Use of Antihypertensives, Blood Pressure, and Estimated Risk of Dementia in Late Life

ImportanceThe utility of antihypertensives and ideal blood pressure (BP) for dementia prevention in late life remains unclear and highly contested.ObjectivesTo assess the associations of hypertension history, antihypertensive use, and baseline measured BP in late life (age >60 years) with dementia and the moderating factors of age, sex, and racial group.Data Source and Study SelectionLongitudinal, population-based studies of aging participating in the Cohort Studies of Memory in an International Consortium (COSMIC) group were included. Participants were individuals without dementia at baseline aged 60 to 110 years and were based in 15 different countries (US, Brazil, Australia, China, Korea, Singapore, Central African Republic, Republic of Congo, Nigeria, Germany, Spain, Italy, France, Sweden, and Greece).Data Extraction and SynthesisParticipants were grouped in 3 categories based on previous diagnosis of hypertension and baseline antihypertensive use: healthy controls, treated hypertension, and untreated hypertension. Baseline systolic BP (SBP) and diastolic BP (DBP) were treated as continuous variables. Reporting followed the Preferred Reporting Items for Systematic Review and Meta-Analyses of Individual Participant Data reporting guidelines.Main Outcomes and MeasuresThe key outcome was all-cause dementia. Mixed-effects Cox proportional hazards models were used to assess the associations between the exposures and the key outcome variable. The association between dementia and baseline BP was modeled using nonlinear natural splines. The main analysis was a partially adjusted Cox proportional hazards model controlling for age, age squared, sex, education, racial group, and a random effect for study. Sensitivity analyses included a fully adjusted analysis, a restricted analysis of those individuals with more than 5 years of follow-up data, and models examining the moderating factors of age, sex, and racial group.ResultsThe analysis included 17 studies with 34 519 community dwelling older adults (20 160 [58.4%] female) with a mean (SD) age of 72.5 (7.5) years and a mean (SD) follow-up of 4.3 (4.3) years. In the main, partially adjusted analysis including 14 studies, individuals with untreated hypertension had a 42% increased risk of dementia compared with healthy controls (hazard ratio [HR], 1.42; 95% CI 1.15-1.76; P = .001) and 26% increased risk compared with individuals with treated hypertension (HR, 1.26; 95% CI, 1.03-1.53; P = .02). Individuals with treated hypertension had no significant increased dementia risk compared with healthy controls (HR, 1.13; 95% CI, 0.99-1.28; P = .07). The association of antihypertensive use or hypertension status with dementia did not vary with baseline BP. There was no significant association of baseline SBP or DBP with dementia risk in any of the analyses. There were no significant interactions with age, sex, or racial group for any of the analyses.Conclusions and RelevanceThis individual patient data meta-analysis of longitudinal cohort studies found that antihypertensive use was associated with decreased dementia risk compared with individuals with untreated hypertension through all ages in late life. Individuals with treated hypertension had no increased risk of dementia compared with healthy controls

Determinants of cognitive performance and decline in 20 diverse ethno-regional groups: A COSMIC collaboration cohort study.

