density of peripheral GBM. Decline in GFR was not associated with changes in these morphometric variables after additionally adjusting for baseline GFR. CONCLUSIONS: In American Indians with type 2 diabetes and preserved GFR at baseline, increasing ACR reflects the progression of earlier structural glomerular lesions, whereas early GFR decline may not accurately reflect such lesions.

Pap tests for cervical cancer screening test and contraception: analysis of data from the CONSTANCES cohort study.

BACKGROUND: In France, a Pap test for cervical cancer screening is recommended every three years for all sexually active women aged 25 to 65 years. Modes of contraception (any or no contraception, with or without a visit to a physician, and with or without a gynecological examination) may influence adhesion to screening: women who use intrauterine device (IUD) should be more up to date with their cervical cancer screening more often than those using other means of contraception. Our objectives were to analyze the association between modes of contraception and Pap tests for screening. METHODS: This cross sectional study is based on the CONSTANCES cohort enabled us to include 16,764 women aged 25-50 years. The factors associated with adhesion to cervical cancer screening (defined by a report of a Pap test within the previous 3 years) was modeled by logistic regression. Missing data were imputed by using multiple imputations. The multivariate analyses were adjusted for sex life, social and demographic characteristics, and health status. RESULTS: Overall, 11.2% (1875) of the women reported that they were overdue for Pap test screening. In the multivariate analysis there was no significant difference between women using an IUD and those pills or implant of pap test overdue ORa:0.9 CI95% [0.8-1.1], ORa 1.3 CI95% [0.7-2.7] respectively. Women not using contraceptives and those using non-medical contraceptives (condoms, spermicides, etc.) were overdue more often ORa: 2.6 CI95% [2.2-3.0] and ORa: 1.8 CI95% [1.6-2.1] respectively than those using an IUD. CONCLUSION: Women seeing medical professionals for contraception are more likely to have Pap tests.

A signature of circulating inflammatory proteins and development of end-stage renal disease in diabetes.

Chronic inflammation is postulated to be involved in the development of end-stage renal disease in diabetes, but which specific circulating inflammatory proteins contribute to this risk remain unknown. To study this, we examined 194 circulating inflammatory proteins in subjects from three independent cohorts with type 1 and type 2 diabetes. In each cohort, we identified an extremely robust kidney risk inflammatory signature (KRIS), consisting of 17 proteins enriched in tumor necrosis factor-receptor superfamily members, that was associated with a 10-year risk of end-stage renal disease. All these proteins had a systemic, non-kidney source. Our prospective study findings provide strong evidence that KRIS proteins contribute to the inflammatory process underlying end-stage renal disease development in both types of diabetes. These proteins point to new therapeutic targets and new prognostic tests to identify subjects at risk of end-stage renal disease, as well as biomarkers to measure responses to treatment of diabetic kidney disease.

Human Early Life Exposome (HELIX) study: a European population-based exposome cohort.

PURPOSE: Essential to exposome research is the collection of data on many environmental exposures from different domains in the same subjects. The aim of the Human Early Life Exposome (HELIX) study was to measure and describe multiple environmental exposures during early life (pregnancy and childhood) in a prospective cohort and associate these exposures with molecular omics signatures and child health outcomes. Here, we describe recruitment, measurements available and baseline data of the HELIX study populations. PARTICIPANTS: The HELIX study represents a collaborative project across six established and ongoing longitudinal population-based birth cohort studies in six European countries (France, Greece, Lithuania, Norway, Spain and the UK). HELIX used a multilevel study design with the entire study population totalling 31 472 mother-child pairs, recruited during pregnancy, in the six existing cohorts (first level); a subcohort of 1301 mother-child pairs where biomarkers, omics signatures and child health outcomes were measured at age 6-11 years (second level) and repeat-sampling panel studies with around 150 children and 150 pregnant women aimed at collecting personal exposure data (third level). FINDINGS TO DATE: Cohort data include urban environment, hazardous substances and lifestyle-related exposures for women during pregnancy and their offspring from birth until 6-11 years. Common, standardised protocols were used to collect biological samples, measure exposure biomarkers and omics signatures and assess child health across the six cohorts. Baseline data of the cohort show substantial variation in health outcomes and determinants between the six countries, for example, in family affluence levels, tobacco smoking, physical activity, dietary habits and prevalence of childhood obesity, asthma, allergies and attention deficit hyperactivity disorder. FUTURE PLANS: HELIX study results will inform on the early life exposome and its association with molecular omics signatures and child health outcomes. Cohort data are accessible for future research involving researchers external to the project.

