Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4x: a phase 2 randomised, double-blind, placebo-controlled trial.

BACKGROUND: Present combination antiretroviral therapy (cART) alone does not cure HIV infection and requires lifelong drug treatment. The potential role of HIV therapeutic vaccines as part of an HIV cure is under consideration. Our aim was to assess the efficacy, safety, and immunogenicity of Vacc-4x, a peptide-based HIV-1 therapeutic vaccine targeting conserved domains on p24(Gag), in adults infected with HIV-1. METHODS: Between July, 2008, and June, 2010, we did a multinational double-blind, randomised, phase 2 study comparing Vacc-4x with placebo. Participants were adults infected with HIV-1 who were aged 18-55 years and virologically suppressed on cART (viral load <50 copies per mL) with CD4 cell counts of 400 × 10(6) cells per L or greater. The trial was done at 18 sites in Germany, Italy, Spain, the UK, and the USA. Participants were randomly assigned (2:1) to Vacc-4x or placebo. Group allocation was masked from participants and investigators. Four primary immunisations, weekly for 4 weeks, containing Vacc-4x (or placebo) were given intradermally after administration of adjuvant. Booster immunisations were given at weeks 16 and 18. At week 28, cART was interrupted for up to 24 weeks. The coprimary endpoints were cART resumption and changes in CD4 counts during treatment interruption. Analyses were by modified intention to treat: all participants who received one intervention. Furthermore, safety, viral load, and immunogenicity (as measured by ELISPOT and proliferation assays) were assessed. The 52 week follow-up period was completed in June, 2011. For the coprimary endpoints the proportion of participants who met the criteria for cART resumption was analysed with a logistic regression model with the treatment effect being assessed in a model including country as a covariate. This study is registered with ClinicalTrials.gov, number NCT00659789. FINDINGS: 174 individuals were screened; because of slow recruitment, enrolment stopped with 136 of a planned 345 participants and 93 were randomly assigned to receive Vacc-4x and 43 to receive placebo. There were no differences between the two groups for the primary efficacy endpoints in those participants who stopped cART at week 28. Of the participants who resumed cART, 30 (34%) were in the Vacc-4x group and 11 (29%) in the placebo group, and percentage changes in CD4 counts were not significant (mean treatment difference -5·71, 95% CI -13·01 to 1·59). However, a significant difference in viral load was noted for the Vacc-4x group both at week 48 (median 23 100 copies per mL Vacc-4x vs 71 800 copies per mL placebo; p=0·025) and week 52 (median 19 550 copies per mL vs 51 000 copies per mL; p=0·041). One serious adverse event, exacerbation of multiple sclerosis, was reported as possibly related to study treatment. Vacc-4x was immunogenic, inducing proliferative responses in both CD4 and CD8 T-cell populations. INTERPRETATION: The proportion of participants resuming cART before end of study and change in CD4 counts during the treatment interruption showed no benefit of vaccination. Vacc-4x was safe, well tolerated, immunogenic, seemed to contribute to a viral-load setpoint reduction after cART interruption, and might be worth consideration in future HIV-cure investigative strategies. FUNDING: Norwegian Research Council GLOBVAC Program and Bionor Pharma ASA.

Detection of HIV drug resistance during antiretroviral treatment and clinical progression in a large European cohort study.