BACKGROUND: With no effective treatments for cognitive decline or dementia, improving the evidence base for modifiable risk factors is a research priority. This study investigated associations between risk factors and late-life cognitive decline on a global scale, including comparisons between ethno-regional groups. METHODS AND FINDINGS: We harmonized longitudinal data from 20 population-based cohorts from 15 countries over 5 continents, including 48,522 individuals (58.4% women) aged 54-105 (mean = 72.7) years and without dementia at baseline. Studies had 2-15 years of follow-up. The risk factors investigated were age, sex, education, alcohol consumption, anxiety, apolipoprotein E ε4 allele (APOE*4) status, atrial fibrillation, blood pressure and pulse pressure, body mass index, cardiovascular disease, depression, diabetes, self-rated health, high cholesterol, hypertension, peripheral vascular disease, physical activity, smoking, and history of stroke. Associations with risk factors were determined for a global cognitive composite outcome (memory, language, processing speed, and executive functioning tests) and Mini-Mental State Examination score. Individual participant data meta-analyses of multivariable linear mixed model results pooled across cohorts revealed that for at least 1 cognitive outcome, age (B = -0.1, SE = 0.01), APOE*4 carriage (B = -0.31, SE = 0.11), depression (B = -0.11, SE = 0.06), diabetes (B = -0.23, SE = 0.10), current smoking (B = -0.20, SE = 0.08), and history of stroke (B = -0.22, SE = 0.09) were independently associated with poorer cognitive performance (p < 0.05 for all), and higher levels of education (B = 0.12, SE = 0.02) and vigorous physical activity (B = 0.17, SE = 0.06) were associated with better performance (p < 0.01 for both). Age (B = -0.07, SE = 0.01), APOE*4 carriage (B = -0.41, SE = 0.18), and diabetes (B = -0.18, SE = 0.10) were independently associated with faster cognitive decline (p < 0.05 for all). Different effects between Asian people and white people included stronger associations for Asian people between ever smoking and poorer cognition (group by risk factor interaction: B = -0.24, SE = 0.12), and between diabetes and cognitive decline (B = -0.66, SE = 0.27; p < 0.05 for both). Limitations of our study include a loss or distortion of risk factor data with harmonization, and not investigating factors at midlife. CONCLUSIONS: These results suggest that education, smoking, physical activity, diabetes, and stroke are all modifiable factors associated with cognitive decline. If these factors are determined to be causal, controlling them could minimize worldwide levels of cognitive decline. However, any global prevention strategy may need to consider ethno-regional differences

Évaluation d un protocole de sevrage de la sédation chez des patients cérébro-lésés

L arrêt de la sédation conduit souvent à l apparition d un syndrome de sevrage. Chez les patients cérébro-lésés, le syndrome de sevrage est délétère compte tenu du risque de réaggravation neurologique. Faute de recommandations, chaque équipe médicale traite le syndrome de sevrage de manière empirique. Cette étude observationnelle évalue un protocole d arrêt de la sédation par l emploi systématique du clorazépate (Tranxène®), benzodiazépine de demi-vie longue associé à la buprénorphine (Temgésic®), en cas de syndrome de sevrage aux morphiniques. C est un agoniste partiel des récepteurs morphiniques dont l affinité pour ces récepteurs est forte, possédant également un effet anti-hyperalgésique. Quarante patients consécutifs cérébro-lésés (traumatisme crânien ou accident vasculaire cérébral grave) ont été inclus. La sédation comprenait du midazolam et du sufentanil ou du fentanyl pendant 14 jours. A l arrêt du midazolam, du clorazépate a été introduit pendant 4 jours. A l arrêt du morphinique (H0) et du clorazépate, des paramètres évaluant le syndrome de sevrage ont été colligés toutes les heures. Sur les 40 patients, 10 n ont pas reçu de buprénorphine car ils n ont pas présenté de syndrome de sevrage aux morphiniques. Pour les 30 autres, les signes de syndrome de sevrage apparaissent en moyenne au bout 7 heures. Les valeurs de fréquence cardiaque, pression artérielle systolique, fréquence respiratoire et agitation sont significativement plus élevées à HB qu à H0 (analyse de variance type ANOVA pour mesures répétées). La buprénorphine corrige les signes de syndrome de sevrage dès la 6ème heure. D autres causes d agitation sont écartées, notamment septique ou métabolique. Aucun patient n a eu de réintroduction des agents de sédation. L association du clorazépate et de la buprénorphine prévient et traite le syndrome de sevrage de la sédation.GRENOBLE1-BU Médecine pharm. (385162101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Les mécanismes d’efflux et la résistance chez Pseudomonas aeruginosa

International audienc

[A protocol for the cessation of sedation in brain-injured patients].

