Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure.

PURPOSE: To analyze final long-term survival and clinical outcomes from the randomized phase III study of sunitinib in gastrointestinal stromal tumor patients after imatinib failure; to assess correlative angiogenesis biomarkers with patient outcomes. EXPERIMENTAL DESIGN: Blinded sunitinib or placebo was given daily on a 4-week-on/2-week-off treatment schedule. Placebo-assigned patients could cross over to sunitinib at disease progression/study unblinding. Overall survival (OS) was analyzed using conventional statistical methods and the rank-preserving structural failure time (RPSFT) method to explore cross-over impact. Circulating levels of angiogenesis biomarkers were analyzed. RESULTS: In total, 243 patients were randomized to receive sunitinib and 118 to placebo, 103 of whom crossed over to open-label sunitinib. Conventional statistical analysis showed that OS converged in the sunitinib and placebo arms (median 72.7 vs. 64.9 weeks; HR, 0.876; P = 0.306) as expected, given the cross-over design. RPSFT analysis estimated median OS for placebo of 39.0 weeks (HR, 0.505, 95% CI, 0.262-1.134; P = 0.306). No new safety concerns emerged with extended sunitinib treatment. No consistent associations were found between the pharmacodynamics of angiogenesis-related plasma proteins during sunitinib treatment and clinical outcome. CONCLUSIONS: The cross-over design provided evidence of sunitinib clinical benefit based on prolonged time to tumor progression during the double-blind phase of this trial. As expected, following cross-over, there was no statistical difference in OS. RPSFT analysis modeled the absence of cross-over, estimating a substantial sunitinib OS benefit relative to placebo. Long-term sunitinib treatment was tolerated without new adverse events.

Glutathione Precursor, N-Acetyl-Cysteine, Modulates EEG Synchronization in Schizophrenia Patients

Background: Glutathione (GSH) dysregulation at the gene, protein and functional levels observed in schizophrenia patients, and schizophrenia-like anomalies in GSH deficit experimental models, suggest that genetic glutathione synthesis impairments represent one major risk factor for the disease (Do et al., 2009). In a randomized, double blind, placebo controlled, add-on clinical trial of 140 patients, the GSH precursor N-Acetyl-Cysteine (NAC, 2g/day, 6 months) significantly improved the negative symptoms and reduced sideeffects due to antipsychotics (Berk et al., 2008). In a subset of patients (n=7), NAC (2g/day, 2 months, cross-over design) also improved auditory evoked potentials, the NMDA-dependent mismatch negativity (Lavoie et al, 2008). Methods: To determine whether increased GSH levels would modulate the topography of functional brain connectivity, we applied a multivariate phase synchronization (MPS) estimator (Knyazeva et al, 2008) to dense-array EEGs recorded during rest with eyes closed at the protocol onset, the point of crossover, and at its end. Results: The whole-head imaging revealed a specific synchronization landscape in NAC compared to placebo condition. In particular, NAC increased MPS over frontal and left temporal regions in a frequency-specific manner. The topography and direction of MPS changes were similar and robust in all 7 patients. Moreover, these changes correlated with the changes in the Liddle's score of disorganization, thus linking EEG synchronization to the improvement of the clinical picture. Conclusions: The data suggest an important pathway towards new therapeutic strategies that target GSH dysregulation in schizophrenia. They also show the utility of MPS mapping as a marker of treatment efficacy.

A new paradigm of neuromuscular electrical stimulation for the quadriceps femoris muscle.

PURPOSE: Neuromuscular electrical stimulation (NMES) with large electrodes and multiple current pathways (m-NMES) has recently been proposed as a valid alternative to conventional NMES (c-NMES) for quadriceps muscle (re)training. The main aim of this study was to compare discomfort, evoked force and fatigue between m-NMES and c-NMES of the quadriceps femoris muscle in healthy subjects. METHODS: Ten healthy subjects completed two experimental sessions (c-NMES and m-NMES), that were randomly presented in a cross-over design. Maximal electrically evoked force at pain threshold, self-reported discomfort at different levels of evoked force, and fatigue-induced force declines during and following a series of 20 NMES contractions were compared between c-NMES and m-NMES. RESULTS: m-NMES resulted in greater evoked force (P < 0.05) and lower discomfort in comparison to c-NMES (P < 0.05-0.001), but fatigue time course and magnitude did not differ between the two conditions. CONCLUSIONS: The use of quadriceps m-NMES appears legitimate for (re)training purposes because it generated stronger contractions and was less discomfortable than c-NMES (due to multiple current pathways and/or lower current density with larger electrodes).

