Impact of Vitamin D Supplementation on Influenza Vaccine Response and Immune Functions in Deficient Elderly Persons: A Randomized Placebo-Controlled Trial.

Background: Immunosenescence contributes to reduced vaccine response in elderly persons, and is worsened by deficiencies in nutrients such as Vitamin (Vit-D). The immune system is a well-known target of Vit-D, which can both potentiate the innate immune response and inhibit the adaptive system, and so modulate vaccination response. Objective: This randomized placebo-controlled double-blind trial investigated whether Vit-D supplementation in deficient elderly persons could improve influenza seroprotection and immune response. Design: Deficient volunteers (Vit-D serum <30 ng/mL) were assigned (V1) to receive either 100,000 IU/15 days of cholecalciferol (D, n = 19), or a placebo (P, n = 19), over a 3 month period. Influenza vaccination was performed at the end of this period (V2), and the vaccine response was evaluated 28 days later (V3). At each visit, serum cathelicidin, immune response to vaccination, plasma cytokines, lymphocyte phenotyping, and phagocyte ROS production were assessed. Results: Levels of serum 25-(OH)D increased after supplementation (D group, V1 vs. V2: 20.7 ± 5.7 vs. 44.3 ± 8.6 ng/mL, p < 0.001). No difference was observed for serum cathelicidin levels, antibody titers, and ROS production in D vs. P groups at V3. Lower plasma levels of TNFα (p = 0.040) and IL-6 (p = 0.046), and higher ones for TFGß (p = 0.0028) were observed at V3. The Th1/Th2 ratio was lower in the D group at V2 (D: 0.12 ± 0.05 vs. P: 0.18 ± 0.05, p = 0.039). Conclusions: Vit-D supplementation promotes a higher TGFß plasma level in response to influenza vaccination without improving antibody production. This supplementation seems to direct the lymphocyte polarization toward a tolerogenic immune response. A deeper characterization of metabolic and molecular pathways of these observations will aid in the understanding of Vit-D's effects on cell-mediated immunity in aging. This clinical trial was registered at clinicaltrials.gov as NCT01893385.

Can the SCD test and terminal uridine nick-end labeling by flow cytometry technique (TUNEL/FCM) be used interchangeably to measure sperm DNA damage in routine laboratory practice?

BACKGROUND: Numerous tests have been proposed to evaluate sperm DNA integrity. To assess the sperm chromatin dispersion (SCD) test in an andrology laboratory, twenty-five men attending Clermont-Ferrand (France) University Hospital's Center for Reproductive Medicine were recruited. Sperm DNA damage was measured in the same semen samples using the SCD test and the Terminal Uridine Nick-end Labeling by flow cytometry technique (TUNEL/FCM) after density gradient centrifugation. RESULTS: SCD test reliability between readings, readers or slides was clearly established with very high agreement between measurements (Intraclass correlation coefficient (ICC) at 0.97, 0.95 and 0.98 respectively). Despite very good agreement between the SCD test and TUNEL/FCM (ICC at 0.94), the SCD test tended to slightly but significantly underestimate DNA damage compared with TUNEL (p = 0.0127). This systematic difference between the two techniques was - 3.39 ± 1.45% (mean ± SE). CONCLUSIONS: Andrology laboratories using the SCD test to measure sperm DNA damage need to know that it appears to give slightly underestimated measurements compared to TUNEL/FCM. However, this systematic underestimation is very small in amplitude. Both techniques give almost perfectly congruent results. Our study underlines the importance for each laboratory to validate its method to assess sperm DNA damage before implementing it in routine andrology lab practice.

CONTEXTE: Plusieurs tests sont disponibles pour évaluer l'intégrité de l'ADN spermatique. Afin d'évaluer l'applicabilité de la technique de dispersion de la chromatine spermatique (SCD) dans un laboratoire d'andrologie, nous avons recruté 25 patients pris en charge au Centre de Médecine de la Reproduction du centre hospitalo-universitaire de Clermont-Ferrand (France). L'altération de l'ADN spermatique a été mesurée en ayant recours au test SCD et au test Terminal Uridine Nick-end Labeling en cytométrie en flux (TUNEL/CMF) dans les mêmes échantillons pour les deux techniques, après avoir réalisé un gradient de densité. RÉSULTATS: Pour le test SCD, la concordance entre les lectures, les lecteurs et les lames a été clairement établie avec un accord quasiment parfait entre les mesures (Coefficient de corrélation intra-classe (CCI) respectivement à 0,97, 0,95 et 0,98). Malgré une bonne concordance entre le test SCD et le test TUNEL/CMF (CCI à 0,94), le test SCD tend à sous-estimer légèrement mais de façon significative l'altération de l'ADN spermatique en comparaison avec le test TUNEL (p = 0,0127). Cette différence systématique entre les 2 techniques était de − 3.39 ± 1.45% (moyenne ± erreur standard). CONCLUSIONS: les laboratoires d'andrologie utilisant le test SCD pour mesurer l'altération de l'ADN spermatique doivent savoir qu'il donne apparemment des valeurs légèrement sous-estimées en comparaison du test TUNEL/CMF. Cependant, cette sous-estimation systématique est. de faible amplitude et les deux techniques donnent des résultats presque parfaitement concordants dans notre étude. Cette dernière montre bien que chaque laboratoire doit valider sa méthode sur site pour évaluer l'altération de l'ADN spermatique avant de le mettre en place en pratique quotidienne en andrologie.

