Patterns of Adherence to Raltegravir-Based Regimens and the Risk of Virological Failure Among HIV-Infected Patients: The RALTECAPS Cohort Study.

ABSTRACT:: Adherence patterns and their influence on virologic outcome are well characterized for protease inhibitor (PI)- and non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. We aimed to determine how patterns of adherence to raltegravir influence the risk of virological failure. We conducted a prospective multicenter cohort following 81 HIV-infected antiretroviral-naive or experienced subjects receiving or starting twice-a-day raltegravir-based antiretroviral therapy. Their adherence patterns were monitored using the Medication Events Monitoring System. During follow-up (188 days, ±77), 12 (15%) of 81 subjects experienced virological failure. Longer treatment interruption [adjusted odds ratio per 24-hour increase: 2.4; 95% confidence interval: 1.2 to 6.9; P < 0.02] and average adherence (odds ratio per 5% increase: 0.68; 95% confidence interval: 0.46 to 1.00, P < 0.05) were both independently associated with virological failure controlling for prior duration of viral suppression. Timely interdose intervals and high levels of adherence to raltegravir are both necessary to control HIV replication.

Intravitreal ranibizumab for AMD : the individual rhythm of OCT guided retreatment intervals

Purpose: We intended to determine whether the need for retreatmentwith intravitreal ranibizumab follows an individual rhythm in patientswith exudative AMD. Setting: Prospective mono-centre cohort study.Methods: Prospective study. 48 patients with exudative AMD. 3 loadingdoses of ranibizumab, followed by a 12 months PRN regimen guided byearly exudative signs on SD-OCT. An intensified follow-up allowed todetect recurrences early.Results:Mean VA improved by 6.4 letters at month 3 and by 13.1 letters atmonth 12, with a mean of 8.0 injections (range 0-12) during the maintenancephase. The intra-individual variance of the intervals was relativelysmall and ranged within 20% of themean interval in 91% of patients.Thefirst interval was within 1 week of the mean interval in 84% of patients.The retreatment criteria were stable in 89% of patients.Conclusion: The relative stability of the intra-individual intervalsmay allowsimplifying the care for AMDpatients.Theremay be a predictive role for thefirst interval after the loading phase. The functional results of this PRNregimenwith early retreatmentwere excellent. Financial disclosure:None.

Does less frequent routine monitoring of patients on a stable, fully suppressed cART regimen lead to an increased risk of treatment failure?

OBJECTIVE: To investigate whether HIV-infected patients on a stable and fully suppressive combination antiretroviral therapy (cART) regimen could safely be monitored less often than the current recommendations of every 3 months. DESIGN: Two thousand two hundred and forty patients from the EuroSIDA study who maintained a stable and fully suppressed cART regimen for 1 year were included in the analysis. METHODS: Risk of treatment failure, defined by viral rebound, fall in CD4 cell count, development of new AIDS-defining illness, serious opportunistic infection or death, in the 12 months following a year of a stable and fully suppressed regimen was assessed. RESULTS: One hundred thirty-one (6%) patients experienced treatment failure in the 12 months following a year of stable therapy, viral rebound occurred in 99 (4.6%) patients. After 3, 6 and 12 months, patients had a 0.3% [95% confidence interval (CI) 0.1-0.5], 2.2% (95% CI 1.6-2.8) and 6.0% (95% CI 5.0-7.0) risk of treatment failure, respectively. Patients who spent more than 80% of their time on cART with fully suppressed viraemia prior to baseline had a 38% reduced risk of treatment failure, hazard ratio 0.62 (95% CI 0.42-0.90, P = 0.01). CONCLUSION: Patients who have responded well to cART and are on a well tolerated and durably fully suppressive cART regimen have a low chance of experiencing treatment failure in the next 3-6 months. Therefore, in this subgroup of otherwise healthy patients, it maybe reasonable to extend visit intervals to 6 months, with cost and time savings to both the treating clinics and the patients.

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.

Pediatric reference intervals for plasma free and total metanephrines established with a parametric approach: Relevance to the diagnosis of neuroblastoma.