OBJECTIVE(S): To investigate the relationship between detection of HIV drug resistance by 2 years from starting antiretroviral therapy and the subsequent risk of progression to AIDS and death. DESIGN: Virological failure was defined as experiencing two consecutive viral loads of more than 400 copies/ml in the time window between 0.5 and 2 years from starting antiretroviral therapy (baseline). Patients were grouped according to evidence of virological failure and whether there was detection of the International AIDS Society resistance mutations to one, two or three drug classes in the time window. METHODS: Standard survival analysis using Kaplan-Meier curves and Cox proportional hazards regression model with time-fixed covariates defined at baseline was employed. RESULTS: We studied 8229 patients in EuroSIDA who started antiretroviral therapy and who had at least 2 years of clinical follow-up. We observed 829 AIDS events and 571 deaths during 38,814 person-years of follow-up resulting in an overall incidence of new AIDS and death of 3.6 per 100 person-years of follow-up [95% confidence interval (CI):3.4-3.8]. By 96 months from baseline, the proportion of patients with a new AIDS diagnosis or death was 20.3% (95% CI:17.7-22.9) in patients with no evidence of virological failure and 53% (39.3-66.7) in those with virological failure and mutations to three drug classes (P = 0.0001). An almost two-fold difference in risk was confirmed in the multivariable analysis (adjusted relative hazard = 1.8, 95% CI:1.2-2.7, P = 0.005). CONCLUSION: Although this study shows an association between the detection of resistance at failure and risk of clinical progression, further research is needed to clarify whether resistance reflects poor adherence or directly increases the risk of clinical events via exhaustion of drug options.

Photodynamic Diagnosis of Non-muscle-invasive Bladder Cancer with Hexaminolevulinate Cystoscopy: A Meta-analysis of Detection and Recurrence Based on Raw Data.

BACKGROUND: Studies on hexaminolevulinate (HAL) cystoscopy report improved detection of bladder tumours. However, recent meta-analyses report conflicting effects on recurrence. OBJECTIVE: To assess available clinical data for blue light (BL) HAL cystoscopy on the detection of Ta/T1 and carcinoma in situ (CIS) tumours, and on tumour recurrence. DESIGN, SETTING, AND PARTICIPANTS: This meta-analysis reviewed raw data from prospective studies on 1345 patients with known or suspected non-muscle-invasive bladder cancer (NMIBC). INTERVENTION: A single application of HAL cystoscopy was used as an adjunct to white light (WL) cystoscopy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We studied the detection of NMIBC (intention to treat [ITT]: n=831; six studies) and recurrence (per protocol: n=634; three studies) up to 1 yr. DerSimonian and Laird's random-effects model was used to obtain pooled relative risks (RRs) and associated 95% confidence intervals (CIs) for outcomes for detection. RESULTS AND LIMITATIONS: BL cystoscopy detected significantly more Ta tumours (14.7%; p<0.001; odds ratio [OR]: 4.898; 95% CI, 1.937-12.390) and CIS lesions (40.8%; p<0.001; OR: 12.372; 95% CI, 6.343-24.133) than WL. There were 24.9% patients with at least one additional Ta/T1 tumour seen with BL (p<0.001), significant also in patients with primary (20.7%; p<0.001) and recurrent cancer (27.7%; p<0.001), and in patients at high risk (27.0%; p<0.001) and intermediate risk (35.7%; p=0.004). In 26.7% of patients, CIS was detected only by BL (p<0.001) and was also significant in patients with primary (28.0%; p<0.001) and recurrent cancer (25.0%; p<0.001). Recurrence rates up to 12 mo were significantly lower overall with BL, 34.5% versus 45.4% (p=0.006; RR: 0.761 [0.627-0.924]), and lower in patients with T1 or CIS (p=0.052; RR: 0.696 [0.482-1.003]), Ta (p=0.040; RR: 0.804 [0.653-0.991]), and in high-risk (p=0.050) and low-risk (p=0.029) subgroups. Some subgroups had too few patients to allow statistically meaningful analysis. Heterogeneity was minimised by the statistical analysis method used. CONCLUSIONS: This meta-analysis confirms that HAL BL cystoscopy significantly improves the detection of bladder tumours leading to a reduction of recurrence at 9-12 mo. The benefit is independent of the level of risk and is evident in patients with Ta, T1, CIS, primary, and recurrent cancer.