In utero exposure to arsenic in tap water and congenital anomalies: A French semi-ecological study.

INTRODUCTION: Congenital anomalies (CA) are responsible for high rates of mortality and long-term disabilities. Research on their risk factors including environmental factors is needed. Studies on exposure to arsenic (As) in tap water and the risk of CA have not provided conclusive evidence, particularly when levels of exposure were low (from 10 to 50 µg As/L). The main objective of this study was to assess the association between exposure to As in tap water and the risk of any major CA. The secondary objectives were to assess this association for the most common types of congenital anomalies (in the heart, musculoskeletal, urinary and nervous systems). METHODS: A semi-ecological study was conducted from births recorded at the University Hospital of Clermont-Ferrand, France, in 2003, 2006 and 2010. The medico-obstetric data were available at individual level. Children with congenital anomalies were identified from the database of the regional registry of congenital anomalies: the Centre d'Etudes des Malformations Congénitales Auvergne (CEMC-Auvergne). As exposure was estimated from the concentrations of As measured during sanitary control of tap water supplied in the mothers' commune of residence (aggregate data). French guidelines for As in tap water were used to identify the two groups: "≥ 10 µg As/L group" and "[0-10) µg As/L group". Multivariable logistic regression models were fit. RESULTS: 5263 children (5.1% with a CA) were included. In stratified analysis by gender of the child, positive associations between As exposure exceeding 10 µg/L and risk of any major CA (adjusted OR = 2.41; 95%CI: 1.36-4.14) and of congenital heart anomalies (adjusted OR = 3.66; 95%CI: 1.62-7.64) were only shown for girls. No association was found for boys. CONCLUSION: This French semi-ecological study provides additional arguments for the association between exposure to As exceeding 10 µg/L in tap water and the risk of CA especially in a context of low exposure. Further studies are needed to better understand the interaction between arsenic exposure and child gender.

Do estimates of blood loss differ between student midwives and midwives? A multicenter cross-sectional study.

OBJECTIVE: the principal objective of this study was to assess the quality of blood loss estimates by midwives and student midwives. The secondary objectives were: to assess the intraobserver agreement of visual blood estimates and the rate of underestimation of blood loss by participants, and to estimate the sensitivity, specificity, and negative likelihood ratio of these estimates for clinically pertinent blood losses (≥ 500mL and ≥ 1000mL). DESIGN: multicenter cross-sectional study. SETTING: thirty-three French maternity units and 35 French midwifery schools participated in this study. PARTICIPANTS: volunteer French midwifery students (n = 463) and practicing midwives (n = 578). INTERVENTION: an online survey showed 16 randomly ordered photographs of 8 different simulated blood quantities (100, 150, 200, 300, 500, 850, 1000, and 1500mL) with a reference 50-mL image in each photo and asked participants to estimate the blood loss. The visual blood loss estimates were compared with Fisher's exact test. Intraobserver agreement for these estimates was assessed with a weighted kappa coefficient, and the negative predictive values (probability of no hemorrhage when visual estimate was negative) were calculated from prevalence rates in the literature. FINDINGS: of the 16,656 estimates obtained, 34.1% were accurate, 37.2% underestimated the quantity presented, and 28.7% overestimated it. Analyses of the intraobserver reproducibility between the two estimates of the same photograph showed that agreement was highest (weighted kappa ≥ 0.8) for the highest values (1000mL, 1500mL). For each volume considered, students underestimated blood loss more frequently than midwives. In both groups, the negative predictive values regarding postpartum hemorrhage (PPH) diagnosis (severe or not) were greater than 98%. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: student midwives tended to underestimate the quantity of blood loss more frequently than the midwives. Postpartum hemorrhage (≥ 500mL) was always identified, but severe postpartum hemorrhage (≥ 1000mL) was identified in fewer than half the cases. These results should be taken into account in training both student midwives and practicing professionals.

Exposure to arsenic in tap water and gestational diabetes: A French semi-ecological study.