Plasma copeptin, kidney disease, and risk for cardiovascular morbidity and mortality in two cohorts of type 2 diabetes.

BACKGROUND: Cardiovascular disease and kidney damage are tightly associated in people with type 2 diabetes. Experimental evidence supports a causal role for vasopressin (or antidiuretic hormone) in the development of diabetic kidney disease (DKD). Plasma copeptin, the COOH-terminal portion of pre-provasopressin and a surrogate marker of vasopressin, was shown to be positively associated with the development and progression of DKD. Here we assessed the association of plasma copeptin with the risk of cardiovascular events during follow-up in two prospective cohorts of type 2 diabetic patients, and we examined if this association could be mediated by deleterious effects of vasopressin on the kidney. METHODS: We studied 3098 and 1407 type 2 diabetic patients from the French cohorts DIABHYCAR and SURDIAGENE, respectively. We considered the incidence during follow-up (median: 5 years) of a combined end point composed of myocardial infarction, coronary revascularization, hospitalization for congestive heart failure, or cardiovascular death. Copeptin concentration was measured in baseline plasma samples by an immunoluminometric assay. RESULTS: The cumulative incidence of cardiovascular events during follow-up by sex-specific tertiles of baseline plasma copeptin was 15.6% (T1), 18.7% (T2) and 21.7% (T3) in DIABHYCAR (p = 0.002), and 27.7% (T1), 34.1% (T2) and 47.6% (T3) in SURDIAGENE (p < 0.0001). Cox proportional hazards survival regression analyses confirmed the association of copeptin with cardiovascular events in both cohorts: hazard ratio with 95% confidence interval for T3 vs. T1 was 1.29 (1.04-1.59), p = 0.02 (DIABHYCAR), and 1.58 (1.23-2.04), p = 0.0004 (SURDIAGENE), adjusted for sex, age, BMI, duration of diabetes, systolic blood pressure, arterial hypertension, HbA1c, total cholesterol, HDL-cholesterol, triglycerides, estimated glomerular filtration rate (eGFR), urinary albumin concentration (UAC), active tobacco smoking, and previous history of myocardial infarction at baseline. No interaction was observed between plasma copeptin and eGFR (p = 0.40) or UAC (p = 0.61) categories on the risk of cardiovascular events in analyses of pooled cohorts. CONCLUSIONS: Plasma copeptin was positively associated with major cardiovascular events in people with type 2 diabetes. This association cannot be solely accounted for by the association of copeptin with kidney-related traits.

Prognostic Values of Inflammatory and Redox Status Biomarkers on the Risk of Major Lower-Extremity Artery Disease in Individuals With Type 2 Diabetes.

OBJECTIVE: Inflammation and oxidative stress play an important role in the pathogenesis of lower-extremity artery disease (LEAD). We assessed the prognostic values of inflammatory and redox status biomarkers on the risk of LEAD in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: Plasma concentrations of tumor necrosis factor-α receptor 1 (TNFR1), angiopoietin-like 2, ischemia-modified albumin (IMA), fluorescent advanced glycation end products, protein carbonyls, and total reductive capacity of plasma were measured at baseline in the SURDIAGENE (Survie, Diabete de type 2 et Genetique) cohort. Major LEAD was defined as the occurrence during follow-up of peripheral revascularization or lower-limb amputation. RESULTS: Among 1,412 participants at baseline (men 58.2%, mean [SD] age 64.7 [10.6] years), 112 (7.9%) developed major LEAD during 5.6 years of follow-up. High plasma concentrations of TNFR1 (hazard ratio [95% CI] for second vs. first tertile 1.12 [0.62-2.03; P = 0.71] and third vs. first tertile 2.16 [1.19-3.92; P = 0.01]) and of IMA (2.42 [1.38-4.23; P = 0.002] and 2.04 [1.17-3.57; P = 0.01], respectively) were independently associated with an increased risk of major LEAD. Plasma concentrations of TNFR1 but not IMA yielded incremental information, over traditional risk factors, for the risk of major LEAD as follows: C-statistic change (0.036 [95% CI 0.013-0.059]; P = 0.002), integrated discrimination improvement (0.012 [0.005-0.022]; P < 0.001), continuous net reclassification improvement (NRI) (0.583 [0.294-0.847]; P < 0.001), and categorical NRI (0.171 [0.027-0.317]; P = 0.02). CONCLUSIONS: Independent associations exist between high plasma TNFR1 or IMA concentrations and increased 5.6-year risk of major LEAD in people with type 2 diabetes. TNFR1 allows incremental prognostic information, suggesting its use as a biomarker for LEAD.