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The demand of social skills interventions for people with ASD has grown in recent years. The main goal of this research was to study social skills: "responding to interaction" and "initiating interaction", and to capture whether there were differences between an initial and a final session in a program for children with ASD. Additionally, we aimed to compare social skills patterns according to the VIQ level. The sample (N = 20) was divided into 2 subgroups depending on whether the VIQ was > 90 or < 90. We employed a mixed methods approach based on a systematic observation of social behaviors. The observational design was nomothetic, follow-up, and multidimensional. Once we confirmed inter-observer reliability for the ad hoc observational instrument we performed descriptive statistics and polar coordinate analysis using LINCE software. The results show high intragroup and intergroup variability. In general, participants with VIQ < 90 showed a better improvement in responding to interaction, whereas participants with VIQ > 90 showed more complex patterns to initiate interactions. The polar coordinate technique was useful for detecting significant relationships between autism's social micro-behaviors. Results and information obtained through observational methodology could allow professionals to understand communication and interaction of participants.

In vivo pharmacological inhibition of soluble epoxide hydrolase (sEH) reduces inflammatory diseases, including acute pancreatitis (AP). Adamantyl ureas are very potent sEH inhibitors, but the lipophilicity and metabolism of the adamantane group compromise their overall usefulness. Herein, we report that the replacement of a methylene unit of the adamantane group by an oxygen atom increases the solubility, permeability, and stability of three series of urea-based sEH inhibitors. Most of these oxa-analogues are nanomolar inhibitors of both the human and murine sEH. Molecular dynamics simulations rationalize the molecular basis for their activity and suggest that the presence of the oxygen atom on the adamantane scaffold results in active site rearrangements to establish a weak hydrogen bond. The 2-oxaadamantane 22, which has a good solubility, microsomal stability, and selectivity for sEH, was selected for further in vitro and in vivo studies in models of cerulein-induced AP. Both in prophylactic and treatment studies, 22 diminished the overexpression of inflammatory and endoplasmic reticulum stress markers induced by cerulein and reduced the pancreatic damage.

285 Background: Despite the advent of immunotherapy in urothelial cancer, there is still a need to find effective cytotoxic agents beyond first line. Vinflunine is EMA approved and used in several European countries. Docetaxel is widely used in second line. Cabazitaxel is a taxane with clinical activity in docetaxel-refractory cancers. A randomised study was conducted to compare its efficacy vs vinflunine. Methods: This was a multicenter, randomised, open-label, phase II/III study, following a Simon’s optimal method with early stopping rules based on an interim futility analysis. The study (NCT01830231) was supported by a research grant from Sanofi. The trial was aiming at superiority of cabazitaxel compared to vinflunine in patients progressing to platinum. ECOG, anemia and liver metastases were stratification factors. The primary objective for the phase II study was overall response rate (ORR), and overall survival (OS) for the phase III. Secondary objectives included safety and progression free survival (PFS). Results: 70 patients were included in the phase II across 19 institutions in Europe. Baseline characteristics were well balanced between the two arms. Mean age 63 years; 56 (80%) were men. No statistically significant differences were detected between arms for ORR (p=0.26). Three patients (13%) obtained a partial response on cabazitazel (95% CI, 2.7–32.4) and six patients (30%) in the vinflunine arm (95% CI, 11.9–54.3). Median PFS for cabazitaxel was 1.9 months versus 2.9 months for vinflunine (p=0.039). The study did not proceed to phase III since the futility analysis showed a lack of efficacy of cabazitaxel. A trend for OS benefit was found favouring vinflunine (median 7.6 versus 5.5 months). Grade 3-4 related adverse events were seen in 41% patients with no difference between arms. The most frequent toxicities associated with cabazitaxel were asthenia, diarrhea, anemia and febrile neutropenia. Conclusions: This phase II/III second line bladder trial comparing cabazitaxel with vinflunine was closed early when the phase II showed a lack of efficacy of the cabazitaxel arm. Vinflunine results were consistent with those observed in the phase III. Clinical trial information: NCT01830231.

BackgroundThe proportion of older people has dramatically increased in recent decades. Moreover, social and demographic trends show a global increase of older people at risk of loneliness and lack of social relationships. The objective of this study was to evaluate the process, the effectiveness and the cost-effectiveness of a planned 22 weekly group sessions called School of Health for Older People to reduce social isolation.MethodsThis is a mixed methods multi-approach evaluation that includes: 1) A qualitative evaluation among coordinators and participants taking part in the intervention, through in depth-interviews and focus groups, respectively. The main topics covered will be positive and negative aspects of the intervention, suggestions for its improvement, opinions on different aspects of the intervention, and perceived benefits; 2) A quantitative quasi-experimental design, comparing a group of individuals taking part in the intervention with another group with similar characteristics not receiving the intervention. Data will be collected at the beginning and at the end of the intervention. Social support will be measured through questions drawn from the Medical Outcomes Study and the National Social Life, Health, and Aging Project questionnaires. Psychological morbidity will be measured through Goldberg's General Health Questionnaire, and Health-related Quality of Life will be measured through the EuroQoL questionnaire. Information on visits to the primary care center in the years before and after the intervention will be obtained from the electronic records of the primary care centers; 3) A cost-utility analysis, which will be conducted from a health system (primary care) perspective, including direct costs of the program and the primary care health services used. The effects of the intervention will be measured on quality-adjusted life years.DiscussionThere is an urgent need for studies assessing the effectiveness and the efficiency of potential interventions to reduce social isolation among older persons. The results of this study will help to fill the knowledge gap in this area and might be especially useful for the development of social and public health policies and programs for older people in disadvantaged neighborhoods in urban areas.Trial registrationNCT03142048 retrospectively registered (April 11, 2017).