Incidencia de la incapacidad temporal por contingencia común y profesional en la muestra continua de vidas laborales en 2009

Objetivo: Describir la incidencia de la incapacidad temporal por contingencia común (ITcc) y profesional (ITcp) iniciada en 2009 en afiliados a la Seguridad Social (SS) que forman parte de la Muestra Continua de Vida Laboral.Métodos: Cohorte formada por 873.008 afiliados a la SS en España que registraron 163.008 episodios de IT con un tiempo acumulado total en riesgo de 675.923,6 trabajadores-año. Se estimó la tasa de incidencia de todos los primeros episodios de IT y por trastornos musculo-esqueléticos (TME) según variables demográficas y laborales. Posteriormente se calcularon las razones de tasas crudas (RTc) y ajustadas (RTa) mediante un modelo de regresión Poisson.Resultados: La incidencia de la ITcc e ITcp fue de 23,1 y 1,0 casos por 100 trabajadores-año, respectivamente. La incidencia por ITcc fue superior en mujeres, en menores de 26 años y en Navarra (32,8 casos por 100 trabajadores-año), y por ITcp las mayores incidencias se observaron en hombres y en Galicia. Por diagnóstico, los TME presentaron 424,7 casos y 3,6 casos por 10.000 trabajadores-año según contingencia común y profesional respectivamente. Por otra parte, los trabajadores temporales tuvieron más riesgo de desarrollar ITcp (RTa=1,09;IC95%=1,04-1,15) e ITcc (RTa=1,02;IC95%=1,01-1,03) respecto a los permanentes.Conclusiones: La incidencia de la IT sigue un mismo patrón según edad, régimen de afiliación y relación laboral. Por tipo de contingencia se observaron diferencias en la ocupación, sexo, tamaño de empresa, comunidad autónoma y actividad económica. Es necesario estudiar con más detenimiento las diferencias observadas por actividad económica y tipo de relación contractual.

¿La incidencia de la pobreza discrimina por razones de género? : Análisis de los factores determinantes en el caso español

El presente trabajo traslada el debate académico alrededor del mayor riesgo de pobreza que afrontan las mujeres en relación a los hombres al contexto español. Tras una breve revisión bibliográfica de los datos disponibles sobre la pobreza femenina en países industrializados y sus posibles causantes, se ponen a prueba esos mismos factores potencialmente culpables en el caso español. Del EU-SILC de 2010 se ha sacado una muestra formada únicamente por mujeres y hombres que o bien viven solos o con hijos a su cargo y, partiendo de ella, el método de la regresión logística ha concluido que hay factores exclusivamente explicativos de la pobreza femenina. Ser madre soltera, ser joven (entre 16 y 25 años) y no haber nacido en España tienen una importante capacidad explicativa de la pobreza femenina mientras no son significativas como explicación de la pobreza masculina. Si a estos factores añadimos no tener un trabajo, un bajo logro educativo y no recibir ningún subsidio individual, obtenemos un conjunto de factores que explican un 26.8% de los casos de mujeres españolas pobres que viven solas o son madres solteras. Estos datos ponen de relieve la necesidad de más investigaciones al respecto que consigan un mayor poder explicativo.

Lack of association between beta-herpesvirus infection and bronchiolitis obliterans syndrome in lung transplant recipients in the era of antiviral prophylaxis.