Distortion control for delay-sensitive sources

We investigate the problem of finding minimum-distortion policies for streaming delay-sensitive but distortion-tolerant data. We consider cross-layer approaches which exploit the coupling between presentation and transport layers. We make the natural assumption that the distortion function is convex and decreasing. We focus on a single source-destination pair and analytically find the optimum transmission policy when the transmission is done over an error-free channel. This optimum policy turns out to be independent of the exact form of the convex and decreasing distortion function. Then, for a packet-erasure channel, we analytically find the optimum open-loop transmission policy, which is also independent of the form of the convex distortion function. We then find computationally efficient closed-loop heuristic policies and show, through numerical evaluation, that they outperform the open-loop policy and have near optimal performance.

Prevalence of Burnout syndrome in health professionals of an onco-hematological pediatric hospital

OBJECTIVE To identify the prevalence of Burnout Syndrome in medical professionals, nurses and nursing technicians working in an Onco-Hematological Pediatric Hospital in São Paulo. METHOD An exploratory, descriptive study with cross-sectional design and quantitative approach, with a sample of 188 health professionals. Data were collected using two self-report instruments: the Maslach Burnout Inventory (MBI-HSS) which is a biosocial data form, and a non-participant observation guide. RESULTS High depersonalization for nurses (29.8%), low job performance for physicians (27.8%), and of nursing technicians (25.5%). High scores were identified in at least two domains of Burnout in 19.2% of nurses, 16.8% of nursing technicians, and 16.6% of doctors. CONCLUSION Health professionals are highly vulnerable to each of the dimensions of Burnout syndrome - namely emotional exhaustion, alienation, and low job performance/satisfaction- in the hospital work.

Effectiveness of a drug dosing service provided by community pharmacists in polymedicated elderly patients with renal impairment a comparative study

Background: Drug dosing errors are common in renal-impaired patients. Appropriate dosing adjustment and drug selection is important to ensure patients" safety and to avoid adverse drug effects and poor outcomes. There are few studies on this issue in community pharmacies. The aims of this study were, firstly, to determine the prevalence of dosing inadequacy as a consequence of renal impairment in patients over 65 taking 3 or more drug products who were being attended in community pharmacies and, secondly, to evaluate the effectiveness of the community pharmacist"s intervention in improving dosing inadequacy in these patients when compared with usual care. Methods: The study was carried out in 40 Spanish community pharmacies. The study had two phases: the first, with an observational, multicentre, cross sectional design, served to determine the dosing inadequacy, the drug-related problems per patient and to obtain the control group. The second phase, with a controlled study with historical control group, was the intervention phase. When dosing adjustments were needed, the pharmacists made recommendations to the physicians. A comparison was made between the control and the intervention group regarding the prevalence of drug dosing inadequacy and the mean number of drug-related problems per patient. Results: The mean of the prevalence of drug dosing inadequacy was 17.5% [95% CI 14.6-21.5] in phase 1 and 15.5% [95% CI 14.5-16.6] in phase 2. The mean number of drug-related problems per patient was 0.7 [95% CI 0.5-0.8] in phase 1 and 0.50 [95% CI 0.4-0.6] in phase 2. The difference in the prevalence of dosing inadequacy between the control and intervention group before the pharmacists" intervention was 0.73% [95% CI (−6.0) - 7.5] and after the pharmacists" intervention it was 13.5% [95% CI 8.0 - 19.5] (p < 0.001) while the difference in the mean of drug-related problems per patient before the pharmacists" intervention was 0.05 [95% CI( -0.2) - 0.3] and following the intervention it was 0.5 [95% CI 0.3 - 0.7] (p < 0.001). Conclusion: A drug dosing adjustment service for elderly patients with renal impairment in community pharmacies can increase the proportion of adequate drug dosing, and improve the drug-related problems per patient. Collaborative practice with physicians can improve these results.

Evidence of an interannual effect of maternal immunization on the immune response of juveniles in a long-lived colonial bird.