International audienceOBJECTIVES: The cessation of sedation in brain-injured patients may result in severe agitation and/or acute withdrawal syndrome related to the prolonged administration of large doses of benzodiazepines and/or opioids. The aim of the present study was to assess the clinical efficacy of a written protocol to withdraw sedation for these patients. STUDY DESIGN: Observational prospective study. PATIENTS AND METHODS: After approval by the Institutional Review Board, 40 severely brain-injured patients were included. They had received continuous administration of midazolam and sufentanil or fentanyl for median 15 days. On cessation of midazolam infusion, patients were given clorazepate for 3 days. On cessation of opioid infusion and clorazepate, clinical data were collected for 48 hours: heart rate, systolic blood pressure, respiratory rate, agitation, and pupil diameter. If an opioid withdrawal syndrome occurred, patients received a 48-hour continuous infusion of buprenorphine. RESULTS: Of 40 patients, there were 10 who did not require buprenorphine. An agitation occurred 5 hours (1-21) after cessation of opioid, associated with tachycardia, arterial hypertension, and tachypnea. After 6 hours buprenorphine treatment, these parameters were normalized. No patient needed the reintroduction of the initial sedation. CONCLUSION: The cessation of sedation in severely brain-injured patients can be successfully managed with the use of clorazepate, associated with buprenorphine in the presence of agitation

Imbalanced weighting of proactive and reactive control as a marker of risk-taking propensity.

According to the dual mechanisms of control (DMC), reactive and proactive control are involved in adjusting behaviors when maladapted to the environment. However, both contextual and inter-individual factors increase the weight of one control mechanism over the other, by influencing their cognitive costs. According to one of the DMC postulates, limited reactive control capacities should be counterbalanced by greater proactive control to ensure control efficiency. Moreover, as the flexible weighting between reactive and proactive control is key for adaptive behaviors, we expected that maladaptive behaviors, such as risk-taking, would be characterized by an absence of such counterbalance. However, to our knowledge, no studies have yet investigated this postulate. In the current study, we analyzed the performances of 176 participants on two reaction time tasks (Simon and Stop Signal tasks) and a risk-taking assessment (Balloon Analog Risk Taking, BART). The post-error slowing in the Simon task was used to reflect the spontaneous individuals' tendency to proactively adjust behaviors after an error. The Stop Signal Reaction Time was used to assess reactive inhibition capacities and the duration of the button press in the BART was used as an index of risk-taking propensity. Results showed that poorer reactive inhibition capacities predicted greater proactive adjustments after an error. Furthermore, the higher the risk-taking propensity, the less reactive inhibition capacities predicted proactive behavioral adjustments. The reported results suggest that higher risk-taking is associated with a smaller weighting of proactive control in response to limited reactive inhibition capacities. These findings highlight the importance of considering the imbalanced weighting of reactive and proactive control in the analysis of risk-taking, and in a broader sense, maladaptive behaviors

De novo Sequencing and Native Mass Spectrometry Reveals Hetero-Association of Dirigent Protein Homologs and Potential Interacting Proteins in Forsythia × intermedia

The discovery of dirigent proteins (DPs) and their functions in plant phenol biochemistry was made over two decades ago with Forsythia × intermedia. Stereo-selective, DP-guided, monolignol-derived radical coupling in vitro was then reported to afford the optically active lignan, (+)-pinoresinol from coniferyl alcohol, provided one-electron oxidase/oxidant capacity was present. It later became evident that DPs have several distinct sub-families. In vascular plants, DPs hypothetically function, along with other essential enzymes/proteins (e.g. oxidases), as part of lignin/lignan forming complexes (LFCs). Herein, we used an integrated bottom-up, top-down, and native mass spectrometry approach to detect potential interacting proteins in a DP-enriched solubilized protein fraction from Forsythia × intermedia, via adaptation of our initial report of DP solubilization and purification. Because this hybrid species lacks a published genome, de novo sequencing was performed using publicly available transcriptome and genomic data from closely related species. We detected and identified two new DP homologs, which appear to form hetero-trimers. Molecular dynamics simulations suggest that similar hetero-trimers were possible between Arabidopsis DP homologs with comparable sequence similarity. Other identified proteins in the DP-enriched preparation were putatively associated with DP function or the cell wall. Although their co-occurrence after extraction and chromatographic separation is suggestive for components of a protein complex in vivo, none were found to form stable complexes with DPs under the specific experimental conditions we have explored. Nevertheless, our integrated mass spectrometry method development helps prepare for future investigations directed to detect hypothetical LFCs and other related complexes isolated from plant biomass fractionation