BACKGROUND: Urine catecholamines, vanillylmandelic, and homovanillic acid are recognized biomarkers for the diagnosis and follow-up of neuroblastoma. Plasma free (f) and total (t) normetanephrine (NMN), metanephrine (MN) and methoxytyramine (MT) could represent a convenient alternative to those urine markers. The primary objective of this study was to establish pediatric centile charts for plasma metanephrines. Secondarily, we explored their diagnostic performance in 10 patients with neuroblastoma. PROCEDURE: We recruited 191 children (69 females) free of neuroendocrine disease to establish reference intervals for plasma metanephrines, reported as centile curves for a given age and sex based on a parametric method using fractional polynomials models. Urine markers and plasma metanephrines were measured in 10 children with neuroblastoma at diagnosis. Plasma total metanephrines were measured by HPLC with coulometric detection and plasma free metanephrines by tandem LC-MS. RESULTS: We observed a significant age-dependence for tNMN, fNMN, and fMN, and a gender and age-dependence for tMN, fNMN, and fMN. Free MT was below the lower limit of quantification in 94% of the children. All patients with neuroblastoma at diagnosis were above the 97.5th percentile for tMT, tNMN, fNMN, and fMT, whereas their fMN and tMN were mostly within the normal range. As expected, urine assays were inconstantly predictive of the disease. CONCLUSIONS: A continuous model incorporating all data for a given analyte represents an appealing alternative to arbitrary partitioning of reference intervals across age categories. Plasma metanephrines are promising biomarkers for neuroblastoma, and their performances need to be confirmed in a prospective study on a large cohort of patients. Pediatr Blood Cancer 2015;62:587-593. © 2015 Wiley Periodicals, Inc.

Fluorescence flow cytometer to determine urine particle reference intervals in doping control samples.

Background: Urine is still the matrix of choice to fight against doping, because it can be collected non-invasively during anti-doping tests. Most of the World Anti-Doping Agency's accredited laboratories have more than 20 years experience in analyzing this biological fluid and the majority of the compounds listed in the 2010 Prohibited List - International Standard are eliminated through the urinary apparatus. Storing and transporting urine samples for doping analyses does not include a specific protocol to prevent microbial and thermal degradation. The use of a rapid and reliable screening method could enable determine reference intervals for urine specimens in doping control samples and evaluate notably the prevalence of microbial contamination known to be responsible for the degradation of chemical substances in urine.Methods: The Sysmex(R) UF-500i is a recent urine flow cytometer analyzer capable of quantifying BACT and other urinary particles such as RBC, WBC, EC, DEBRIS, CAST, PATH. CAST, YLC, SRC as well as measuring urine conductivity. To determine urine anti-doping reference intervals, 501 samples received in our laboratory over a period of two months were submitted to an immediate examination. All samples were collected and then transported at room temperature. Analysis of variance was performed to test the effects of factors such as gender, test type [in-competition, out-of-competition] and delivery time.Results: The data obtained showed that most of the urine samples were highly contaminated with bacteria. The other urine particles were also very different according to the factors.Conclusions: The Sysmex(R) UF-500i was capable of providing a snapshot of urine particles present in the samples at the time of the delivery to the laboratory. These particles, BACT in particular, gave a good idea of the possible microbial degradation which had and/or could have occurred in the sample. This information could be used as the first quality control set up in WADA (World Anti-Doping Agency) accredited laboratories to determine if steroid profiles, endogenous and prohibited substances have possibly been altered. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Structured running program for health and performance promotion in hospital employees.

