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One of the main objectives of the European health policy framework is to ensure equitable access to high-quality health services across Europe. Here we examined country-specific kidney transplantation and graft failure rates in children and explore their country- and patient-level determinants. Patients under 20 years of age initiating kidney replacement therapy from January 2007 through December 2015 in 37 European countries participating in the ESPN/ERA-EDTA Registry were included in the analyses. Countries were categorized as low-, middle-, and high-income based on gross domestic product. At five-years of follow-up, 4326 of 6909 children on kidney replacement therapy received their first kidney transplant. Overall median time from kidney replacement therapy start to first kidney transplantation was 1.4 (inter quartile range 0.3-4.3) years. The five-year kidney transplantation probability was 48.8% (95% confidence interval: 45.9-51.7%) in low-income, 76.3% (72.8-79.5%) in middle-income and 92.3% (91.0-93.4%) in high-income countries and was strongly associated with macro-economic factors. Gross domestic product alone explained 66% of the international variation in transplantation rates. Compared with high-income countries, kidney transplantation was 76% less likely to be performed in low-income and 58% less likely in middle-income countries. Overall five-year graft survival in Europe was 88% and showed little variation across countries. Thus, despite large disparities transplantation access across Europe, graft failure rates were relatively similar. Hence, graft survival in low-risk transplant recipients from lower-income countries seems as good as graft survival among all (low, medium, and high risk) graft recipients from high-income countries.

Background De novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D). Methods and findings Seventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970–1973 to 2006–2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3–75.5 years; % women = 20.4%–62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41–1.66; p < 0.001) for 16:0, 1.40 (1.33–1.48; p < 0.001) for 16:1n-7, 1.14 (1.05–1.22; p = 0.001) for 18:0, and 1.16 (1.07–1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%–73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94–1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors. Conclusions Concentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D., Fumiaki Imamura and colleagues investigate the association between concentrations of fatty acid involved in de-novo lipogensis and incidence of Type 2 diabetes., Author summary Why was this study done? De novo lipogenesis (DNL) is a metabolic pathway involved in the endogenous synthesis of specific fatty acids, such as 16:0, 16:1n7, 18:0, and 18:1n9, and it is linked to the pathophysiology of cardiometabolic diseases, including type 2 diabetes (T2D). Circulating or tissue concentrations of these fatty acids have been investigated for the associations with T2D incidence in epidemiological research. However, published studies reported inconsistent associations inconsistently and were subject to publication bias. Summary evidence is not available to date for the associations between these fatty acids and T2D incidence. An integration of available cohort studies would increase statistical power and allow assessment of generalizability, standardization of analytical strategies, and evidence synthesis with the potential publication bias minimized. What did the researchers do and find? As a part of the Fatty Acids and Outcomes Research Consortium (FORCE), we conducted new individual-participant data analyses of 17 cohort studies of a total of 65,225 adults free of T2D at baseline, among whom 15,383 developed incident T2D over up to 20 years of follow-up. The cohort studies analyzed the associations between fatty acids (16:0, 16:1n7, 18:0, and 18:1n9) and the risk of developing T2D with standardized analytic strategy. In pooled analyses, each of the fatty acids was positively associated with a higher risk of developing T2D. The associations were independent of major risk factors for T2D, such as age, sex, race/ethnicity, socioeconomic characteristics, smoking status, physical activity, and obesity. What do these findings mean? The findings provide the first summary evidence to date for the positive relationships of concentrations of the DNL-related fatty acids with a risk of T2D, indicating the strong relevance of DNL and its determinants to the development of T2D. These fatty acids potentially reflect the status of DNL activity, which may be stimulated or suppressed by a combination of carbohydrate intake, alcohol intake, polyunsaturated fatty acid intake, and other lifestyle and clinical factors. Therefore, the current findings indicate the need for investigation into determinants and consequences of elevated concentrations of these fatty acids. Despite several advantages of our individual-level data analysis in this pooling project, the results cannot establish whether elevated concentrations of these fatty acids caused the development of T2D or whether underlying peripheral or hepatic insulin resistance, for example, may elevate both the fatty acid concentrations and the risk of T2D independently.

AimWhile serum fructosamine may be a good marker of glucose control in pregnant women with diabetes, its relationship with macrosomia is still uncertain.MethodsIn 130 hyperglycaemic women with singleton pregnancies (117 gestational diabetes mellitus, 13 pregestational diabetes), serum fructosamine and HbA1c levels were measured at 25 ± 7 weeks of gestation. Levels in mothers of infants with and without macrosomic newborns (birth weight > 4000 g and/or large-for-gestational-age birth weight > 90th percentile) were compared using logistic regression analysis adjusted for macrosomia risk factors.ResultsThese 130 pregnant women were 33 ± 5 years old; their BMI before pregnancy was 27.7 ± 6.9 kg/m2, and they gained 7.5 ± 5.1 kg during the first 6 months of gestation. Glucose control was good according to HbA1c levels (5.3 ± 0.3%; 34 ± 2 mmol/mol), yet 17/130 (13%) newborns had macrosomia: 3900 ± 227 g vs 3057 ± 512 g (P < 0.001) in the others. These mothers were older and had higher parity, whereas their BMI scores before pregnancy and gestational weight gains did not differ. Fructosamine levels were also higher at 221 ± 40 μmol/L vs 192 ± 22 μmol/l (P < 0.001), respectively, and remained significant even after adjusting for maternal age, BMI, parity, type of diabetes, antecedents of macrosomia and excessive gestational weight gain. By contrast, HbA1c did not differ between the two groups. In fact, nearly two-thirds (64.7%) of the mothers of macrosomic newborns had fructosamine levels > 200 μmol/l vs 31.9% of mothers with non-macrosomic newborns (P < 0.05).ConclusionHigh fructosamine levels are associated with macrosomia in the newborns of well-controlled hyperglycaemic pregnant women.

ObjectiveTo use network science to model complex diet relationships a decade before onset of dementia in a large French cohort, the 3-City Bordeaux study.MethodsWe identified cases of dementia incident to the baseline food frequency questionnaire over 12 years of follow-up. For each case, we randomly selected 2 controls among individuals at risk at the age at case diagnosis and matched for age at diet assessment, sex, education, and season of the survey. We inferred food networks in both cases and controls using mutual information, a measure to detect nonlinear associations, and compared food consumption patterns between groups.ResultsIn the nested case-control study, the mean (SD) duration of follow-up and number of visits were 5.0 (2.5) vs 4.9 (2.6) years and 4.1 (1.0) vs 4.4 (0.9) for cases (n = 209) vs controls (n = 418), respectively. While there were few differences in simple, average food intakes, food networks differed substantially between cases and controls. The network in cases was focused and characterized by charcuterie as the main hub, with connections to foods typical of French southwestern diet and snack foods. In contrast, the network of controls included several disconnected subnetworks reflecting diverse and healthier food choices.ConclusionHow foods are consumed (and not only the quantity consumed) may be important for dementia prevention. Differences in predementia diet networks, suggesting worse eating habits toward charcuterie and snacking, were evident years before diagnosis in this cohort. Network methods, which are designed to model complex systems, may advance our understanding of risk factors for dementia.

Objective This multicentric study aimed to evaluate the quality of life (QOL) in children with Hirschsprung's disease (HD). Methods HD patients aged from 6 to 18 years and followed-up in 2 French pediatric surgery centers were included in this study. QOL was assessed using the HAQL questionnaires according to age (6-11 and 12-18), filled by patients and their parents (proxy reports) and correlated with initial disease characteristics, nutritional status, and functional score of Krickenbeck. Results Sixty-three patients were included. The acquisition of satisfactory voluntary bowel movements was found in only 50% of the 6 to 11 years old and 68% of the teenagers. Seventy percentage of the children and 55% of teenagers had soiling issues. The overall HAQLproxy6--11 score was 528/700; best scores were found for "fecal continence" (94/100), "social functioning" (94/100), and "urinary continence" (92/100) whereas the worst scores were for "general well-being" (64/100) and "diurnal fecal continence" (58/100). The overall HAQLproxy12--16 score was 607/700; best scores were for "urinary continence" (96/100) and "social functioning" (93/100). In a multivariate analysis, soiling was the only factor significantly associated with low QOL (P = 0.03). Conclusions Soiling remains frequent in children operated on for HD and negatively affects their QOL. Assessment and treatment of soiling should be the priority for medical teams in the follow-up of these children.