Little is known about the maternal transfer of antibodies in natural host-parasite systems despite its possible evolutionary and ecological implications. In domestic animals, the maternal transfer of antibodies can enhance offspring survival via a temporary protection against parasites, but it can also interfere with the juvenile immune response to antigens. We tested the functional role of maternal antibodies in a natural population of a long-lived colonial seabird, the kittiwake (Rissa tridactyla), using a vaccine (Newcastle disease virus vaccine) to mimic parasite exposure combined with a cross-fostering design. We first investigated the role of prior maternal exposure on the interannual transmission of Ab to juveniles. We then tested the effect of these antibodies on the juvenile immune response to the same antigen. The results show that specific maternal antibodies were transferred to chicks 1 year after maternal exposure and that these antibodies were functional, i.e. they affected juvenile immunity. These results suggest that the role of maternal antibodies may depend on the timing and pattern of offspring exposure to parasites, along with the patterns of maternal exposure and the dynamics of her immune response. Overall, our approach underlines that although the transgenerational transfer of antibodies in natural populations is likely to have broad implications, the nature of these effects may vary dramatically among host-parasite systems, depending on the physiological mechanisms involved and the ecological context.

Dreaming without REM sleep.

To test whether mental activities collected from non-REM sleep are influenced by REM sleep, we suppressed REM sleep using clomipramine 50mg (an antidepressant) or placebo in the evening, in a double blind cross-over design, in 11 healthy young men. Subjects were awakened every hour and asked about their mental activity. The marked (81%, range 39-98%) REM-sleep suppression induced by clomipramine did not substantially affect any aspects of dream recall (report length, complexity, bizarreness, pleasantness and self-perception of dream or thought-like mentation). Since long, complex and bizarre dreams persist even after suppressing REM sleep either partially or totally, it suggests that the generation of mental activity during sleep is independent of sleep stage.

What factors influence long-term antidepressant use in primary care? Findings from the Australian diamond cohort study.

BACKGROUND: Antidepressants are one of the most commonly prescribed drugs in primary care. The rise in use is mostly due to an increasing number of long-term users of antidepressants (LTU AD). Little is known about the factors driving increased long-term use. We examined the socio-demographic, clinical factors and health service use characteristics associated with LTU AD to extend our understanding of the factors that may be driving the increase in antidepressant use. METHODS: Cross-sectional analysis of 789 participants with probable depression (CES-D≥16) recruited from 30 randomly selected Australian general practices to take part in a ten-year cohort study about depression were surveyed about their antidepressant use. RESULTS: 165 (21.0%) participants reported <2 years of antidepressant use and 145 (18.4%) reported ≥2 years of antidepressant use. After adjusting for depression severity, LTU AD was associated with: single (OR 1.56, 95%CI 1.05-2.32) or recurrent episode of depression (3.44, 2.06-5.74); using SSRIs (3.85, 2.03-7.33), sedatives (2.04, 1.29-3.22), or antipsychotics (4.51, 1.67-12.17); functional limitations due to long-term illness (2.81, 1.55-5.08), poor/fair self-rated health (1.57, 1.14-2.15), inability to work (2.49, 1.37-4.53), benefits as main source of income (2.15, 1.33-3.49), GP visits longer than 20min (1.79, 1.17-2.73); rating GP visits as moderately to extremely helpful (2.71, 1.79-4.11), and more self-help practices (1.16, 1.09-1.23). LIMITATIONS: All measures were self-report. Sample may not be representative of culturally different or adolescent populations. Cross-sectional design raises possibility of "confounding by indication". CONCLUSIONS: Long-term antidepressant use is relatively common in primary care. It occurs within the context of complex mental, physical and social morbidities. Whilst most long-term use is associated with a history of recurrent depression there remains a significant opportunity for treatment re-evaluation and timely discontinuation.

Geosynthetic Reinforced Soil for Low-Volume Bridge Abutments, January 2012

This report presents a review of literature on geosynthetic reinforced soil (GRS) bridge abutments, and test results and analysis from two field demonstration projects (Bridge 1 and Bridge 2) conducted in Buchanan County, Iowa, to evaluate the feasibility and cost effectiveness of the use of GRS bridge abutments on low-volume roads (LVRs). The two projects included GRS abutment substructures and railroad flat car (RRFC) bridge superstructures. The construction costs varied from $43k to $49k, which was about 50 to 60% lower than the expected costs for building a conventional bridge. Settlement monitoring at both bridges indicated maximum settlements ≤1 in. and differential settlements ≤ 0.2 in transversely at each abutment, during the monitoring phase. Laboratory testing on GRS fill material, field testing, and in ground instrumentation, abutment settlement monitoring, and bridge live load (LL) testing were conducted on Bridge 2. Laboratory test results indicated that shear strength parameters and permanent deformation behavior of granular fill material improved when reinforced with geosynthetic, due to lateral restraint effect at the soilgeosynthetic interface. Bridge LL testing under static loads indicated maximum deflections close to 0.9 in and non-uniform deflections transversely across the bridge due to poor load transfer between RRFCs. The ratio of horizontal to vertical stresses in the GRS fill was low (< 0.25), indicating low lateral stress on the soil surrounding GRS fill material. Bearing capacity analysis at Bridge 2 indicated lower than recommended factor of safety (FS) values due to low ultimate reinforcement strength of the geosynthetic material used in this study and a relatively weak underlying foundation layer. Global stability analysis of the GRS abutment structure revealed a lower FS than recommended against sliding failure along the interface of the GRS fill material and the underlying weak foundation layer. Design and construction recommendations to help improve the stability and performance of the GRS abutment structures on future projects, and recommendations for future research are provided in this report.