Texte court rédigé à partir de la recommandation nationale de bonnes pratiques cliniques « Conduites à tenir initiales devant des patientes atteintes d’un cancer épithélial de l’ovaire » élaborée par FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY et labélisée par l’INCa »

National audienc

Is the early-onset torsion dystonia (EOTD) linked to TOR1A gene as frequent as expected in France?

International audienceEarly onset torsion dystonia are rare movement disorders. Molecular defect is known for only a subgroup, consisting of a unique and recurrent mutation in the TOR1A gene. We undertook a nationwide census of French TOR1A-mutation carriers and the assessment of clinical associated signs. Overall, 53 index cases and 104 relatives were studied and haplotypes linked to the mutation constructed. The previously reported Ashkenazi-Jewish haplotype was found in 11 families with the remainder carrying distinct haplotypes suggesting independent mutation events. This study demonstrates the scarcity of this disease in France with estimated disease frequency of 0.13:100,000 and mutation frequency of 0.17:100,000

Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial

International audienceBACKGROUND:Early risk-stratified chemotherapy is a standard treatment for breast, colorectal, and lung cancers, but not for high-risk localised prostate cancer. Combined docetaxel and estramustine improves survival in patients with castration-resistant prostate cancer. We assessed the effects of combined docetaxel and estramustine on relapse in patients with high-risk localised prostate cancer.METHODS:We did this randomised phase 3 trial at 26 hospitals in France. We enrolled patients with treatment-naive prostate cancer and at least one risk factor (ie, stage T3-T4 disease, Gleason score of ≥8, prostate-specific antigen concentration >20 ng/mL, or pathological node-positive). All patients underwent a staging pelvic lymph node dissection. Patients were randomly assigned (1:1) to either androgen deprivation therapy (ADT; goserelin 10·8 mg every 3 months for 3 years) plus four cycles of docetaxel on day 2 at a dose of 70 mg/m(2) and estramustine 10 mg/kg per day on days 1-5, every 3 weeks, or ADT only. The randomisation was done centrally by computer, stratified by risk factor. Local treatment was administered at 3 months. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was relapse-free survival in the intention-to-treat population. Follow-up for other endpoints is ongoing. This study is registered with ClinicalTrials.gov, number NCT00055731.FINDINGS:We randomly assigned 207 patients to the ADT plus docetaxel and estramustine group and 206 to the ADT only group. Median follow-up was 8·8 years (IQR 8·1-9·7). 88 (43%) of 207 patients in the ADT plus docetaxel and estramustine group had an event (relapse or death) versus 111 (54%) of 206 in the ADT only group. 8-year relapse-free survival was 62% (95% CI 55-69) in the ADT plus docetaxel and estramustine group versus 50% (44-57) in the ADT only group (adjusted hazard ratio [HR] 0·71, 95% CI 0·54-0·94, p=0·017). Of patients who were treated with radiotherapy and had data available, 31 (21%) of 151 in the ADT plus docetaxel and estramustine group versus 26 (18%) of 143 in the ADT only group reported a grade 2 or higher long-term side-effect (p=0·61). We recorded no excess second cancers (26 [13%] of 207 vs 22 [11%] of 206; p=0·57), and there were no treatment-related deaths.INTERPRETATION:Docetaxel-based chemotherapy improves relapse-free survival in patients with high-risk localised prostate cancer. Longer follow-up is needed to assess whether this benefit translates into improved metastasis-free survival and overall survival.FUNDING:Ligue Contre le Cancer, Sanofi-Aventis, AstraZeneca, Institut National du Cancer