Summary Background Cataract surgery is one of the most common operations in health care. Femtosecond laser-assisted cataract surgery (FLACS) enables more precise ocular incisions and lens fragmentation than does phacoemulsification cataract surgery (PCS). We hypothesised that FLACS might improve outcomes in cataract surgery compared with PCS despite having higher costs. Methods We did a participant-masked randomised superiority clinical trial comparing FLACS and PCS in two parallel groups (permuted block randomisation stratified on centres via a centralised web-based application, allocation ratio 1:1, block size of 2 or 4 for unilateral cases and 2 or 6 for bilateral cases). Five French University Hospitals enrolled consecutive patients aged 22 years or older who were eligible for unilateral or bilateral cataract surgery. Participants, outcome assessors, and technicians carrying out examinations were masked to the surgical treatment allocation until the last follow-up visit and a sham laser procedure was set up for participants randomly assigned to the PCS arm. The primary clinical endpoint was the success rate of surgery, defined as a composite of four outcomes at a 3-month postoperative visit: absence of severe perioperative complication, a best-corrected visual acuity (BCVA) of 0·0 LogMAR (logarithm of the minimum angle of resolution) or better, an absolute refractive error of 0·75 dioptres or less, and unchanged postoperative corneal astigmatism power (≤0·5 dioptres) and axis (≤20°). The primary economic endpoint was the incremental cost per additional patient who had treatment success at 3 months. Primary outcomes were assessed in all randomly assigned patients who met all eligibility criteria (missing data considered as failure). We used mixed logistic regression models or mixed linear regression models for statistical comparisons, adjusted on centres and whether cataract surgery was bilateral or unilateral. The study is registered with ClinicalTrials.gov , NCT01982006 . Findings Of the 907 patients (1476 eyes) randomly assigned between Oct 9, 2013, and Oct 30, 2015, 870 (704 eyes in FLACS group and 685 eyes in the PCS group) were analysed. We identified no significant difference in the success rate of surgery between the FLACS and PCS groups (FLACS: 41·1% [289 eyes]; PCS: 43·6% [299 eyes]); adjusted odds ratio 0·85, 95% CI 0·64–1·12, p=0·250). The incremental cost-effectiveness ratio was €10 703 saved per additional patient who had treatment success with PCS compared with FLACS. We observed no severe adverse events during the femtosecond laser procedure, and most of the complications in the FLACS group related to the primary outcome measures occurred during the phacoemulsification phase or postoperatively. Interpretation Despite its advanced technology, femtosecond laser was not superior to phacoemulsification in cataract surgery and, with higher costs, did not provide an additional benefit over phacoemulsification for patients or health-care systems. Funding French Ministry of Social Affairs and Health.

BACKGROUND: Improved management of growth impairment might have resulted in less growth retardation after pediatric kidney transplantation (KT) over time. We aimed to analyze recent longitudinal growth data after KT in comparison to previous eras, its determinants, and the association with transplant outcome in a large cohort of transplanted children using data from the European Society for Paediatric Nephrology/European Renal Association and European Dialysis and Transplant Association Registry. METHODS: A total of 3492 patients transplanted before 18 years from 1990 to 2012 were included. Height SD scores (SDS) were calculated using recent national or European growth charts. We used generalized equation models to estimate the prevalence of growth deficit and linear mixed models to calculate adjusted mean height SDS. RESULTS: Mean adjusted height post-KT was -1.77 SDS. Height SDS was within normal range in 55%, whereas 28% showed moderate, and 17% severe growth deficit. Girls were significantly shorter than boys, but catch-up growth by 5 years post-KT was observed in both boys and girls. Children 12. CONCLUSIONS: Catch-up growth post-KT remains limited, height SDS did not improve over time, resulting in short stature in nearly half of transplanted children in Europe.

International audience

Background Previous studies have reported on the higher risk of functional decline among older patients with cancer. However, few have focused on factors of functional decline in older persons with cancer and are mainly hospital-based and focus on consequences of cancer treatment. The aim of the study was to identify determinants of functional decline in older subjects with cancer in a population-based study. Methods Using cancer registries, we identified older subjects (age ≥ 65 years) with cancer in three prospective cohort studies from Gironde, a French department. Functional status was measured using the Instrumental Activities of Daily Living (IADL) and the basic Activities of Daily Living (ADL) scales, and functional decline was measured between cancer pre- and post-diagnosis visits. Studied variables were demographic and socioeconomic (age at diagnosis, sex, living alone, education), cancer-related (stage at diagnosis, treatment received), smoking status, health-related (polypharmacy, depressive symptomatology), and geriatric-specific (cognitive impairment or dementia). Analyses were performed using logistic regression models. Results Age (≥85 years), cognitive impairment or dementia, and advanced stage at diagnosis were associated with a higher risk of ADL limitations, whether considering death or not. Age (≥85 years), education and polypharmacy were associated with a higher risk of ADL and/or IADL limitations. Conclusions We identified factors that could impact on ADL and/or IADL limitations in older patients with cancer. The information on these determinants is useful in clinical settings to identify patients with cancer at high risk of functional decline.

PubMedID: 31038179 Background: There is no consensus regarding the timing of dialysis therapy initiation for end-stage kidney disease (ESKD) in children. As studies investigating the association between timing of dialysis initiation and clinical outcomes are lacking, we aimed to study this relationship in a cohort of European children who started maintenance dialysis treatment. Methods: We used data on 2963 children from 21 different countries included in the European Society of Pediatric Nephrology/European Renal Association-European Dialysis and Transplant Association Registry who started renal replacement therapy before 18 years of age between 2000 and 2014. We compared two groups according to the estimated glomerular filtration rate (eGFR) at start: eGFR ?8 mL/min/1.73 m2 (early starters) and eGFR

Background and Purpose— The role of dietary fat on cardiovascular health and mortality remains under debate. Because the APOE is central to the transport and metabolism of lipids, we examined associations between plasma fatty acids and the risk of stroke, coronary heart disease, and mortality by APOE-ε4 genotype. Methods— We included 943 FHS (Framingham Heart Study) and 1406 3C (Three-City) Bordeaux Study participants. Plasma docosahexaenoic, linoleic, arachidonic, and palmitic fatty acids were measured at baseline by gas chromatography. All-cause stroke, ischemic stroke, coronary heart disease, and all-cause mortality events were identified prospectively using standardized protocols. Each cohort used Cox models to separately relate fatty acid levels to the risk of developing each event during ≤10 years of follow-up adjusting for potential confounders and stratifying by APOE genotype (ε4 carriers versus noncarriers). We then meta-analyzed summary statistics using random-effects models. Results— On average, participants had a mean age of 74 years, 61% were women, and 21% (n=483) were APOE-ε4 carriers. Meta-analysis results showed that, only among APOE-ε4 carriers, every SD unit increase in linoleic acid was associated with a reduced risk of all-cause stroke (hazard ratio [HR], 0.54 [95% CI, 0.38–0.78]), ischemic stroke (HR, 0.48 [95% CI, 0.33–0.71]), and all-cause mortality (HR, 0.70 [95% CI, 0.57–0.85]). In contrast, every SD unit increase in palmitic acid was related to an increased risk of all-cause stroke (HR, 1.58 [95% CI, 1.16–2.17]), ischemic stroke (HR, 1.76 [95% CI, 1.26–2.45]), and coronary heart disease (HR, 1.48 [95% CI, 1.09–2.01]), also in APOE-ε4 carriers only. Results for docosahexaenoic acid and arachidonic acid were heterogeneous between cohorts. Conclusions— These exploratory results suggest that APOE-ε4 carriers may be more susceptible to the beneficial or adverse impact of fatty acids on cardiovascular disease and mortality. In this subgroup, higher linoleic acid was protective for stroke and mortality, whereas palmitic acid was a risk factor for stroke and coronary heart disease. The mechanisms underlying these novel findings warrant further investigation.