BACKGROUND: Cytomegalovirus (CMV), human herpesvirus-6 and -7 (HHV-6 and -7) are beta-herpesviruses that commonly reactivate and have been proposed to trigger acute rejection and chronic allograft injury. We assessed the contribution of these viruses in the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation. METHODS: Quantitative real-time polymerase chain reaction of bronchoalveolar lavage samples were performed for CMV, HHV-6 and -7 in a prospective cohort of lung transplant recipients. A time-dependent Cox regression analysis was used to correlate the risk of BOS and acute rejection in patients with and without beta-herpesviruses infection. RESULTS: Ninety-three patients were included in the study over a period of 3 years. A total of 581 samples from bronchoalveolar lavage were obtained. Sixty-one patients (65.6%) had at least one positive result for one of the beta-herpesviruses: 48 patients (51.6%) for CMV and 19 patients (20.4%) for both HHV-6 and -7. Median peak viral load was 3419 copies/mL for CMV, 258 copies/mL for HHV-6, and 665 copies/mL for HHV-7. Acute rejection (>or=grade 2) occurred in 46.2% and BOS (>or=stage 1) in 19.4% of the patients. In the Cox regression model the relative risk of acute rejection or BOS was not increased in patients with any beta-herpesviruses reactivation. Acute rejection was the only independently associated risk factor for BOS. CONCLUSIONS: In lung transplant recipients receiving prolonged antiviral prophylaxis, reactivation of beta-herpesviruses within the allograft was common. However, despite high viral loads in many patients, virus replication was not associated with the development of rejection or BOS.

A simple score for estimating ischemic heart disease in patients with non-traumatic chest pain in primary care

Background: Modelling epidemiological knowledge in validated clinical scores is a practical mean of integrating EBM to usual care. Existing scores about cardiovascular disease have been largely developed in emergency settings, but few in primary care. Such a toll is needed for general practitioners (GP) to evaluate the probability of ischemic heart disease (IHD) in patients with non-traumatic chest pain. Objective: To develop a predictive model to use as a clinical score for detecting IHD in patients with non-traumatic chest-pain in primary care. Methods: A post-hoc secondary analysis on data from an observational study including 672 patients with chest pain of which 85 had IHD diagnosed by their GP during the year following their inclusion. Best subset method was used to select 8 predictive variables from univariate analysis and fitted in a multivariate logistic regression model to define the score. Reliability of the model was assessed using split-group method. Results: Significant predictors were: age (0-3 points), gender (1 point), having at least one cardiovascular risks factor (hypertension, dyslipidemia, diabetes, smoking, family history of CVD; 3 points), personal history of cardiovascular disease (1 point), duration of chest pain from 1 to 60 minutes (2 points), substernal chest pain (1 point), pain increasing with exertion (1 point) and absence of tenderness at palpation (1 point). Area under the ROC curve for the score was of 0.95 (IC95% 0.93; 0.97). Patients were categorised in three groups, low risk of IHD (score under 6; n = 360), moderate risk of IHD (score from 6 to 8; n = 187) and high risk of IHD (score from 9-13; n = 125). Prevalence of IHD in each group was respectively of 0%, 6.7%, 58.5%. Reliability of the model seems satisfactory as the model developed from the derivation set predicted perfectly (p = 0.948) the number of patients in each group in the validation set. Conclusion: This clinical score based only on history and physical exams can be an important tool in the practice of the general physician for the prediction of ischemic heart disease in patients complaining of chest pain. The score below 6 points (in more than half of our population) can avoid demanding complementary exams for selected patients (ECG, laboratory tests) because of the very low risk of IHD. Score above 6 points needs investigation to detect or rule out IHD. Further external validation is required in ambulatory settings.

Polymorphisms in Toll-like receptor 9 influence the clinical course of HIV-1 infection.