Introduction Our institution (University hospital) is encouraging physical activities for health through various popular sporting events in the city of Lausanne, the biggest of which is a road race of 2, 4, 10 and 20km. Objective To create an efficient and sustainable training program in preparation of the race for a group of motivated hospital employees without any prior experience with structured training and to identifying the benefits and limitations encountered.. Methods Subjects of various fitness levels were recruited by add and agreed to undergo lab and field testing before a 12-week 3 times/week running program, based on maximal aerobic speed (MAS-30/30 sec intervals), running technique exercises and endurance training. The interval session was the only one supervised. Their goal was the 10km (11 subjects) and the 20km (6 subjects). Results A group of 17 subjects (7 male and 10 female), mean age 36.6±7.3 years, VO2max 44.0±5.5 ml/kg/min, filed test interval MAS 15.1±2.4 km/h started the program. 2 were lost because of injury (while skiing). Adherence to interval sessions was excellent, although 3 weekly training sessions proved to be difficult for most of the subjects. Performance in the race was satisfying for all of them, 6/7 subjects having improved their running time from the previous year, the others participated for the first time and 7/8 completed the race satisfyingly, one DNF-ed because of sinusitis. Repeat MAS field test was available for 6 subjects, who improved by 5.9% (p<0.01). Subjectively, all of the participants were very satisfied with improvement, interaction with colleagues from various professions, and with self achievement and confidence. Conclusions Implementation of a structured training program for recreational or non-athletes can be very successful in creating a better self-confidence, a better working environment inside a hospital facility and obviously in improvement of physical fitness and athletic performance. Above all, it can only encourage health institutions to promote the health of their own employees through physical activity, which can allow people to connect through sports. As a result, subjects in this study tend to encourage other employees to be more active and are hungry for more advice and continued offers for physical activities benefiting both them and the institution through better efficiency at work and less absenteeism common to more active people.

First evidence for the two-body charmless baryonic decay

The results of a search for the rare two-body charmless baryonic decays TeX and TeX are reported. The analysis uses a data sample, corresponding to an integrated luminosity of 0.9 fb−1, of pp collision data collected by the LHCb experiment at a centre-of-mass energy of 7 TeV. An excess of TeX candidates with respect to background expectations is seen with a statistical significance of 3.3 standard deviations. This is the first evidence for a two-body charmless baryonic B 0 decay. No significant TeX signal is observed, leading to an improvement of three orders of magnitude over previous bounds. If the excess events are interpreted as signal, the 68.3% confidence level intervals on the branching fractions are $ TeX $ where the first uncertainty is statistical and the second is systematic.

LC-MS/MS based assay and reference intervals in children and adolescents for oxysterols elevated in Niemann-Pick diseases.

BACKGROUND: Niemann-Pick type C (NP-C) is a rare progressive neurodegenerative lipid storage disorder with heterogeneous clinical presentation and challenging diagnostic procedures. Recently oxysterols have been reported to be specific biomarkers for NP-C but knowledge on the intra-individual variation and on reference intervals in children and adolescents are lacking. METHODS: We established a LC-MS/MS assay to measure Cholestane-3β, 5α, 6β-triol (C-triol) and 7-Ketocholesterol (7-KC) following Steglich esterification. To assess reference intervals and intra-individual variation we determined oxysterols in 148 children and adolescents from 0 to 18 years and repeat measurements in 19 of them. RESULTS: The reported method is linear (r>0.99), sensitive (detection limit of 0.03 ng/mL [0.07 nM] for C-triol, and 0.54 ng/mL [1.35 nM] for 7-KC) and precise, with an intra-day imprecision of 4.8% and 4.1%, and an inter-day imprecision of 7.0% and 11.0% for C-triol (28 ng/ml, 67 nM) and 7-KC (32 ng/ml, 80 nM), respectively. Recoveries for 7-KC and C-triol range between 93% and 107%. The upper reference limit obtained for C-triol is 40.4 ng/mL (95% CI: 26.4-61.7 ng/mL, 96.0 nM, 95% CI: 62.8-146.7 nM) and 75.0 ng/mL for 7-KC (95% CI: 55.5-102.5 ng/mL, 187.2 nM, 95% CI: 138.53-255.8 nM), with no age or gender dependency. Both oxysterols have a broad intra-individual variation of 46%±23% for C-triol and 52%±29% for 7-KC. Nevertheless, all Niemann-Pick patients showed increased C-triol levels including Niemann-Pick type A and B patients. CONCLUSIONS: The LC-MS/MS assay is a robust assay to quantify C-triol and 7-KC in plasma with well documented reference intervals in children and adolescents to screen for NP-C in the pediatric population. In addition our results suggest that especially the C-triol is a biomarker for all three Niemann-Pick diseases.