Few data are available regarding dietary habits of the elderly, especially about dairy products (DPs) (total DP and milk, fresh DP, and cheese), whereas these are part of healthy habits. The aim was to describe the socio-demographic characteristics, food, and nutritional intakes of elderly DP consumers. The sample consisted of 1584 participants from the Three-City-Bordeaux cohort (France), who answered a food frequency questionnaire and a 24-h dietary recall. Socio-demographic characteristics, practice of physical activity, Body Mass Index, and polymedication were registered. The sample was 76.2 years (SD 5.0 years) on average, 35% were in line with the French dietary guidelines for DP (3 or 4 servings of DP/day), while 49% were below, and 16% above. Women were significantly more likely to declare the highest total DP (&ge, 4 times/day), milk (&gt, 1 time/day), and fresh DP (&gt, 1.5 times/day) frequency consumption. The highest cheese frequency consumers (&gt, 1.5 times/day) were more likely men, married, and ex-smokers. The highest frequency of fresh DP intake was significantly associated with the lowest energy and lipid intakes, and that of cheese with the highest consumption of charcuteries, meat, and alcohol. This cross-sectional analysis confirmed that the socio-demographics and dietary characteristics varied across DP sub-types consumed, which encourages individual consideration of these confounders in further analyses.

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.

IntroductionGuidelines for the treatment of steroid-dependent nephrotic syndrome (SDNS) and frequently relapsing nephrotic syndrome (FRNS) are lacking. Given the substantial impact of SDNS/FRNS on quality of life, strategies aiming to provide long-term remission while minimising treatment side effects are needed. Several studies confirm that rituximab is effective in preventing early relapses in SDNS/FRNS; however, the long-term relapse rate remains high (~70% at 2 years). This trial will assess the association of intravenous immunoglobulins (IVIgs) to rituximab in patients with SDNS/FRNS and inform clinicians on whether IVIg’s immunomodulatory properties can alter the course of the disease and reduce the use of immunosuppressive drugs and their side effects.Methods and analysisWe conduct an open-label multicentre, randomised, parallel group in a 1:1 ratio, controlled, superiority trial to assess the safety and efficacy of a single infusion of rituximab followed by IVIg compared with rituximab alone in childhood-onset FRNS/SDNS. The primary outcome is the occurrence of first relapse within 24 months. Patients are allocated to receive either rituximab alone (375 mg/m²) or rituximab followed by IVIg, which includes an initial Ig dose of 2 g/kg, followed by 1.5 g/kg injections once a month for the following 5 months (maximum dose: 100 g).Ethics and disseminationThe study has been approved by the ethics committee (Comité de Protection des Personnes) of Ouest I and authorised by the French drug regulatory agency (Agence Nationale de Sécurité du Médicament et des Produits de Santé). Results of the primary study and the secondary aims will be disseminated through peer-reviewed publications.Trial registration numberNCT03560011.

International audience; The age-associated reduction in the proliferation of neural stem cells (NSCs) has been associated with cognitive decline. Numerous factors have been shown to modulate this process, including dietary components. Frequent consumption of caffeine has been correlated with an increased risk of cognitive decline, but further evidence of a negative effect on hippocampal progenitor proliferation is limited to animal models. Here, we used a human hippocampal progenitor cell line to investigate the effects of caffeine on hippocampal progenitor integrity and proliferation specifically. The effects of five caffeine concentrations (0 mM = control, 0.1 mM ∼ 150 mg, 0.25 mM ∼ 400 mg, 0.5 mM ∼ 750 mg, and 1.0 mM ∼ 1500 mg) were measured following acute (1 day) and repeated (3 days) exposure. Immunocytochemistry was used to quantify hippocampal progenitor integrity (i.e., SOX2- and Nestin-positive cells), proliferation (i.e., Ki67-positive cells), cell count (i.e., DAPI-positive cells), and apoptosis (i.e., CC3-positive cells). We found that progenitor integrity was significantly reduced in supraphysiological caffeine conditions (i.e., 1.0 mM ∼ 1500 mg), but relative to the lowest caffeine condition (i.e., 0.1 mM ∼ 150 mg) only. Moreover, repeated exposure to supraphysiological caffeine concentrations (i.e., 1.0 mM ∼ 1500 mg) was found to affect proliferation, significantly reducing % Ki67-positive cells relative to control and lower caffeine dose conditions (i.e., 0.1 mM ∼ 150 mg and 0.25 mM ∼ 400 mg). Caffeine treatment did not influence apoptosis and there were no significant differences in any measure between lower doses of caffeine (i.e., 0.1 mM, 0.25 mM, 0.5 mM) - representative of daily human caffeine intake - and control conditions. Our study demonstrates that dietary components such as caffeine can influence NSC integrity and proliferation and may be indicative of a mechanism by which diet affects cognitive outcomes.

[EN] Several studies have investigated the differential vulnerability of hippocampal subfields during aging and Alzheimer's disease (AD). Results were often contradictory, mainly because these works were based on concatenations of cross-sectional measures in cohorts with different ages or stages of AD, in the absence of a longitudinal design. Here, we investigated 327 participants from a population-based cohort of nondemented older adults with a 14-year clinical follow-up. MRI at baseline and 4 years later were assessed to measure the annualized rates of hippocampal subfields atrophy in each participant using an automatic segmentation pipeline with subsequent quality control. On the one hand, CA4 dentate gyrus was significantly more affected than the other subfields in the whole population (CA1-3: -0.68%/year; subiculum: -0.99%/year; and CA4-DG: -1.39%/year; p < 0.0001). On the other hand, the annualized rate of CA1-3 atrophy was associated with an increased risk of developing Alzheimer's clinical syndrome over time, independently of age, gender, educational level, and ApoE4 genotype (HR = 2.0; CI 95% 1.4-3.0). These results illustrate the natural history of hippocampal subfields atrophy during aging and AD by showing that the dentate gyrus is the most vulnerable subfield to the effects of aging while the cornu-ammonis is the primary target of AD pathophysiological processes, years before symptom onset., The 3C Study is conducted under a partnership agreement among the Institut National de la Sante et de la Recherche Medicale (INSERM), Bordeaux University, and Sanofi. The Fondation pour la Recherche Medicale funded the preparation and initiation of the study. The 3C Study is also supported by Caisse Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sante, Mutuelle Generale de l'Education Nationale, Institut de la Longevite, Conseils Regionaux d'Aquitaine et Bourgogne, Fondation de France, and the Ministry of Research-INSERM Programme "Cohortes et collections de donnees biologiques". The follow-ups have also been funded by ANR 2007LVIE 003, the "Fondation Plan Alzheimer," and the Caisse Nationale de Solidarite pour l'Autonomie (CNSA). This work benefited from the support of the project DeepvolBrain of the French National Research Agency (ANR-18-CE45-0013) and by the Spanish DPI2017-87743-R grant from the Ministerio de Economia, Industria y Competitividad of Spain. In addition, this study was achieved within the context of the Laboratory of Excellence TRAIL ANR-10-LABX-57 for the BigDataBrain project. Finally, the authors thank the Investments for the future Program IdEx Bordeaux (ANR10-IDEX-03-02, HL-MRI Project), Cluster of excellence CPU, and the CNRS. VP also received grants from Fondation Bettencourt Schueller (CCA-Inserm-Bettencourt). The sponsors did not participate in any aspect of the design or performance of the study, including data collection, management, analysis, and the interpretation or preparation, review, and approval of the manuscript.

International audience; PURPOSE:To report the incidence of acute postoperative endophthalmitis (POE) after macular surgery in France between 2006 and 2016 and to identify associated factors.METHODS:This retrospective database study included all hospital discharge records involving a surgical procedure for an epiretinal membrane or a macular hole in France from January 2006 to October 2016. Acute POE was identified by two codes in the tenth edition of the International Classification of Diseases within 42 days of a macular surgical procedure in the French national administrative database.RESULTS:In France, 152 034 macular surgical procedures for epiretinal membranes or macular holes were recorded from 1 January 2006 to 31 October 2016. Suspected acute POE was reported in 381 cases. The incidence of POE was 0.25% overall, 0.30% for epiretinal membrane surgery and 0.14% for macular hole surgery. In multivariable Poisson regression analysis, epiretinal membrane surgery was associated with POE [incidence rate ratio (IRR), 2.24; 95% CI, 1.62-3.11; p < 0.001]. For epiretinal membrane surgery, the 2010-2011 period was significantly associated with a higher risk of POE (IRR, 1.66; 95% CI, 1.13-2.42; p = 0.03).CONCLUSION:The incidence of POE after macular surgery was 0.25% overall in France between 2006 and 2016 and twice higher for epiretinal membrane surgery than for macular hole surgery. For epiretinal surgery only, the incidence of POE was higher in 2010-2011 (period of the switch to transconjunctival vitrectomy) than in the rest of the study period.