BACKGROUND: The clinical course of HIV-1 infection is highly variable among individuals, at least in part as a result of genetic polymorphisms in the host. Toll-like receptors (TLRs) have a key role in innate immunity and mutations in the genes encoding these receptors have been associated with increased or decreased susceptibility to infections. OBJECTIVES: To determine whether single-nucleotide polymorphisms (SNPs) in TLR2-4 and TLR7-9 influenced the natural course of HIV-1 infection. METHODS: Twenty-eight SNPs in TLRs were analysed in HAART-naive HIV-positive patients from the Swiss HIV Cohort Study. The SNPs were detected using Sequenom technology. Haplotypes were inferred using an expectation-maximization algorithm. The CD4 T cell decline was calculated using a least-squares regression. Patients with a rapid CD4 cell decline, less than the 15th percentile, were defined as rapid progressors. The risk of rapid progression associated with SNPs was estimated using a logistic regression model. Other candidate risk factors included age, sex and risk groups (heterosexual, homosexual and intravenous drug use). RESULTS: Two SNPs in TLR9 (1635A/G and +1174G/A) in linkage disequilibrium were associated with the rapid progressor phenotype: for 1635A/G, odds ratio (OR), 3.9 [95% confidence interval (CI),1.7-9.2] for GA versus AA and OR, 4.7 (95% CI,1.9-12.0) for GG versus AA (P = 0.0008). CONCLUSION: Rapid progression of HIV-1 infection was associated with TLR9 polymorphisms. Because of its potential implications for intervention strategies and vaccine developments, additional epidemiological and experimental studies are needed to confirm this association.

Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality

BACKGROUND: Data on the association between subclinical thyroid dysfunction and coronary heart disease (CHD) and mortality are conflicting. PURPOSE: To summarize prospective evidence about the relationship between subclinical thyroid dysfunction and CHD and mortality. DATA SOURCES: MEDLINE (1950 to January 2008) without language restrictions and reference lists of retrieved articles were searched. STUDY SELECTION: Two reviewers screened and selected cohort studies that measured thyroid function and then followed persons prospectively to assess CHD or mortality. DATA EXTRACTION: By using a standardized protocol and forms, 2 reviewers independently abstracted and assessed studies. DATA SYNTHESIS: Ten of 12 identified studies involved population-based cohorts that included 14 449 participants. All 10 population-based cohort studies examined risks associated with subclinical hypothyroidism (2134 CHD events and 2822 deaths), whereas only 5 examined risks associated with subclinical hyperthyroidism (1392 CHD events and 1993 deaths). In a random-effects model, the relative risk (RR) for subclinical hypothyroidism for CHD was 1.20 (95% CI, 0.97 to 1.49; P for heterogeneity = 0.14; I(2 )= 33.4%). Risk estimates were lower when higher-quality studies were pooled (RR, 1.02 to 1.08) and were higher among participants younger than 65 years (RR, 1.51 [CI, 1.09 to 2.09] for studies with mean participant age <65 years and 1.05 [CI, 0.90 to 1.22] for studies with mean participant age > or =65 years). The RR was 1.18 (CI, 0.98 to 1.42) for cardiovascular mortality and 1.12 (CI, 0.99 to 1.26) for total mortality. For subclinical hyperthyroidism, the RR was 1.21 (CI, 0.88 to 1.68) for CHD, 1.19 (CI, 0.81 to 1.76) for cardiovascular mortality, and 1.12 (CI, 0.89 to 1.42) for total mortality (P for heterogeneity >0.50; I(2 )= 0% for all studies). LIMITATIONS: Individual studies adjusted for different potential confounders, and 1 study provided only unadjusted data. Publication bias or selective reporting of outcomes could not be excluded. CONCLUSION: Subclinical hypothyroidism and hyperthyroidism may be associated with a modest increased risk for CHD and mortality, with lower risk estimates when pooling higher-quality studies and larger CIs for subclinical hyperthyroidism

Predictive Value of Readiness, Importance, and Confidence in Ability to Change Drinking and Smoking

