Host genome influences on susceptibility to HIV-1

In vitro and in vivo analyses identified a significant component of heritability in cellular or host susceptibility to HIV-1. The bases for susceptibility can be traced to genetic differences (inter-species) resulting from evolutionary adaptation to exogenous (and endogenous) retroviral infections, and to intra-species and inter-individual (human) differences associated with genetic variation. We have completed large scale evolutionary analysis of genes involved in HIV life cycle and pathogenesis, as well as participating and conducting genome-wide association studies, linkage analysis, and transcriptome analysis. These studies allowed a better understanding of the influence of common human variants in HIV-1 susceptibility and define a number of experimental challenges in the filed: understanding of the role of rare and private mutations in susceptibility, and the development of better tools for the integration of data from large-scale studies.

Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.

IMPORTANCE: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. OBJECTIVE: To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). DATA SOURCES: Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators. STUDY SELECTION: Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. DATA EXTRACTION AND SYNTHESIS: Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. MAIN OUTCOMES AND MEASURES: Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. RESULTS: The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality. CONCLUSIONS AND RELEVANCE: Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.

Pulmonary metastasectomy in colorectal cancer patients with previously resected liver metastasis: pooled analysis.

BACKGROUND: Data addressing the outcomes and patterns of recurrence after pulmonary metastasectomy (PM) in patients with colorectal cancer (CRC) and previously resected liver metastasis are limited. METHODS: We searched the PubMed database for studies assessing PM in CRC and gathered individual data for patients who had PM and a previous curative liver resection. The influence of potential factors on overall survival (OS) was analyzed through univariate and multivariate analysis. RESULTS: Between 1983 and 2009, 146 patients from five studies underwent PM and had previous liver resection. The median interval from resection of liver metastasis until detection of lung metastasis and the median follow-up from PM were 23 and 48 months, respectively. Five-year OS and recurrence-free survival rates calculated from the date of PM were 54.4 and 29.3 %, respectively. Factors predicting inferior OS in univariate analysis included thoracic lymph node (LN) involvement and size of largest lung nodule ≥2 cm. Adjuvant chemotherapy and whether lung metastasis was detected synchronous or metachronous to liver metastasis had no influence on survival. In multivariate analysis, thoracic LN involvement emerged as the only independent factor (hazard ratio 4.86, 95 % confidence interval 1.56-15.14, p = 0.006). CONCLUSIONS: PM offers a chance for long-term survival in selected patients with CRC and previously resected liver metastasis. Thoracic LN involvement predicted poor prognosis; therefore, significant efforts should be undertaken for adequate staging of the mediastinum before PM. In addition, adequate intraoperative LN sampling allows proper prognostic stratification and enrollment in novel adjuvant therapy trials.

Prédiction des complications après duodénopancréatectomie céphalique: validation d'un score de complications postopératoires = Prediction of complications after pancreaticoduodenectomy: validation of a postoperative complication score

Objectifs La chirurgie pancréatique reste associée à une morbidité postopératoire importante. Les efforts sont concentrés la plupart du temps sur la diminution de cette morbidité, mais la détection précoce de patients à risque de complications pourrait être une autre stratégie valable. Un score simple de prédiction des complications après duodénopancréatectomie céphalique a récemment été publié par Braga et al. La présente étude a pour but de valider ce score et de discuter de ses possibles implications cliniques. Méthodes De 2000 à 2015, 245 patients ont bénéficié d'une duodénopancréatectomie céphalique dans notre service. Les complications postopératoires ont été recensées selon la classification de Dindo et Clavien. Le score de Braga se base sur quatre paramètres : le score ASA (American Society of Anesthesiologists), la texture du pancréas, le diamètre du canal de Wirsung (canal pancréatique principal) et les pertes sanguines intra-opératoires. Un score de risque global de 0 à 15 peut être calculé pour chaque patient. La puissance de discrimination du score a été calculée en utilisant une courbe ROC (receiver operating characteristic). Résultats Des complications majeures sont apparues chez 31% des patients, alors que 17% des patients ont eu des complications majeures dans l'article de Braga. La texture du pancréas et les pertes sanguines étaient statistiquement significativement corrélées à une morbidité accrue. Les aires sous la courbe étaient respectivement de 0.95 et 0.99 pour les scores classés en quatre catégories de risques (de 0 à 3, 4 à 7, 8 à 11 et 12 à 15) et pour les scores individuels (de 0 à 15). Conclusions Le score de Braga permet donc une bonne discrimination entre les complications mineures et majeures. Notre étude de validation suggère que ce score peut être utilisé comme un outil pronostique de complications majeures après duodénopancréatectomie céphalique. Les implications cliniques, c'est-à-dire si les stratégies de prise en charge postopératoire doivent être adaptées en fonction du risque individuel du patient, restent cependant à élucider. -- Objectives Pancreatic surgery remains associated with important morbidity. Efforts are most commonly concentrated on decreasing postoperative morbidity, but early detection of patients at risk could be another valuable strategy. A simple prognostic score has recently been published. This study aimed to validate this score and discuss possible clinical implications. Methods From 2000 to 2012, 245 patients underwent pancreaticoduodenectomy. Complications were graded according to the Dindo-Clavien classification. The Braga score is based on American Society of Anesthesiologists score, pancreatic texture, Wirsung duct diameter, and blood loss. An overall risk score (from 0 to 15) can be calculated for each patient. Score discriminant power was calculated using a receiver operating characteristic curve. Results Major complications occurred in 31% of patients compared to 17% in Braga's data. Pancreatic texture and blood loss were independently statistically significant for increased morbidity. The areas under curve were 0.95 and 0.99 for 4-risk categories and for individual scores, respectively. Conclusions The Braga score discriminates well between minor and major complications. Our validation suggests that it can be used as prognostic tool for major complications after pancreaticoduodenectomy. The clinical implications, i.e., whether postoperative treatment strategies should be adapted according to the patient's individual risk, remain to be elucidated.