To assess the evolution in prevalence, awareness and control of hypertension for over 10 years in Pernambuco State, Northeast Brazil, two cross-sectional studies were conducted based on random samples of households in urban and rural areas, in 2006 and 2015/2016, involving adults aged 20 years or older. Hypertension was defined as systolic blood pressure of at least 140mmHg or diastolic blood pressure of at least 90mmHg as well as the reported use of antihypertensive medication. A logistic regression analysis was conducted to estimate the influence of the social, behavioral and anthropometric determinants on hypertension. Although social and behavioral factors improved in this 10-year period, overweight and abdominal obesity increased. Approximately one third of the adult population of Pernambuco had hypertension in 2006 and this prevalence was maintained in 2015/2016. In rural areas, awareness concerning hypertension rose from 44.8% in 2006 to 67.3% in 2015/2016, and control from 5.3% to 27.1%, so that awareness and control were similar in urban and rural areas in 2015/2016. After an adjustment for potential confounding factors, the likelihood of having hypertension more than doubled among men (OR = 2.03; p < 0.001), middle (OR = 4.41; p < 0.001) and old-age subjects (OR = 14.44; p < 0.001), and those who had abdominal obesity (OR = 2.04; p < 0.001) in urban areas and among middle-aged (OR = 2.56; p < 0.001), less educated individuals (OR = 2.21; p = 0.006) and those who were overweight (OR = 2.23; p < 0.001) in rural areas. Despite the favorable evolution in the management of hypertension in Pernambuco, public health measures focused in vulnerable populations are still required, mainly in rural areas, to improve primary prevention and decrease the disease rate. Resumo: O estudo teve como objetivo avaliar a evolução da prevalência, conhecimento e controle da hipertensão arterial ao longo de 10 anos no Estado de Pernambuco, Nordeste do Brasil. Foram realizados dois estudos transversais em amostras aleatórias em domicílios em áreas urbanas e rurais, em 2006 e 2015/2016, incluindo adultos com 20 anos ou mais. A hipertensão arterial foi definida como pressão sistólica de pelo menos 140mmHg ou pressão diastólica de pelo menos 90mmHg ou o uso referido de medicação anti-hipertensiva. Foi realizada análise de regressão logística para estimar a influência dos determinantes sociais, comportamentais e antropométricos sobre a hipertensão. Os fatores sociais e comportamentais melhoraram ao longo da década em questão, mas as taxas de sobrepeso e de obesidade abdominal aumentaram. Aproximadamente um terço da população adulta de Pernambuco apresentava hipertensão em 2006, e essa prevalência foi mantida em 2015/2016. Nas áreas rurais, o conhecimento da hipertensão aumentou de 44,8% em 2006 para 67,3% em 2015/2016, e o controle aumentou de 5,3% para 27,1%, de maneira que o conhecimento e o controle foram muito semelhantes entre áreas urbanas e rurais em 2015/2016. Após ajustar para potenciais fatores de confusão, a probabilidade de apresentar hipertensão mais do que dobrou entre homens (OR = 2,03; p < 0,001), adultos jovens (OR = 4,41; p < 0,001) e idosos (OR = 14,44; p < 0,001), e entre aqueles com obesidade abdominal (OR = 2,04; p < 0,001) nas áreas urbanas e adultos jovens (OR = 2,56; p < 0,001), pessoas com menor escolaridade (OR = 2,21; p = 0,006) e pessoas com sobrepeso (OR = 2,23; p < 0,001) nas áreas rurais. Apesar da evolução favorável no manejo da hipertensão no Estado de Pernambuco, são necessárias medidas de saúde pública focadas nas populações mais vulneráveis, principalmente nas áreas rurais, para melhorar a prevenção primária e impedir o aumento da hipertensão. Resumen: El objetivo de este estudio fue evaluar la evolución de la prevalencia, concienciación y control de la hipertensión durante 10 años en el Estado de Pernambuco, Nordeste brasileño. Se llevaron a cabo dos estudios transversales, basados en muestras aleatorias de hogares ubicados en áreas urbanas y rurales, en 2006 y 2015/2016, implicando a adultos con 20 años y más edad. La hipertensión fue definida como presión arterial sistólica de al menos 140mmHg, presión arterial diastólica de al menos 90mmHg, o el consumo informado de medicación antihipertensiva. Se realizó un análisis de regresión logística para estimar la influencia de los determinantes sociales, comportamentales y antropométricos en la hipertensión. Los factores sociales y comportamentales mejoraron durante este período de 10 años, a pesar de que sobrepeso y la obesidad abdominal aumentaron. Aproximadamente un tercio de la población adulta de Pernambuco sufría hipertensión en 2006 y esta prevalencia se mantuvo en 2015/2016. En las áreas rurales, la concienciación sobre la hipertensión aumentó de un 44,8% en 2006, a un 67,3% en 2015/2016, y el control de un 5,3% a un 27,1%, así pues la concienciación y control fueron similares en áreas urbanas y rurales en 2015/2016. Tras el ajuste para los factores potenciales de confusión, la probabilidad de sufrir hipertensión es más del doble entre hombres (OR = 2,03; p < 0,001) de mediana edad (OR = 4,41; p < 0,001) e individuos de edad avanzada (OR = 14,44; p < 0,001), y aquellos que sufrieron obesidad abdominal (OR = 2,04; p < 0,001) en áreas urbanas, y entre los de mediana edad (OR = 2,56; p < 0,001), individuos menos educados (OR = 2,21; p = 0,006) y quienes sufrían sobrepeso (OR = 2,23; p < 0,001) en áreas rurales. A pesar de la evolución favorable en la gestión de la hipertensión en Pernambuco, se necesitan medidas de salud pública que se centren en las poblaciones vulnerables, principalmente en las áreas rurales, para mejorar la prevención primaria y frenar el incremento de la enfermedad.

Background Physical activity may decrease the risk of dementia; however, previous cohort studies seldom investigated the different types of physical activity and household activities. Our objective was to analyze the links between two physical activity types and dementia in older people. Methods The study used data from the prospective observational Three-city cohort and included 1550 community-dwelling individuals aged 72 to 87 without dementia at baseline. Physical activity was assessed with the Voorrips questionnaire. Two sub-scores were calculated to assess household/transportation activities and leisure/sport activities. Restricted cubic spline and proportional hazard Cox models were used to estimate the non-linear exposure-response curve for the dementia risk and the appropriate activity level thresholds. Models were adjusted for possible confounders, including socio-demographic variables, comorbidities, depressive symptoms and APOE genotype. Results The median age was 80 years, and 63.6% of participants were women. After a median follow-up of 4.6 years, dementia was diagnosed in 117 participants (7.6%). An inverse J-shaped association was found between household/transportation physical activity sub-score and dementia risk, which means that the risk is lowest for the moderately high values and then re-increases slightly for the highest values. The results remained significant when this sub-score was categorized in three classes (low, moderate, and high), with hazard ratios (95% confidence interval) of 0.55 (0.35–0.87) and 0.62 (0.38–1.01) for moderate and high activity levels, respectively. No significant effect was found for leisure/sport activities. Conclusions The 5-year risk of dementia was significantly and negatively associated with the household/transportation activity level, but not with the leisure and sport activity sub-score. This highlights the importance of considering all physical activity types in 72 years or older people.