Background: Visual analog scales (VAS) are used to assess readiness to changeconstructs, which are often considered critical for change.Objective: We studied whether 3 constructs -readiness to change, importance of changing and confidence inability to change- predict risk status 6 months later in 20 year-old men with either orboth of two behaviors: risky drinking and smoking. Methods: 577 participants in abrief intervention randomized trial were assessed at baseline and 6 months later onalcohol and tobacco consumption and with three 1-10 VAS (readiness, importance,confidence) for each behavior. For each behavior, we used one regression model foreach constructs. Models controlled for receipt of a brief intervention and used thelowest level (1-4) in each construct as the reference group (vs medium (5-7) and high(8-10) levels).Results: Among the 475 risky drinkers, mean (SD) readiness, importance and confidence to change drinking were 4.0 (3.1), 2.8 (2.2) and 7.2 (3.0).Readiness was not associated with being alcohol-risk free 6 months later (OR 1.3[0.7; 2.2] and 1.4 [0.8; 2.6] for medium and high readiness). High importance andhigh confidence were associated with being risk free (OR 0.9 [0.5; 1.8] and 2.9 [1.2;7.5] for medium and high importance; 2.1 [1.0;4.8] and 2.8 [1.5;5.6] for medium andhigh confidence). Among the 320 smokers, mean readiness, importance andconfidence to change smoking were 4.6 (2.6), 5.3 (2.6) and 5.9 (2.6). Neitherreadiness nor importance were associated with being smoking free (OR 2.1 [0.9; 4.7]and 2.1 [0.8; 5.8] for medium and high readiness; 1.4 [0.6; 3.4] and 2.1 [0.8; 5.4] formedium and high importance). High confidence was associated with being smokingfree (OR 2.2 [0.8;6.6] and 3.4 [1.2;9.8] for medium and high confidence).Conclusions: For drinking and smoking, high confidence in ability to change wasassociated -with similar magnitude- with a favorable outcome. This points to thevalue of confidence as an important predictor of successful change.

Effectiveness of pharmacist care in the improvement of adherence to antidepressants: a systematic review and meta-analysis

BACKGROUND: Pharmacists can play a decisive role in the management of ambulatory patients with depression who have poor adherence to antidepressant drugs. OBJECTIVE: To systematically evaluate the effectiveness of pharmacist care in improving adherence of depressed outpatients to antidepressants. METHODS: A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted. RCTs were identified through electronic databases (MEDLINE, Cochrane Central Register of Controlled Trials, Institute for Scientific Information Web of Knowledge, and Spanish National Research Council) from inception to April 2010, reference lists were checked, and experts were consulted. RCTs that evaluated the impact of pharmacist interventions on improving adherence to antidepressants in depressed patients in an outpatient setting (community pharmacy or pharmacy service) were included. Methodologic quality was assessed and methodologic details and outcomes were extracted in duplicate. RESULTS: Six RCTs were identified. A total of 887 patients with an established diagnosis of depression who were initiating or maintaining pharmacologic treatment with antidepressant drugs and who received pharmacist care (459 patients) or usual care (428 patients) were included in the review. The most commonly reported interventions were patient education and monitoring, monitoring and management of toxicity and adverse effects, adherence promotion, provision of written or visual information, and recommendation or implementation of changes or adjustments in medication. Overall, no statistical heterogeneity or publication bias was detected. The pooled odds ratio, using a random effects model, was 1.64 (95% CI 1.24 to 2.17). Subgroup analysis showed no statistically significant differences in results by type of pharmacist involved, adherence measure, diagnostic tool, or analysis strategy. CONCLUSIONS: These results suggest that pharmacist intervention is effective in the improvement of patient adherence to antidepressants. However, data are still limited and we would recommend more research in this area, specifically outside of the US.

Skeletal muscle mitochondrial energetics are associated with maximal aerobic capacity and walking speed in older adults.