INTRODUCTION: The increase in the prevalence of gestational diabetes mellitus (GDM) and its consequences for mother and children prompts research on their risk factors including environmental factors. Studies on exposure to arsenic (As) in tap water and the risk of GDM have not provided conclusive evidence, particularly when levels of exposure were low (from 10 to 50µg As/L). The main objective of this study was to assess the association between exposure to As in tap water and the risk of GDM. METHODS: A semi-ecological study was conducted from births recorded at the University Hospital of Clermont-Ferrand, France, in 2003, 2006 and 2010. Individual medical/obstetric data were available. As exposure was estimated from the concentrations of As measured during sanitary control of tap water supplied in the mothers' commune of residence (aggregate data). French guidelines for As in tap water were used to identify groups potentially exposed, designated "As +" (≥ 10µg As/L) and "As -" (< 10µg As/L). Multivariate logistic regression analysis was performed. RESULTS: 5053 women (5.7% with a GDM) were included. Overall, women in the As + group had a higher risk of GDM than those in the As - group (adjusted OR = 1.62; 95%CI: 1.01-2.53). Stratified analysis of pre-pregnancy body mass index (BMI) showed a positive association only for obese or overweight women (adjusted OR = 2.30; 95%CI: 1.13-4.50). CONCLUSION: This French semi-ecological study provides additional arguments for an association between As exposure and the risk of GDM in particular in a context of low exposure. Further studies are needed to assess a potential interaction between As exposure and body mass index.

General Practitioners' Barriers to Prescribe Physical Activity: The Dark Side of the Cluster Effects on the Physical Activity of Their Type 2 Diabetes Patients.

AIMS/HYPOTHESIS: To describe barriers to physical activity (PA) in type 2 diabetes patients and their general practitioners (GPs), looking for practitioner's influence on PA practice of their patients. METHODS: We conducted a cross-sectional study on GPs (n = 48) and their type 2 diabetes patients (n = 369) measuring respectively barriers to prescribe and practice PA using a self-assessment questionnaire: barriers to physical activity in diabetes (BAPAD). Statistical analysis was performed accounting hierarchical data structure. Similar practitioner's patients were considered a cluster sharing common patterns. RESULTS: The higher the patient's BAPAD score, the higher the barriers to PA, the higher the risk to declare practicing no PA (p<0.001), low frequency and low duration of PA (p<0.001). A high patient's BAPAD score was also associated with a higher risk to have HbA1c ≥7% (53 mmol/mol) (p = 0.001). The intra-class correlation coefficient between type 2 diabetes patients and GPs was 34%, indicating a high cluster effect. A high GP's BAPAD score, regarding the PA prescription, is predictive of a high BAPAD score with their patients, regarding their practice (p = 0.03). CONCLUSION/INTERPRETATION: Type 2 diabetes patients with lower BAPAD score, thus lower barriers to physical activity, have a higher PA level and a better glycemic control. An important and deleterious cluster effect between GPs and their patients is demonstrated: the higher the GP's BAPAD score, the higher the type 2 diabetes patients' BAPAD score. This important cluster effect might designate GPs as a relevant lever for future interventions regarding patient's education towards PA and type 2 diabetes management.

The Role of Psychological Factors in Persistent Pain After Cesarean Delivery.

UNLABELLED: This French multicenter prospective cohort study recruited 391 patients to investigate the risk factors for persistent pain after elective cesarean delivery, focusing on psychosocial aspects adjusted for other known medical factors. Perioperative data were collected and specialized questionnaires were completed to assess reports of pain at the site of surgery. Three dependent outcomes were considered: pain at the third month after surgery (M3, n = 268; risk = 28%), pain at the sixth month after surgery (M6, n = 239; risk = 19%), and the cumulative incidence (up to M6) of neuropathic pain, as assessed using the Douleur Neuropathique 4 questionnaire (n = 218; risk = 24.5%). The neuropathic aspect of reported pain changed over time in more than 60% of cases, pain being more intense if associated with neuropathic features. Whatever the dependent outcome, a high mental component of quality of life (SF-36) was protective. Pain at M3 was also predicted by pain reported during current pregnancy and a history of miscarriage. Pain at M6 was also predicted by report of a postoperative complication. Incident neuropathic pain was predicted by pain reported during current pregnancy, a previous history of a peripheral neuropathic event, and preoperative anxiety. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00812734. PERSPECTIVE: Persistent pain after cesarean delivery has a relatively frequent neuropathic aspect but this is less stable than that after other surgeries. When comparing the risk factor analyses with published data for hysterectomy, the influence of preoperative psychological factors seems less important, possibly because of the different context and environment.

Cluster Detection Tests in Spatial Epidemiology: A Global Indicator for Performance Assessment.