Use of GRADE for assessment of evidence about prognosis : rating confidence in estimates of event rates in broad categories of patients.

Main concepts : The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach defines quality of evidence as confidence in effect estimates; this conceptualization can readily be applied to bodies of evidence estimating the risk of future of events (that is, prognosis) in broadly defined populations In the field of prognosis, a body of observational evidence (including single arms of randomized controlled trials) begins as high quality evidence. The five domains GRADE considers in rating down confidence in estimates of treatment effect-that is, risk of bias, imprecision, inconsistency, indirectness, and publication bias-as well as the GRADE criteria for rating up quality, also apply to estimates of the risk of future of events from a body of prognostic studies Applying these concepts to systematic reviews of prognostic studies provides a ful approach to determine confidence in estimates of overall prognosis in broad populations.

The Confidence Information Ontology: a step towards a standard for asserting confidence in annotations.

Biocuration has become a cornerstone for analyses in biology, and to meet needs, the amount of annotations has considerably grown in recent years. However, the reliability of these annotations varies; it has thus become necessary to be able to assess the confidence in annotations. Although several resources already provide confidence information about the annotations that they produce, a standard way of providing such information has yet to be defined. This lack of standardization undermines the propagation of knowledge across resources, as well as the credibility of results from high-throughput analyses. Seeded at a workshop during the Biocuration 2012 conference, a working group has been created to address this problem. We present here the elements that were identified as essential for assessing confidence in annotations, as well as a draft ontology--the Confidence Information Ontology--to illustrate how the problems identified could be addressed. We hope that this effort will provide a home for discussing this major issue among the biocuration community. Tracker URL: https://github.com/BgeeDB/confidence-information-ontology Ontology URL: https://raw.githubusercontent.com/BgeeDB/confidence-information-ontology/master/src/ontology/cio-simple.obo

Thyroid function in the elderly and sex hormones in elderly men: reference intervals and associations with health

Aims: The aims were to create clinically feasible reference intervals for thyroidstimulating hormone (TSH) and free thyroxine (FT4) and to analyze associations between thyroid function and self-rated health, neuropsychiatric symptoms, depression and dementia in the elderly. The second aim was also to establish reference intervals for sex hormones and to analyze associations between sex hormone levels and self-rated health, symptoms, depression and dementia in elderly men. Subjects and methods: The study population comprised 1252 subjects aged 65 years or over, living in the municipality of Lieto, south-western Finland. Self-rated health, life satisfaction, symptoms, depression, and dementia were assessed with specific questions, clinical examination and tools such as the Zung Self-report Depression Scale and the Mini-Mental State Examination. Independent variables were dichotomized, and associations of these variables with TSH, FT4 or sex hormone levels were assessed. Levels of TSH and FT4 in thyroid disease–free women and women treated with thyroxine were also compared. Results: Elevated concentrations of thyroid peroxidase antibodies (TPOAb) or thyroglobulin antibodies (TgAb) were found to have a marked effect on the upper reference limit for TSH among women, who were thyroid antibody positive more higher than suggested in several recent guidelines. After age adjustment, there were no associations between TSH levels and self-rated health, life satisfaction, or most neuropsychiatric symptoms in the thyroid disease-free population. Although women with thyroxine treatment for primary hypothyroidism had far higher TSH levels than thyroid disease-free women, there were no differences between thyroid-disease free women and women with stable thyroxine treatment regarding self-rated health, life satisfaction or symptoms. Age had a significant positive association with luteinizing hormone (LH), follicle 2 practice, one range in men aged 65 years or over can be used for T, E2 and FSH measured with the AutoDelfia method, but two separate reference intervals should be used for fT, LH and SHBG. After adjustment for age, higher levels of T and fT were associated with better self-rated health (SRH) in the reference population. After adjustment for age and body mass index (BMI), there were no associations between sex hormone concentrations and self-rated health, life satisfaction or most symptoms in concentration. Conclusion: Age-specific reference intervals were derived for thyroid function and sex hormones based on comprehensive data from a community-dwelling population with a high participation rate. The results do not support the need to decrease the upper reference limit for TSH or to lower the optimal TSH target in levothyroxine treatment in older adults, as recommended in recent guidelines. Older age or being overweight symptoms among elderly men. The associations of single symptoms with T levels were inconsistent among elderly men, although the association of low T level with diagnosed depression might be clinically significant.