BACKGROUND: Lower ambulatory performance with aging may be related to a reduced oxidative capacity within skeletal muscle. This study examined the associations between skeletal muscle mitochondrial capacity and efficiency with walking performance in a group of older adults. METHODS: Thirty-seven older adults (mean age 78 years; 21 men and 16 women) completed an aerobic capacity (VO peak) test and measurement of preferred walking speed over 400 m. Maximal coupled (State 3; St3) mitochondrial respiration was determined by high-resolution respirometry in saponin-permeabilized myofibers obtained from percutanous biopsies of vastus lateralis (n = 22). Maximal phosphorylation capacity (ATP) of vastus lateralis was determined in vivo by P magnetic resonance spectroscopy (n = 30). Quadriceps contractile volume was determined by magnetic resonance imaging. Mitochondrial efficiency (max ATP production/max O consumption) was characterized using ATP per St3 respiration (ATP/St3). RESULTS: In vitro St3 respiration was significantly correlated with in vivo ATP (r = .47, p = .004). Total oxidative capacity of the quadriceps (St3*quadriceps contractile volume) was a determinant of VO peak (r = .33, p = .006). ATP (r = .158, p = .03) and VO peak (r = .475, p < .0001) were correlated with preferred walking speed. Inclusion of both ATP/St3 and VO peak in a multiple linear regression model improved the prediction of preferred walking speed (r = .647, p < .0001), suggesting that mitochondrial efficiency is an important determinant for preferred walking speed. CONCLUSIONS: Lower mitochondrial capacity and efficiency were both associated with slower walking speed within a group of older participants with a wide range of function. In addition to aerobic capacity, lower mitochondrial capacity and efficiency likely play roles in slowing gait speed with age.

Long-term outcome of idiopathic steroid-resistant nephrotic syndrome: a multicenter study.

Long-term outcome of idiopathic steroid-resistant nephrotic syndrome was retrospectively studied in 78 children in eight centers for the past 20 years. Median age at onset was 4.4 years (1.1-15.0 years) and the gender ratio was 1.4. Median follow-up period was 7.7 years (1.0-19.7 years). The disease in 45 patients (58%) was initially not steroid-responsive and in 33 (42%) it was later non-responsive. The main therapeutic strategies included administration of ciclosporine (CsA) alone (n = 29; 37%) and CsA + mycophenolate mofetil (n = 18; 23%). Actuarial patient survival rate after 15 years was 97%. Renal survival rate after 5 years, 10 years and 15 years was 75%, 58% and 53%, respectively. An age at onset of nephrotic syndrome (NS) > 10 years was the only independent predictor of end-stage renal disease (ESRD) in a multivariate analysis using a Cox regression model (P < 0.001). Twenty patients (26%) received transplants; ten showed recurrence of the NS: seven within 2 days, one within 2 weeks, and two within 3-5 months. Seven patients lost their grafts, four from recurrence. Owing to better management, kidney survival in idiopathic steroid-resistant nephrotic syndrome (SRNS) has improved during the past 20 years. Further prospective controlled trials will delineate the potential benefit of new immunosuppressive treatment.

J-shaped association between serum glucose and functional outcome in acute ischemic stroke.

BACKGROUND AND PURPOSE: Hyperglycemia after stroke is associated with larger infarct volume and poorer functional outcome. In an animal stroke model, the association between serum glucose and infarct volume is described by a U-shaped curve with a nadir ≈7 mmol/L. However, a similar curve in human studies was never reported. The objective of the present study is to investigate the association between serum glucose levels and functional outcome in patients with acute ischemic stroke. METHODS: We analyzed 1446 consecutive patients with acute ischemic stroke. Serum glucose was measured on admission at the emergency department together with multiple other metabolic, clinical, and radiological parameters. National Institutes of Health Stroke Scale (NIHSS) score was recorded at 24 hours, and Rankin score was recorded at 3 and 12 months. The association between serum glucose and favorable outcome (Rankin score ≤2) was explored in univariate and multivariate analysis. The model was further analyzed in a robust regression model based on fractional polynomial (-2-2) functions. RESULTS: Serum glucose is independently correlated with functional outcome at 12 months (OR, 1.15; P=0.01). Other predictors of outcome include admission NIHSS score (OR, 1.18; P<0001), age (OR, 1.06; P<0.001), prestroke Rankin score (OR, 20.8; P=0.004), and leukoaraiosis (OR, 2.21; P=0.016). Using these factors in multiple logistic regression analysis, the area under the receiver-operator characteristic curve is 0.869. The association between serum glucose and Rankin score at 12 months is described by a J-shaped curve with a nadir of 5 mmol/L. Glucose values between 3.7 and 7.3 mmol/L are associated with favorable outcome. A similar curve was generated for the association of glucose and 24-hour NIHSS score, for which glucose values between 4.0 and 7.2 mmol/L are associated with a NIHSS score <7. Discussion-Both hypoglycemia and hyperglycemia are dangerous in acute ischemic stroke as shown by a J-shaped association between serum glucose and 24-hour and 12-month outcome. Initial serum glucose values between 3.7 and 7.3 mmol/L are associated with favorable outcome.