Prediction of Complications After Pancreaticoduodenectomy: Validation of a Postoperative Complication Score.

OBJECTIVES: Pancreatic surgery remains associated with important morbidity. Efforts are most commonly concentrated on decreasing postoperative morbidity, but early detection of patients at risk could be another valuable strategy. A simple prognostic score has recently been published. This study aimed to validate this score and discuss possible clinical implications. METHODS: From 2000 to 2012, 245 patients underwent a pancreaticoduodenectomy. Complications were graded according to the Dindo-Clavien Classification. The Braga score is based on American Society of Anesthesiologists score, pancreatic texture, Wirsung duct diameter, and blood loss. An overall risk score (0-15) can be calculated for each patient. Score discriminant power was calculated using a receiver operating characteristic curve. RESULTS: Major complications occurred in 31% of patients compared with 17% in Braga's data. Pancreatic texture and blood loss were independently statistically significant for increased morbidity. Areas under the curve were 0.95 and 0.99 for 4-risk categories and for individual scores, respectively. CONCLUSIONS: The Braga score discriminates well between minor and major complications. Our validation suggests that it can be used as a prognostic tool for major complications after pancreaticoduodenectomy. The clinical implications, that is, whether postoperative treatment strategies should be adapted according to the patient's individual risk, remain to be elucidated.

Does evolution lead to maximizing behavior?

A long-standing question in biology and economics is whether individual organisms evolve to behave as if they were striving to maximize some goal function. We here formalize this "as if" question in a patch-structured population in which individuals obtain material payoffs from (perhaps very complex multimove) social interactions. These material payoffs determine personal fitness and, ultimately, invasion fitness. We ask whether individuals in uninvadable population states will appear to be maximizing conventional goal functions (with population-structure coefficients exogenous to the individual's behavior), when what is really being maximized is invasion fitness at the genetic level. We reach two broad conclusions. First, no simple and general individual-centered goal function emerges from the analysis. This stems from the fact that invasion fitness is a gene-centered multigenerational measure of evolutionary success. Second, when selection is weak, all multigenerational effects of selection can be summarized in a neutral type-distribution quantifying identity-by-descent between individuals within patches. Individuals then behave as if they were striving to maximize a weighted sum of material payoffs (own and others). At an uninvadable state it is as if individuals would freely choose their actions and play a Nash equilibrium of a game with a goal function that combines self-interest (own material payoff), group interest (group material payoff if everyone does the same), and local rivalry (material payoff differences).

Continuum of care for persons with common mental health disorders in Nunavik: a descriptive study.

BACKGROUND: Changing Directions, Changing Lives, the Mental Health Strategy for Canada, prioritizes the development of coordinated continuums of care in mental health that will bridge the gap in services for Inuit populations. OBJECTIVE: In order to target ways of improving the services provided in these contexts to individuals in Nunavik with depression or anxiety disorders, this research examines delays and disruptions in the continuum of care and clinical, individual and organizational characteristics possibly associated with their occurrences. DESIGN: A total of 155 episodes of care involving a common mental disorder (CMD), incident or recurring, were documented using the clinical records of 79 frontline health and social services (FHSSs) users, aged 14 years and older, living in a community in Nunavik. Each episode of care was divided into 7 stages: (a) detection; (b) assessment; (c) intervention; (d) planning the first follow-up visit; (e) implementation of the first follow-up visit; (f) planning a second follow-up visit; (g) implementation of the second follow-up visit. Sequential analysis of these stages established delays for each one and helped identify when breaks occurred in the continuum of care. Logistic and linear regression analysis determined whether clinical, individual or organizational characteristics influenced the breaks and delays. RESULTS: More than half (62%) the episodes of care were interrupted before the second follow-up. These breaks mostly occurred when planning and completing the first follow-up visit. Episodes of care were more likely to end early when they involved anxiety disorders or symptoms, limited FHSS teams and individuals over 21 years of age. The median delay for the first follow-up visit (30 days) exceeded guideline recommendations significantly (1-2 weeks). CONCLUSION: Clinical primary care approaches for CMDs in Nunavik are currently more reactive than preventive. This suggests that recovery services for those affected are suboptimal.

Barn owl feathers as biomonitors of mercury: sources of variation in sampling procedures.

Given their central role in mercury (Hg) excretion and suitability as reservoirs, bird feathers are useful Hg biomonitors. Nevertheless, the interpretation of Hg concentrations is still questioned as a result of a poor knowledge of feather physiology and mechanisms affecting Hg deposition. Given the constraints of feather availability to ecotoxicological studies, we tested the effect of intra-individual differences in Hg concentrations according to feather type (body vs. flight feathers), position in the wing and size (mass and length) in order to understand how these factors could affect Hg estimates. We measured Hg concentration of 154 feathers from 28 un-moulted barn owls (Tyto alba), collected dead on roadsides. Median Hg concentration was 0.45 (0.076-4.5) mg kg(-1) in body feathers, 0.44 (0.040-4.9) mg kg(-1) in primary and 0.60 (0.042-4.7) mg kg(-1) in secondary feathers, and we found a poor effect of feather type on intra-individual Hg levels. We also found a negative effect of wing feather mass on Hg concentration but not of feather length and of its position in the wing. We hypothesize that differences in feather growth rate may be the main driver of between-feather differences in Hg concentrations, which can have implications in the interpretation of Hg concentrations in feathers. Finally, we recommend that, whenever possible, several feathers from the same individual should be analysed. The five innermost primaries have lowest mean deviations to both between-feather and intra-individual mean Hg concentration and thus should be selected under restrictive sampling scenarios.