Reference intervals for 24 laboratory parameters determined in 24-hour urine collections.

BACKGROUND: Reference intervals for many laboratory parameters determined in 24-h urine collections are either not publicly available or based on small numbers, not sex specific or not from a representative sample. METHODS: Osmolality and concentrations or enzymatic activities of sodium, potassium, chloride, glucose, creatinine, citrate, cortisol, pancreatic α-amylase, total protein, albumin, transferrin, immunoglobulin G, α1-microglobulin, α2-macroglobulin, as well as porphyrins and their precursors (δ-aminolevulinic acid and porphobilinogen) were determined in 241 24-h urine samples of a population-based cohort of asymptomatic adults (121 men and 120 women). For 16 of these 24 parameters creatinine-normalized ratios were calculated based on 24-h urine creatinine. The reference intervals for these parameters were calculated according to the CLSI C28-A3 statistical guidelines. RESULTS: By contrast to most published reference intervals, which do not stratify for sex, reference intervals of 12 of 24 laboratory parameters in 24-h urine collections and of eight of 16 parameters as creatinine-normalized ratios differed significantly between men and women. For six parameters calculated as 24-h urine excretion and four parameters calculated as creatinine-normalized ratios no reference intervals had been published before. For some parameters we found significant and relevant deviations from previously reported reference intervals, most notably for 24-h urine cortisol in women. Ten 24-h urine parameters showed weak or moderate sex-specific correlations with age. CONCLUSIONS: By applying up-to-date analytical methods and clinical chemistry analyzers to 24-h urine collections from a large population-based cohort we provide as yet the most comprehensive set of sex-specific reference intervals calculated according to CLSI guidelines for parameters determined in 24-h urine collections.

Labor Market Signaling and Self-Confidence: Wage Compression and the Gender Pay Gap

I extend Spence's signaling model by assuming that some workers are overconfident-they underestimate their marginal cost of acquiring education-and some are underconfident. Firms cannot observe workers' productive abilities and beliefs but know the fractions of high-ability, overconfident, and underconfident workers. I find that biased beliefs lower the wage spread and compress the wages of unbiased workers. I show that gender differences in self-confidence can contribute to the gender pay gap. If education raises productivity, men are overconfident, and women underconfident, then women will, on average, earn less than men. Finally, I show that biased beliefs can improve welfare.

Tracing the Origin and Spread of Agriculture in Europe

The origins of early farming and its spread to Europe have been the subject of major interest for some time. The main controversy today is over the nature of the Neolithic transition in Europe: the extent to which the spread was, for the most part, indigenous and animated by imitatio (cultural diffusion) or else was driven by an influx of dispersing populations (demic diffusion). We analyze the spatiotemporal dynamics of the transition using radiocarbon dates from 735 early Neolithic sites in Europe, the Near East, and Anatolia. We compute great-circle and shortest-path distances from each site to 35 possible agricultural centers of origin—ten are based on early sites in the Middle East and 25 arehypothetical locations set at 58 latitude/longitude intervals. We perform a linear fit of distance versus age (and viceversa) for each center. For certain centers, high correlation coefficients (R . 0.8) are obtained. This implies that a steady rate or speed is a good overall approximation for this historical development. The average rate of the Neolithic spread over Europe is 0.6–1.3 km/y (95% confidence interval). This is consistent with the prediction of demic diffusion(0.6–1.1 km/y). An interpolative map of correlation coefficients, obtained by using shortest-path distances, shows thatthe origins of agriculture were most likely to have occurred in the northern Levantine/Mesopotamian area