Neuroanatomical and neuropsychological features of elderly euthymic depressed patients with early- and late-onset.

BACKGROUND: Whether or not cognitive impairment and brain structure changes are trait characteristics of late-life depression is still disputed. Previous studies led to conflicting data possibly because of the difference in the age of depression onset. In fact, several lines of evidence suggest that late-onset depression (LOD) is more frequently associated with neuropsychological deficits and brain pathology than early-onset depression (EOD). To date, no study explored concomitantly the cognitive profile and brain magnetic resonance imaging (MRI) patterns in euthymic EOD and LOD patients. METHOD: Using a cross-sectional design, 41 remitted outpatients (30 with EOD and 11 with LOD) were compared to 30 healthy controls. Neuropsychological evaluation concerned working memory, episodic memory, processing speed, naming capacity and executive functions. Volumetric estimates of the amygdala, hippocampus, entorhinal and anterior cingulate cortex were obtained using both voxel-based and region of interest morphometric methods. White matter hyperintensities were assessed semiquantitatively. RESULTS: Both cognitive performance and brain volumes were preserved in euthymic EOD patients whereas LOD patients showed a significant reduction of episodic memory capacity and a higher rate of periventricular hyperintensities compared to both controls and EOD patients. CONCLUSION: Our results support the dissociation between EOD thought to be mainly related to psychosocial factors and LOD that is characterized by increasing vascular burden and episodic memory decline.

Increased eeg synchronization in schizophrenia patients by the glutathione precursor, n-acetyl-cysteine

Background: Glutathione (GSH) dysregulation at the gene, protein and functional levels observed in schizophrenia patients, and schizophrenia-like anomalies in GSH deficit experimental models, suggest that genetic glutathione synthesis impairments represent one major risk factor for the disease (Do et al., 2009). In a randomized, double blind, placebo controlled, add-on clinical trial of 140 patients, the GSH precursor N-Acetyl-Cysteine (NAC, 2 g/day, 6 months) significantly improved the negative symptoms and reduced side-effects due to antipsychotics (Berk et al., 2008). In a subset of patients (n=7), NAC (2 g/day, 2 months, cross-over design) also improved auditory evoked potentials, the NMDAdependent mismatch negativity (Lavoie et al, 2008). Methods: To determine whether increased GSH levels would modulate the topography of functional brain connectivity, we applied a multivariate phase synchronization (MPS) estimator (Knyazeva et al, 2008) to dense-array EEGs recorded during rest with eyes closed at the protocol onset, the point of crossover, and at its end. Phase synchronization phenomena are appealing because they can be associated to synchronized phases while the amplitudes stay uncorrelated. MPS measures the degree of interactions among the recorded neuronal oscillators by quantifiying to what extent they behave like a macro-oscillator (i.e. the oscillators are phase synchronous). To assess the whole-head synchronization topography, we computed the MPS sensor-wise over the cluster of locations defined by the sensor itself and he surrounding ones belonging to its second-order neighborhood (Carmeli et al, 2005). Such a cluster spans about 12 cm on average. Abstracts 245 Results: The whole-head imaging revealed a specific synchronization landscape in NAC compared to placebo condition. In particular, NAC increased MPS over frontal and left temporal regions in a frequency-specific manner. Importantly, the topography and direction of MPS changes were similar and robust in all 7 patients. Moreover, these changes correlated with the changes in the Liddle's score of disorganization (Liddle, 1987) thus linking EEG synchronization to the improvement of clinical picture. Discussion: The data suggest an important pathway towards new therapeutic strategies that target GSH dysregulation in schizophrenia. They also show the utility of MPS mapping as a marker of treatment efficacy.