Older persons comprise a growing proportion of the European population and may have a distinct epidemiological oral profile requiring specific preventive and curative care poorly documented. The objectives of this study were to assess the oral health status of people ≥90 years of age in France, to compare their perceived and observed oral care needs and to investigate the oral problems associated with a low oral health-related quality-of-life (OHRQoL).An oral cross-sectional study was performed during the 25th follow-up of a cohort of older persons being followed up prospectively for screening of dementia over a 15-year period in Gironde and Dordogne, France. Clinical oral indices were determined by oral examinations conducted at the participants' place of living. Cohen's Kappa coefficient was used to assess the agreement between perceived and observed oral care needs. Oral problems associated with a low OHRQoL, measured with the Geriatric Oral Health Assessment Index (GOHAI50) were investigated with logistic regression. Odds ratios (OR) were estimated with their 95% confidence intervals (CI).Data from 90 persons were analysed (76% female; median age=93 years; 20% living in an institution). Plaque and calculus were present in 93% and 58% respectively, of the 74 dentate participants. The mean number of decayed, missing, and filled teeth was 26.5 (±5.3); 66% of the participants had at least one untreated decayed tooth. Among the 85 participants with tooth loss not replaced by a fixed denture, two thirds had a removable dental prosthesis; 84% of these prostheses were considered to be maladapted. Among the 39 participants who felt unable to consult a dentist (43%), lack of transportation was the most frequently cited reason. Although 88% of the participants needed oral care, only 26% perceived that they had such a need (Kappa=0.06). Oral problems associated with a GOHAI50 were the absence of posterior occluding teeth (OR=7.15; 95%CI=1.53-33.35; P=0.012), feeling of dry mouth (OR=11.94; 95%CI=3.21-44.39; P=0.0002) and oral pain (OR=9.06; 95%CI=1.91-69.00; P=0.033).Persons ≥90 years of age have considerable preventive and curative dental care needs that impact their quality-of-life but they are rarely aware and lack transportation. NCT04065828.

BACKGROUND: While physical frailty and malnutrition/obesity (parameters easily measured by a nurse) are not the same, older persons who are malnourished/obese are more likely to be frail and there is a potential overlap between these conditions. The objective was to examine the relationship between gait speed (GS) and body mass index (BMI) in men and women aged 75 years and older. DESIGN: Cross-sectional analysis. SETTING, PARTICIPANTS: Data from the Aging Multidisciplinary Investigation (AMI), a French prospective cohort study with participants randomly selected from the farmer Health Insurance rolls. MEASUREMENTS: Usual GS was measured over a 4 meters-track. BMI was categorized using clinical cut-points for European populations: (e.g

Background: Diet has been recognized as a modifiable risk factor for breast cancer. Highlighting predictive diet-related biomarkers would be of great public health relevance to identify at-risk subjects. The aim of this exploratory study was to select diet-related metabolites discriminating women at higher risk of breast cancer using untargeted metabolomics. Methods: Baseline plasma samples of 200 incident breast cancer cases and matched controls, from a nested case–control study within the Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) cohort, were analyzed by untargeted LC-MS. Diet-related metabolites were identified by partial correlation with dietary exposures, and best predictors of breast cancer risk were then selected by Elastic Net penalized regression. The selection stability was assessed using bootstrap resampling. Results: 595 ions were selected as candidate diet–related metabolites. Fourteen of them were selected by Elastic Net regression as breast cancer risk discriminant ions. A lower level of piperine (a compound from pepper) and higher levels of acetyltributylcitrate (an alternative plasticizer to phthalates), pregnene-triol sulfate (a steroid sulfate), and 2-amino-4-cyano butanoic acid (a metabolite linked to microbiota metabolism) were observed in plasma from women who subsequently developed breast cancer. This metabolomic signature was related to several dietary exposures such as a “Western” dietary pattern and higher alcohol and coffee intakes. Conclusions: Our study suggested a diet-related plasma metabolic signature involving exogenous, steroid metabolites, and microbiota-related compounds associated with long-term breast cancer risk that should be confirmed in large-scale independent studies. Impact: These results could help to identify healthy women at higher risk of breast cancer and improve the understanding of nutrition and health relationship.

International audience; PURPOSE: Ocular and brain microcirculation share embryological and histological similarities. The retinal vascular fractal dimension (FD) is a marker of retinal vascular complexity of the vascular tree. The purpose of this study was to explore the relationship between cerebral blood flow (CBF), retinal vascular FD and other retinal vascular markers. METHODS: Cross-sectional analysis comprising 26 individuals >/=65 years old from the Cognitive REServe and Clinical ENDOphenotype (CRESCENDO) cohort of relative healthy older adults. Retinal vascular FD was measured from fundus photographs by using the semi-automated Singapore Eye Vessel Assessment (SIVA) software. CBF was estimated using a 2D pulsed ASL MRI sequence. Associations between blood flow and retinal parameters were analysed using linear regression models adjusted for age and sex. RESULTS: Cerebral blood flow was positively associated with venular FD (R(2) = 0.32, p = 0.03). This association was stronger in the anterior versus posterior brain territories (R(2) = 0.35 [p = 0.001] versus R(2) = 0.16 [p = 0.07], respectively). Global CBF was correlated with arteriolar branching angle (R(2) = 0.23, p = 0.01) and tortuosity (R(2) = 0.20, p = 0.02). Global CBF was not correlated with other SIVA parameters. CONCLUSIONS: Retinal venular complexity summarized by the FD was associated with cerebral blood flow as well as retinal arteriolar tortuosity and branching angle. Larger prospective clinical studies are needed to confirm these results.

Aims Does Diabetic Retinopathy (DR) relate to a previous dramatic reduction of HbA1c in Type 2 Diabetes (T2D)? Methods In patients hospitalized for T2D, we collected HbA1c values from previous years, and we defined “Rapid declinors” by a more than −3% reduction between two consecutive HbA1c, and “sustained moderate declinors” by HbA1c declining less than −3%. We analyzed the relation between DR and previous HbA1c courses, adjusted for other risk factors. Results Our 680 patients had a mean HbA1c at 8.7 ± 1.7% at admission and 8.7 ± 1.8 to 9.0 ± 2.2% during previous years (1500 HbA1C values collected), and 24% had a DR. A previous rapid decline of HbA1c occurred in 13.5% of subjects and related to DR (OR = 1.86, 95%CI:1.02–3.40), especially proliferative (OR = 2.64, 95%CI:1.02–6.80), after adjustment for age, gender, body mass index, arterial hypertension and diabetic kidney disease, blood lipids and statin treatment, duration of diabetes and mean previous HbA1c. A previous moderate reduction of HbA1c as occurred in 28.3% other subjects was not related to DR. Conclusions In subjects hospitalized for T2D, a previous rapid decline of HbA1c was related to proliferative DR, whereas a sustained moderate decline appeared to be safe.

Background. Nut consumption may reduce age-related diseases and lead to better health and well-being in aging. Many conditions of aging develop over decades, and thus earlier lifestyle factors may particularly influence later health. Methods. In 1998 and 2002, we administered food frequency questionnaires to assess nut consumption (peanuts, walnuts, and other nuts and peanut butter) in women in the Nurses’ Health Study in their 50 s/early 60 s. In 2012, those who survived beyond 65 years with no chronic diseases, no reported memory impairment, no physical disabilities, and intact mental health were considered “healthy agers.” We used multivariable logistic regression to estimate odds ratios for healthy versus usual aging, controlled for sociodemographic, behavioral, dietary, and other potential confounding factors. Results. Of 33,931 participants at midlife, 16% became “healthy agers.” After age adjustment, we observed a significant association between total nut consumption at midlife and higher odds of healthy aging, with strongest associations observed excluding peanut butter (odds ratio (OR) = 1.46, 95% confidence interval (CI) 1.32–1.62, ≥3 servings/week versus none). Findings were attenuated after further control for covariates, including overall diet quality (OR = 1.14, 95% CI 1.02–1.28, P trend = 0.05). For nut types, we found statistically significantly higher odds of healthy aging across peanuts, walnuts, and other nuts after age adjustment. After full control for confounders, only walnut consumption remained associated with healthy aging (P trend = 0.0001); for example, the OR was 1.20 (95% CI 1.00–1.44) for ≥2 servings/week versus none. Conclusions. Women consuming nuts at midlife have a greater likelihood of overall health and well-being at older ages. Nut consumption may represent a simple intervention to explore and promote healthy aging.