In cluster detection of disease, the use of local cluster detection tests (CDTs) is current. These methods aim both at locating likely clusters and testing for their statistical significance. New or improved CDTs are regularly proposed to epidemiologists and must be subjected to performance assessment. Because location accuracy has to be considered, performance assessment goes beyond the raw estimation of type I or II errors. As no consensus exists for performance evaluations, heterogeneous methods are used, and therefore studies are rarely comparable. A global indicator of performance, which assesses both spatial accuracy and usual power, would facilitate the exploration of CDTs behaviour and help between-studies comparisons. The Tanimoto coefficient (TC) is a well-known measure of similarity that can assess location accuracy but only for one detected cluster. In a simulation study, performance is measured for many tests. From the TC, we here propose two statistics, the averaged TC and the cumulated TC, as indicators able to provide a global overview of CDTs performance for both usual power and location accuracy. We evidence the properties of these two indicators and the superiority of the cumulated TC to assess performance. We tested these indicators to conduct a systematic spatial assessment displayed through performance maps.

Spatial heterogeneity of type I error for local cluster detection tests.

BACKGROUND: Just as power, type I error of cluster detection tests (CDTs) should be spatially assessed. Indeed, CDTs' type I error and power have both a spatial component as CDTs both detect and locate clusters. In the case of type I error, the spatial distribution of wrongly detected clusters (WDCs) can be particularly affected by edge effect. This simulation study aims to describe the spatial distribution of WDCs and to confirm and quantify the presence of edge effect. METHODS: A simulation of 40 000 datasets has been performed under the null hypothesis of risk homogeneity. The simulation design used realistic parameters from survey data on birth defects, and in particular, two baseline risks. The simulated datasets were analyzed using the Kulldorff's spatial scan as a commonly used test whose behavior is otherwise well known. To describe the spatial distribution of type I error, we defined the participation rate for each spatial unit of the region. We used this indicator in a new statistical test proposed to confirm, as well as quantify, the edge effect. RESULTS: The predefined type I error of 5% was respected for both baseline risks. Results showed strong edge effect in participation rates, with a descending gradient from center to edge, and WDCs more often centrally situated. CONCLUSIONS: In routine analysis of real data, clusters on the edge of the region should be carefully considered as they rarely occur when there is no cluster. Further work is needed to combine results from power studies with this work in order to optimize CDTs performance.

An empiric weight computation for record linkage using linearly combined fields' similarity scores.

Record linkage is the task of identifying which records from one or more data sources refer to the same entity. Many record linkage methods were introduced and applied over the last decades. In general, the principle is to compare a range of available identifier fields in record pairs among different data sources, in order to make a linkage decision. The Fellegi-Sunter probabilistic record linkage (PRL-FS) is one of the most commonly used methods. To obtain a better performance, Winkler proposed an enhanced PRL-FS method (PRL-W) that takes into account field similarity, but its implementation requires the estimation of much more parameters which complicates the task. Consequently, we propose to develop a method that contains the best features in the PRL-FS and the PRL-W methods: simplicity of parameters estimation and consideration of fields' similarities. We hypothesize that our record linkage method outperforms the PRL-FS, and can achieve a similar performance of the PRL-W. This paper presents briefly the PRL-FS and PRL-W methods, and describes in details how to combine fields' similarity scores to create a novel record pair weight. Simulated data sets were used to assess and to compare these three methods regarding their ability to reduce the rates of false matches and false non-matches.

Performance map of a cluster detection test using extended power.

BACKGROUND: Conventional power studies possess limited ability to assess the performance of cluster detection tests. In particular, they cannot evaluate the accuracy of the cluster location, which is essential in such assessments. Furthermore, they usually estimate power for one or a few particular alternative hypotheses and thus cannot assess performance over an entire region. Takahashi and Tango developed the concept of extended power that indicates both the rate of null hypothesis rejection and the accuracy of the cluster location. We propose a systematic assessment method, using here extended power, to produce a map showing the performance of cluster detection tests over an entire region. METHODS: To explore the behavior of a cluster detection test on identical cluster types at any possible location, we successively applied four different spatial and epidemiological parameters. These parameters determined four cluster collections, each covering the entire study region. We simulated 1,000 datasets for each cluster and analyzed them with Kulldorff's spatial scan statistic. From the area under the extended power curve, we constructed a map for each parameter set showing the performance of the test across the entire region. RESULTS: Consistent with previous studies, the performance of the spatial scan statistic increased with the baseline incidence of disease, the size of the at-risk population and the strength of the cluster (i.e., the relative risk). Performance was heterogeneous, however, even for very similar clusters (i.e., similar with respect to the aforementioned factors), suggesting the influence of other factors. CONCLUSIONS: The area under the extended power curve is a single measure of performance and, although needing further exploration, it is suitable to conduct a systematic spatial evaluation of performance. The performance map we propose enables epidemiologists to assess cluster detection tests across an entire study region.