Meta-analysis : subclinical thyroid dysfunction and the risk for coronary heart disease and mortality

Rapport de synthèse : Description : ce travail de thèse évalue de façon systématique les études sur l'association entre les dysfonctions thyroïdiennes infracliniques d'une part, et la maladie coronarienne et la mortalité d'autre part. Les hypothyroïdies infracliniques affectent environ 4-5% de la population adulte alors que la prévalence de l'hyperthyroïdie infraclinique est inférieure (environ 1%). L'éventuelle association entre elles pourrait justifier un dépistage systématique des dysfonctions thyroïdiennes infracliniques. Les précédentes études sur l'association entre l'hypothyroïdie infraclinique et la maladie coronarienne ont donné des résultats conflictuels. La parution de nouveaux articles récents basés sur de grandes cohortes prospectives nous a permis d'effectuer une méta-analyse basée uniquement sur des études de cohorte prospectives, augmentant ainsi la validité des résultats. Résultats: 10 des 12 études identifiées pour notre revue systématique sont basées sur des cohortes issues de la population générale («population-based »), regroupant en tout 14 449 participants. Ces 10 études examinent toutes le risque associé à l'hypothyroïdie infraclinique (avec 2134 événements coronariens et 2822 décès), alors que 5 étudient également le risque associé à l'hyperthyroïdie infraclinique (avec 1392 événements coronariens et 1993 décès). En utilisant un modèle statistique de type random-effect model, le risque relatif [RR] lié à l'hypothyroïdie infraclinique pour la maladie coronarienne est de 1.20 (intervalle de confiance [IC] de 95%, 0.97 à 1.49). Le risque diminue lorsque l'on regroupe uniquement les études de meilleure qualité (RR compris entre 1.02 et 1.08). Il est plus élevé parmi les participants de moins de 65 ans (RR, 1.51 [IC, 1.09 à 2.09] et 1.05 [IC, 0.90 à 1.22] pour les études dont l'âge moyen des participants est >_ 65 ans). Le RR de la mortalité cardiovasculaire est de 1.18 (IC, 0.98 à 1.42) et de 1.12 (IC, 0.99 à 1.26) pour la mortalité totale. En cas d'hyperthyroïdie infraclinique, les RR de la maladie coronarienne sont de 1.21 (IC, 0.88 à 1.68), de 1.19 (IC, 0.81 à 1.76) pour la mortalité cardiovasculaire, et de 1.12 (IC, 0.89 à 1.42) pour la mortalité totale. Conclusions et perspectives : nos résultats montrent que les dysfonctions thyroïdiennes infracliniques (hypothyroïdie et hyperthyroïdie infracliniques) représentent un facteur de risque modifiable, bien que modéré, de la maladie coronarienne et de la mortalité. L'efficacité du traitement de ces dysfonctions thyroïdiennes infracliniques doit encore être prouvée du point de vue cardiovasculaire et de la mortalité. Il est nécessaire d'effectuer des études contrôlées contre placebo avec le risque cardiovasculaire et la mortalité comme critères d'efficacité, avant de pouvoir proposer des recommandations sur le dépistage des ces dysfonctions thyroïdiennes dans la population adulte.