Background Relapsing nephrotic syndrome (NS) after transplantation can be a challenge to treat. The result of the consequent long-lasting proteinuria is the loss of the graft. Disease recurrence after renal transplantation occurs in around half of cases, and the efficacy of therapeutic strategies is often limited. Recently, ofatumumab, a second-generation and fully human anti-CD20 monoclonal antibody, has been shown to be effective in severe situations. Methods We retrospectively collected data from the medical records of children with recurrence of NS after renal transplantation treated with ofatumumab in France, after failure of previous treatments. Results Six patients were included in this study in five centers with a median duration of follow-up of 10.5 months. Two different ofatumumab regimens were administered. The primary outcome was proteinuria at 6 months after the last dose of ofatumumab. No patient achieved a complete remission, 3/6 had a partial remission, and 3/6 had no response to ofatumumab. Four patients exhibited a minor allergic reaction with the first infusion. One patient died of infection, as a consequence of multiple factors. No malignancies were observed; however, the time of follow-up was not sufficient to see such disease. Conclusions Altogether, these results suggest ofatumumab has a poor efficacy in treating recurrence of NS after renal transplantation. However, it could be discussed in multidrug-resistant refractory NS, but infectious complications and overimmunosuppression have to be balanced. There is a need for further studies to confirm these findings and safety and to determine a standardized protocol in this indication.

While the neural correlates of age-related episodic memory decline have been extensively studied, the precise involvement of the Posterior Cingulate Cortex (PCC) and posterior parietal cortex (the precuneus and the angular gyrus), remains unclear. The present study examined functional and structural neural correlates of age-related episodic memory change assessed over 12 years in 120 older adults (range 76-90 years). Episodic memory performance was measured using the Free and Cued Selective Reminding Test (FCSRT); functional connectivity metrics were computed from resting-state fMRI images and structural connectivity metrics were assessed through microstructural properties of reconstructed tract using a native space pipeline. We found that FCSRT change was significantly associated with the functional connectivity between the ventral PCC and three parietal regions, the ventral superior, the inferior part of the precuneus, and the rostro dorsal part of the angular gyrus. This association was independent of hippocampal volume. In addition, we found the that change in FCSRT scores was associated with fractional anisotropy of the tract connecting the ventral PCC and the ventral superior part of the precuneus. Change in episodic memory in aging was therefore related to a combination of high functional connectivity and low structural connectivity between the ventral PCC and the ventral superior part of the precuneus.

Background and AimsThe association between hyperuricemia and CKD progression is not well established in Europe and, to our knowledge, has not yet been investigated using longitudinal measurements.MethodWe used data from CKD-REIN, a prospective cohort study conducted in 40 representative French nephrology clinics, which included 3033 patients with CKD stages 3 to 5 between 2013 and 2016. Patients who had no serum uric acid or no creatinine measure at within 6 months of their inclusion date in the CKD-REIN study were excluded. All uric acid measures were taken into account, from inclusion to the occurrence of renal replacement therapy (RRT), death, or end of follow-up, whichever came first. We used a shared random-effect model for the joint analysis of individual trajectories of uric acid and the hazard of the composite outcome (RRT or death before RRT) and each specific event separately. Hazard ratio were adjusted (aHR) for age, sex, primary kidney disease, metabolic syndrome, cardiovascular disease, proteinuria (< 30, 30-300, > 300 mg/day), and the CKD-EPI estimated glomerular filtration rate (eGFR) at baseline. In a sensitivity analysis, we further adjusted for individual eGFR trajectory.ResultsA total of 2781 patients (65.5% men, median age 69 years) were included. At baseline, the median eGFR was 31.8 mL/min/1.73m2 and the median uric acid value was 425 µmol/L. During a median follow-up of 3.2 years, 434 patients received RRT and 264 died before RRT. At any time of follow-up, an increase of 100 µmol/l of the current value of uric acid was associated with a 16% increased hazard of RRT or death before RRT (aHR 1.16, 95% CI 1.07-1.26). The estimated effect of uric acid was similar with RRT (aHR 1.18, 95% CI 1.04-1.34) and death before RRT (aHR 1.16, 95% CI 1.05-1.28). When further adjusted for eGFR trajectory, the estimated effect of uric acid on the composite outcome was much weaker (aHR 1.06, 95% CI 0.98-1.16).ConclusionA higher current level of uric acid is associated with a strong increase in the hazard of RRT or death before RRT in European patients with CKD stage 3 to 5. However, the association is much weaker after adjustment for eGFR trajectory. Further analyses are necessary to better understand the dynamic of the association between uric acid and GFR.

Introduction Prodromal non-motor symptoms precede, often by decades, motor signs and diagnosis of Parkinson's disease. It is however still uncertain if cognitive changes belong to the spectrum of non-motor prodromal Parkinson's disease. Thanks to the very long-term follow-up of the PAQUID population-based cohort, we assessed trajectories of cognitive complaints and functioning over a 13-year period before the diagnosis of late onset Parkinson's disease. Methods This study relies on a matched nested case-control sample selected from the cohort. Of the 3777 initial subjects of the cohort, 43 developed incident Parkinson's disease over the follow-up. The mean age at diagnosis was 78.0 (standard deviation = 5.8) years and 46.5% were men. These cases were matched to 86 elderly control subjects. Scores of different cognitive domains, daily function, and depressive symptoms were described throughout the follow-up using mixed-effects models. Results No significant global cognitive decline preceded the diagnosis of late onset Parkinson's disease. However, psychomotor speed appeared significantly slower 2 years before the diagnosis and depressive symptoms 12 years before. Global score of instrumental activities of daily living became altered 2–3 years preceding the diagnosis of late onset Parkinson's disease, including the use of public transportation that was altered ten years before the diagnosis. Conclusion In late onset Parkinson's disease, while global cognitive functions seem preserved, psychomotor speed starts to decline 2 years before the diagnosis and activities of daily living are also impacted. Depressive symptoms appear very early in the prediagnosic phase.

IMPORTANCE: Although retinal multimodal imaging is needed for diagnosing reticular pseudodrusen (RPD), the incidence of RPD in the general population typically has been assessed only using fundus photographs, which may underestimate their incidence. OBJECTIVES: To describe the incidence of RPD using retinal color photographs, spectral-domain optical coherence tomography scans, fundus autofluorescence, and near-infrared reflectance images among individuals 77 years of age or older and to analyze the associated risk factors of RPD. DESIGN, SETTING, AND PARTICIPANTS: The ALIENOR (Antioxydants, Lipides Essentiels, Nutrition et Maladies Oculaires) Study is a cohort of French individuals 77 years of age or older. Data for this study were collected between February 22, 2011, and February 15, 2017, with a mean (SD) follow-up of 3.7 (1.0) years (range, 1.2-5.6 years). At baseline, 501 individuals were eligible to participate. Of 1002 eyes, 197 had prevalent RPD, advanced age-related macular degeneration, or ungradable images. Of the remaining 805 eyes, 333 were missing follow-up data; therefore, the statistical analyses included data from 472 eyes. Data management and statistical analyses were performed between March 15, 2017, and April 5, 2019. MAIN OUTCOMES AND MEASURES: Reticular pseudodrusen were considered as present if detected by at least 2 of the following imaging methods: color fundus photographs, fundus autofluorescence, near-infrared reflectance, and spectral-domain optical coherence tomography images. RESULTS: Of the 472 eyes analyzed, 263 (55.7%) were from female participants, and the mean (SD) age was 81.9 (3.2) years. Forty-three eyes developed RPD, corresponding to an annual incidence rate of 2.9% (95% CI, 1.9%-4.4%) per participant and an estimated 5-year risk of 13.5%. In multivariable analysis, 4 risk factors of incident RPD were identified: subfoveal choroidal thinning (hazard ratio [HR], 0.99; 95% CI, 0.99-1.00 per 10-μm decrease in thickness; P = .02) and the presence of the minor allelic variants rs10490924 for ARMS2 (HR, 3.57; 95% CI, 1.80-7.10; P

AimsDoes Diabetic Retinopathy (DR) relate to a previous dramatic reduction of HbA1c in Type 2 Diabetes (T2D)?MethodsIn patients hospitalized for T2D, we collected HbA1c values from previous years, and we defined “Rapid declinors” by a more than −3% reduction between two consecutive HbA1c, and “sustained moderate declinors” by HbA1c declining less than −3%. We analyzed the relation between DR and previous HbA1c courses, adjusted for other risk factors.ResultsOur 680 patients had a mean HbA1c at 8.7 ± 1.7% at admission and 8.7 ± 1.8 to 9.0 ± 2.2% during previous years (1500 HbA1C values collected), and 24% had a DR. A previous rapid decline of HbA1c occurred in 13.5% of subjects and related to DR (OR = 1.86, 95%CI:1.02–3.40), especially proliferative (OR = 2.64, 95%CI:1.02–6.80), after adjustment for age, gender, body mass index, arterial hypertension and diabetic kidney disease, blood lipids and statin treatment, duration of diabetes and mean previous HbA1c. A previous moderate reduction of HbA1c as occurred in 28.3% other subjects was not related to DR.ConclusionsIn subjects hospitalized for T2D, a previous rapid decline of HbA1c was related to proliferative DR, whereas a sustained moderate decline appeared to be safe.