Gender inequalities in occupational health related to the unequal distribution of working and employment conditions: a systematic review

Gender inequalities exist in work life, but little is known about their presence in relation to factors examined in occupation health settings. The aim of this study was to identify and summarize the working and employment conditions described as determinants of gender inequalities in occupational health in studies related to occupational health published between 1999 and 2010. A systematic literature review was undertaken of studies available in MEDLINE, EMBASE, Sociological Abstracts, LILACS, EconLit and CINAHL between 1999 and 2010. Epidemiologic studies were selected by applying a set of inclusion criteria to the title, abstract, and complete text. The quality of the studies was also assessed. Selected studies were qualitatively analysed, resulting in a compilation of all differences between women and men in the prevalence of exposure to working and employment conditions and work-related health problems as outcomes. Most of the 30 studies included were conducted in Europe (n=19) and had a cross-sectional design (n=24). The most common topic analysed was related to the exposure to work-related psychosocial hazards (n=8). Employed women had more job insecurity, lower control, worse contractual working conditions and poorer self-perceived physical and mental health than men did. Conversely, employed men had a higher degree of physically demanding work, lower support, higher levels of effort-reward imbalance, higher job status, were more exposed to noise and worked longer hours than women did. This systematic review has identified a set of working and employment conditions as determinants of gender inequalities in occupational health from the occupational health literature. These results may be useful to policy makers seeking to reduce gender inequalities in occupational health, and to researchers wishing to analyse these determinants in greater depth.

Contribution of genome-wide significant single-nucleotide polymorphisms and antiretroviral therapy to dyslipidemia in HIV-infected individuals: a longitudinal study.

BACKGROUND: HIV-infected individuals have an increased risk of myocardial infarction. Antiretroviral therapy (ART) is regarded as a major determinant of dyslipidemia in HIV-infected individuals. Previous genetic studies have been limited by the validity of the single-nucleotide polymorphisms (SNPs) interrogated and by cross-sectional design. Recent genome-wide association studies have reliably associated common SNPs to dyslipidemia in the general population. METHODS AND RESULTS: We validated the contribution of 42 SNPs (33 identified in genome-wide association studies and 9 previously reported SNPs not included in genome-wide association study chips) and of longitudinally measured key nongenetic variables (ART, underlying conditions, sex, age, ethnicity, and HIV disease parameters) to dyslipidemia in 745 HIV-infected study participants (n=34 565 lipid measurements; median follow-up, 7.6 years). The relative impact of SNPs and ART to lipid variation in the study population and their cumulative influence on sustained dyslipidemia at the level of the individual were calculated. SNPs were associated with lipid changes consistent with genome-wide association study estimates. SNPs explained up to 7.6% (non-high-density lipoprotein cholesterol), 6.2% (high-density lipoprotein cholesterol), and 6.8% (triglycerides) of lipid variation; ART explained 3.9% (non-high-density lipoprotein cholesterol), 1.5% (high-density lipoprotein cholesterol), and 6.2% (triglycerides). An individual with the most dyslipidemic antiretroviral and genetic background had an approximately 3- to 5-fold increased risk of sustained dyslipidemia compared with an individual with the least dyslipidemic therapy and genetic background. CONCLUSIONS: In the HIV-infected population treated with ART, the weight of the contribution of common SNPs and ART to dyslipidemia was similar. When selecting an ART regimen, genetic information should be considered in addition to the dyslipidemic effects of ART agents.

Anàlisi del coneixement, de l'actitud i de l'ús que fan els cuidadors informals dels malalts d' Alzheimer en el domicili, de les contencions mecàniques i farmacològiques

L’objectiu d’aquest estudi consisteix en saber quins coneixements posseeixen, quines actituds i quin ús fan els cuidadors informals de persones diagnosticades d’Alzheimer en el domicili, de les contencions mecàniques i farmacològiques. Aquest projecte es tracta d’un disseny exploratori, descriptiu i transversal. Per a realitzar-lo es prendrà com a mostra a cuidadors principals informals, que tinguin al seu càrrec persones diagnosticades d’Alzheimer que siguin usuàries de l’atenció primària dels serveis sanitaris públics, de la província de Barcelona. L’estudi integrarà dues fases: la primera consistirà en realitzar una prova pilot a un nombre reduït de persones que servirà per avaluar i perfeccionar l’eina de la recollida de dades (els instruments a emprar seran una enquesta d’elaboració pròpia i entrevistes) i la segona consistirà en efectuar la recollida de dades a partir de l’enquesta modificada i validada en la fase anterior. En la fase pilot es realitzarà l’anàlisi de les dades a través de la tècnica coneguda com <> i en la fase següent, s’utilitzarà el paquet estadístic SPSS versió 21.0.0.