Healthy lifestyles are promising targets for prevention of cognitive aging, yet the optimal time windows for interventions remain unclear. We selected a case-control sample nested within the Nurses’ Health Study (starting year 1976, mean age = 51 years), including 14,956 women aged ≥70 years who were free of both stroke and cognitive impairment at enrollment in a cognitive substudy (1995–2001). Cases (n = 1,496) were women with the 10% worst slopes of cognitive decline, and controls (n = 7,478) were those with slopes better than the median. We compared the trajectories of body mass index (weight (kg)/height (m)2), alternate Mediterranean diet (A-MeDi) score, and physical activity between groups, from midlife through 1 year preceding the cognitive substudy. In midlife, cases had higher body mass index than controls (mean difference (MD) = 0.59 units, 95% confidence interval (CI): 0.39, 0.80), lower physical activity (MD = –1.41 metabolic equivalent of task–hours/week, 95% CI: –2.07, –0.71), and worse A-MeDi scores (MD = –0.16 points, 95% CI: –0.26, –0.06). From midlife through later life, compared with controls, cases had consistently lower A-MeDi scores but a deceleration of weight gain and a faster decrease in physical activity. In conclusion, maintaining a healthy lifestyle since midlife may help reduce cognitive decline in aging. At older ages, both deceleration of weight gain and a decrease in physical activity may reflect early signs of cognitive impairment.

Background Ketoacidosis is a severe metabolic complication mainly reported in diabetic patients. Therapeutic fasting is a millennial worldwide practice, believed to improve a large panel of health conditions, but its efficiency and safety profile have not yet been established. We report here a case of euglycemic ketoacidosis in a non-diabetic woman. Case description A 51-year-old woman without a history of excessive alcohol use or medical history, except for a depressive disorder, was admitted in the emergency room for altered general status, deep asthenia, muscular weakness, articular pain, nausea, vomiting, and consciousness disorders. She was practicing during the previous 48 h a therapeutic fasting following a progressive restrictive diet for 4 d. She was diagnosed with ketoacidosis and hospitalized in the intensive care unit. Her laboratory test results indicated pH 7.28, bicarbonate 7 mmol/L, significant ketone bodies, glycemia 8.9 mmol/L without glycosuria, and negative blood alcohol assessment. Glycated hemoglobin was 5.5%, and blood glucose never went above 9 mmol/L. Serum concentrations of free fatty acids were high at 1.13 mmol/L (normal range: 0.13–0.45). Plasma insulin and peptide C were in the normal ranges. Comprehensive plasma and urinary biochemistry panels, including energetic substrates, and chromatography of amino acids and organic acids did not indicate any energetic or metabolic deficiency. The ketoacidosis regressed, and the overall outcome was favorable after intravenous glucose infusion for 48 h, without insulin requirement. Conclusions This report is the first case, to our knowledge, of euglycemic ketoacidosis thought to be induced by therapeutic fasting in a non-diabetic patient. Practitioners should be aware of this complication of fasting.

BackgroundThis study aims to develop a method to estimate the potential of preemptive kidney transplantation (PKT) by identifying patients who were transplanted after a dialysis period (non-preemptive kidney transplantation (NPKT)) despite being medically suitable for PKT.MethodsAll children (

International audience; Introduction: In animal models, refined carbohydrates (RF) worsen Alzheimer's disease (AD). However, the long-term effects of high RF intake on the risk of dementia and AD are poorly described in epidemiological studies. Moreover, the interaction between RF and the apolipoprotein E ε4 allele (APOE-4) is unknown. Our study investigated whether RF-rich diets are associated with the risk of dementia and AD.Methods: The glycemic load (GL) was quantified in 2777 elderly participants from the French Three-City Study to estimate RF intake. Then, the associations between GL and risk of dementia and AD, and the interaction with APOE-4 over a 12-year period were assessed using proportional hazards models.Results: After adjustment for potential confounders, high afternoon-snack GL was associated with increased dementia and AD risk in APOE-4 carriers (hazard ratio = 1.27 [1.03-1.56]).Discussion: This study highlights that RF-rich diets are a risk factor for dementia and AD in APOE-4 carriers.; Introduction : Dans les modèles animaux, les glucides raffinés (RF) aggravent la maladie d'Alzheimer (MA). Cependant, les effets à long terme d'une forte consommation de RF sur le risque de démence et de MA sont peu décrits dans les études épidémiologiques. De plus, l'interaction entre les RF et l'allèle de l'apolipoprotéine E ε4 (APOE-4) est inconnue. Notre étude a cherché à savoir si les régimes alimentaires riches en RF sont associés au risque de démence et de MA.Méthodes : La charge glycémique (GL) a été quantifiée chez 2777 participants âgés de l'étude française des Trois-Cités pour estimer l'apport en RF. Ensuite, les associations entre la GL et le risque de démence et de MA, et l'interaction avec l'APOE-4 sur une période de 12 ans ont été évaluées à l'aide de modèles de risques proportionnels.Résultats : Après ajustement pour les facteurs de confusion potentiels, un taux élevé de GL pendant le goûter a été associé à un risque accru de démence et de MA chez les porteurs d'APOE-4 (rapport de risque = 1,27 [1,03-1,56]).Discussion : Cette étude souligne que les régimes riches en RF sont un facteur de risque de démence et de MA chez les porteurs d'APOE-4.

In biomedical research, various longitudinal markers measuring different quantities are often collected over time. For example, repeated measures of psychometric scores are very informative about the degradation process toward dementia. These trajectories are generally nonlinear with an acceleration of the decline a few years before the diagnosis and a large heterogeneity between psychometric tests depending on the underlying cognitive function to be evaluated and the metrological properties of the test. Comparing the times of acceleration of the decline before diagnosis between cognitive tests is useful to better understand the natural history of the disease. Our objective is to propose a bivariate random changepoint model that allows for the comparison of the mean time of change between two markers. A frequentist approach is proposed that gives validated statistical tests to assess the temporal order of the changepoints. Using a spline transformation function, the model is designed to handle non-Gaussian data, that are common for cognitive scores which frequently exhibit a strong ceiling effect. The procedure is assessed through a simulation study and applied to a French cohort of elderly to identify the order of the decline of several cognitive scores. The whole methodology has been implemented in a R package freely available.

Background and AimsMetabolic acidosis is a common complication of CKD and may contribute to CKD progression. However, the association between serum bicarbonate and CKD progression has not yet been investigated using longitudinal measurements.MethodWe used data from CKD-REIN, a prospective cohort study conducted in 40 representative French nephrology clinics which included 3033 patients with CKD stages 3 to 5 between 2013 and 2016. Patients who had no serum bicarbonate or no creatinine measure at within 6 months of their inclusion date in the CKD-REIN study were excluded. All serum bicarbonate measurements were taken into account, from inclusion to the occurrence of renal replacement therapy (RRT), death, or end of follow-up, whichever came first. We used a shared random-effect model for the joint analysis of individual trajectories of serum bicarbonate and the hazard of the composite outcome (RRT or death before RRT) and each specific event separately. Hazard ratio were adjusted (aHR) for age, sex, primary kidney disease, metabolic syndrome, cardiovascular disease, proteinuria (< 30, 30-300, > 300 mg/day), and the CKD-EPI estimated glomerular filtration rate (eGFR) at baseline.ResultsA total of 2977 patients (65.4% men, median age 69 years) were included. At baseline, the median eGFR was 31.8 mL/min/1.73m2 and the median bicarbonate concentration was 25 mmol/L. During a median follow-up of 4.5 years, 615 patients received RRT and 378 died before RRT. At any time of follow-up, a decrease of 1 mmol/l of the current level of serum bicarbonate was associated with a significantly increased hazard of RRT or death before RRT (aHR 1.05, 95%CI 1.02-1.08). The estimated effect was stronger on death before RRT (aHR 1.05, 95% CI 1.00-1.09) than on RRT (aHR 1.02, 95% CI 0.99-1.06).ConclusionA lower current level of serum bicarbonate is associated with an increased mortality in patients with CKD stage 3 to 5.

Pseudo-values provide a method to perform regression analysis for complex quantities with right-censored data. A further complication, interval-censored data, appears when events such as dementia are studied in an epidemiological cohort. We propose an extension of the pseudo-value approach for interval-censored data based on a semi-parametric estimator computed using penalised likelihood and splines. This estimator takes interval-censoring and competing risks into account in an illness-death model. We apply the pseudo-value approach to three mean value parameters of interest in studies of dementia: the probability of staying alive and non-demented, the restricted mean survival time without dementia and the absolute risk of dementia. Simulation studies are conducted to examine properties of pseudo-values based on this semi-parametric estimator. The method is applied to the French cohort PAQUID, which included more than 3,000 non-demented subjects, followed for dementia for more than 25 years.

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.

International audience; Objective: Extensive research using water-diffusion MRI reported age-related modifications of cerebral White Matter (WM). Moreover, water-diffusion parameter modifications have been frequently associated with cognitive performances in the elderly sample, reinforcing the idea of aging inducing microstructural disconnection of the brain which in turn impacts cognition. However, only few studies really assessed over-time modifications of these parameters and their relationship with episodic memory outcome of elderly. Materials and Methods: One-hundred and thirty elderly subjects without dementia (74.1 +/- 4.1 years; 47% female) were included in this study. Diffusion tensor imaging (DTI) was performed at two-time points (3.49 +/- 0.68 years apart), allowing the assessment of changes in water-diffusion parameters over time using a specific longitudinal pipeline. White matter hyperintensity (WMH) burden and gray matter (GM) atrophy were also measured on FLAIR and T1-weighted sequences collected during these two MRI sessions. Free and cued verbal recall scores assessed at the last follow-up of the cohort were used as episodic memory outcome. Changes in water-diffusion parameters over time were included in serial linear regression models to predict retrieval or storage ability of elderly. Results: GM atrophy and an increase in mean diffusivity (MD) and WMH load between the two-time points were observed. The increase in MD was significantly correlated with WMH load and the different memory scores. In models accounting for the baseline cognitive score, GM atrophy, or WMH load, MD changes still significantly predict free verbal recall, and not total verbal recall, suggesting the specific association with the retrieval deficit in healthy aging. Conclusion: In elderly, microstructural WM changes are good predictors of lower free verbal recall performances. Moreover, this contribution is not only driven by WMH load increase. This last observation is in line with studies reporting early water-diffusion modification in WM tissue during aging, resulting lately in the appearance of WMH on conventional MRI.

BACKGROUND: Nonophthalmologist physicians do not confidently perform direct ophthalmos-copy. The use of artificial intelligence to detect papilledema and other optic-disk abnormalities from fundus photographs has not been well studied METHODS: We trained, validated, and externally tested a deep-learning system to classify optic disks as being normal or having papilledema or other abnormalities from 15,846 retrospectively collected ocular fundus photographs that had been obtained with pharmacologic pupillary dilation and various digital cameras in persons from multiple ethnic populations. Of these photographs, 14,341 from 19 sites in 11 coun-tries were used for training and validation, and 1505 photographs from 5 other sites were used for external testing. Performance at classifying the optic-disk ap-pearance was evaluated by calculating the area under the receiver-operating-characteristic curve (AUC), sensitivity, and specificity, as compared with a reference standard of clinical diagnoses by neuro-ophthalmologists RESULTS: The training and validation data sets from 6779 patients included 14,341 photo-graphs: 9156 of normal disks, 2148 of disks with papilledema, and 3037 of disks with other abnormalities. The percentage classified as being normal ranged across sites from 9.8 to 100%; the percentage classified as having papilledema ranged across sites from zero to 59.5%. In the validation set, the system discriminated disks with papilledema from normal disks and disks with nonpapilledema abnor-malities with an AUC of 0.99 (95% confidence interval [CI], 0.98 to 0.99) and normal from abnormal disks with an AUC of 0.99 (95% CI, 0.99 to 0.99). In the external-testing data set of 1505 photographs, the system had an AUC for the detection of papilledema of 0.96 (95% CI, 0.95 to 0.97), a sensitivity of 96.4% (95% CI, 93.9 to 98.3), and a specificity of 84.7% (95% CI, 82.3 to 87.1).CONCLUSIONSA deep-learning system using fundus photographs with pharmacologically dilated pupils differentiated among optic disks with papilledema, normal disks, and disks with nonpapilledema abnormalities. (Funded by the Singapore National Medical Research Council and the SingHealth Duke–NUS Ophthalmology and Visual Sci-ences Academic Clinical Program.)

PurposeTo analyse and compare the prevalence of epiretinal membranes (ERMs) obtained using either standard retinal colour images or spectral‐domain optical coherence tomography (SD‐OCT) in a population‐based setting of French elderly subjects.MethodsSix hundred twenty‐four subjects of the Alienor cohort aged 75 years or older underwent both colour fundus imaging and SD‐OCT examinations. The ERMs were graded from retinal images and SD‐OCT macular scans in a masked fashion. On SD‐OCT images, the early ERMs, mature contractile ERMs without foveal modifications and mature contractile ERMs with foveal alterations were distinguished.Results610 (97.8%) subjects had gradable SD‐OCT examinations, and 511 (81.9%) had gradable fundus images in at least one eye. According to colour photographs, 11.6% of participants had definite ERMs. From SD‐OCT images, 52.8% of the subjects had early ERMs, 7.4% had mature ERMs without foveal involvement, and 9.7% had mature ERMs with foveal alterations. Regardless of the imaging method used, the ERMs were more often observed in pseudophakic eyes than in phakic eyes. Comparison of ERM assessment using fundus photographs versus SD‐OCT images demonstrated that the specificity of retinal colour images was good (>89.3%), whereas the sensitivity remained low even though it increased with ERM severity on SD‐OCT images.ConclusionsSpectral‐domain optical coherence tomography (SD‐OCT) examinations have high feasibility in this elderly population and are much more sensitive than standard colour images for ERM assessments, especially in the early stages of the disease. Our results further highlight the need to use SD‐OCT instead of colour retinal photographs for the classification of ERMs in epidemiological studies.

Purpose There is an urgent need to address how to best provide ophthalmic care for patients with retinal disease receiving intravitreal injections with anti-vascular endothelial growth factor agents during the ongoing global COVID-19 pandemic. This article provides guidance for ophthalmologists on how to deliver the best possible care for patients while minimizing the risk of infection. Methods The Vision Academy’s Steering Committee of international retinal disease experts convened to discuss key considerations for managing patients with retinal disease during the COVID-19 pandemic. After reviewing the existing literature on the issue, members put forward recommendations that were systematically refined and voted on to develop this guidance. Results The considerations focus on the implementation of steps to minimize the exposure of patients and healthcare staff to COVID-19. These include the use of personal protective equipment, adherence to scrupulous hygiene and disinfection protocols, pre-screening to identify symptomatic patients, and reducing the number of people in waiting rooms. Other important measures include triaging of patients to identify those at the greatest risk of irreversible vision loss and prioritization of treatment visits over monitoring visits where possible. In order to limit patient exposure, ophthalmologists should refrain from using treatment regimens that require frequent monitoring. Conclusion Management of patients with retinal disease receiving intravitreal injections during the COVID-19 pandemic will require adjustment to regular clinical practice to minimize the risk of exposure of patients and healthcare staff, and to prioritize those with the greatest medical need. The safety of patients and healthcare staff should be of paramount importance in all decision-making.