BACKGROUND AND PURPOSE: FGF21 has emerged as a therapeutic strategy for treating type 2 diabetes mellitus due to its antidiabetic effects, and this has led to the development of long-acting analogues of FGF21. However, these compounds have some limitations, including a need to be administered by s.c. injection and their prolonged pharmacodynamic effect compared with native FGF21, which might be responsible for their reported side effects. EXPERIMENTAL APPROACH: We have previously demonstrated that i.p. administration of haem-regulated eukaryotic translation initiation factor 2a kinase (HRI) activators increases hepatic and circulating levels of FGF21. In this study, we examined the effects of p.o. administration of a new HRI activator, EPB-53, on high-fat diet (HFD)-induced glucose intolerance, hepatic steatosis, and hypertriglyceridaemia, and compared them with those of metformin. KEY RESULTS: EPB-53 administration for the last 2 weeks, to mice fed a HFD for 10 weeks, reduced body weight gain, improved glucose intolerance, and prevented hepatic steatosis and hypertriglyceridaemia, whereas metformin only ameliorated glucose intolerance. Moreover, EPB-53, similar to the reported effects of FGF21, reduced lipogenesis in cultured human hepatocytes and in the liver of mice fed a HFD. Administration of EPB-53 to Fgf21-knockout mice had no effects, demonstrating that its efficacy is dependent on this hormone. CONCLUSIONS AND IMPLICATIONS: Overall, the findings of this study demonstrate that p.o. administration of HRI activators, by increasing FGF21, is a promising strategy for the treatment of type 2 diabetes mellitus and non-alcoholic fatty liver disease.

Over the last 20 years, researchers have been mixing qualitative and quantitative approaches, but mixed methods research represents a new movement that arose in response to the currents of qualitative and quantitative research, considered separately. Little has been published on the use of polar coordinate analysis in psychotherapy. This type of analysis can provide detailed information and integrate the qualitative-quantitative analysis. Even less has been published on the analysis of ASD children's behavior. The main aim of this study was to implement this mixed methods methodology to analyze patterns of social behaviors in a group of adolescents with ASD during a group social competence intervention program. Moreover, we wanted to see whether an observational scale could be combined fruitfully with polar coordinate analysis and to investigate whether typical ASD behaviors show similar interrelations (prospective and retrospective sequentialities) as behaviors observed in psychotherapy. We used an adaptation from the Social Skills Training Program (UC Davis, California). We observed that each participant took a unique course, increasing or decreasing the number and quality of their social behaviors. In accordance with previous literature, results suggest some increment in the amount of appropriate social conduct. We did not detect a generalized progress pattern but agreed that there were changes between the beginning and end of the intervention. Therefore, we consider that observational methodology is useful in the field of psychotherapy and ASD, offering detailed information about changes and development that cannot be obtained with other traditional measures, such as questionnaires.

Cancer-associated pain has traditionally been treated with opioid analgesics, often in escalating doses. Opioid-induced constipation (OIC) is a common problem associated with chronic use of opioid analgesics. Typical treatment strategies to alleviate constipation are based on dietary changes, exercise, and laxatives. However, laxatives have a nonspecific action and do not target underlying mechanisms of OIC. This article will review prevalent, clinical presentation and recommendations for the treatment of OIC. An independent literature search was carried out by the authors. We reviewed the literature for randomized controlled trials that studied the efficacy of laxatives, naloxone, and naloxegol in treating OIC. Newer strategies addressing the causal pathophysiology of OIC are needed for a more effective assessment and management of OIC. Finally, traditional recommended therapies are appraised and compared with the latest pharmacological developments. Future research should address whether naloxegol is more efficacious by its comparison directly with first-line treatments, including laxatives.

Objective: The very low-density lipoprotein receptor (VLDLR) plays an important role in the development of hepatic steatosis. In this study, we investigated the role of Peroxisome Proliferator-Activated Receptor (PPAR)beta/delta and fibroblast growth factor 21 (FGF21) in hepatic VLDLR regulation. Methods: Studies were conducted in wild-type and Ppar beta/delta-null mice, primary mouse hepatocytes, human Huh-7 hepatocytes, and liver biopsies from control subjects and patients with moderate and severe hepatic steatosis. Results: Increased VLDLR levels were observed in liver of Ppar beta/delta-null mice and in Ppar beta/delta-knocked down mouse primary hepatocytes through mechanisms involving the heme-regulated eukaryotic translation initiation factor 2 alpha (e1F2 alpha) kinase (HRI), activating transcription factor (ATF) 4 and the oxidative stress-induced nuclear factor (erythroid-derived2)-like 2 (Nrf2) pathways. Moreover, by using a neutralizing antibody against FGF21, Fgf21-null mice and by treating mice with recombinant FGF21, we show that FGF21 may protect against hepatic steatosis by attenuating endoplasmic reticulum (ER) stress-induced VLDLR upregulation. Finally, in liver biopsies from patients with moderate and severe hepatic steatosis, we observed an increase in VLDLR levels that was accompanied by a reduction in PPAR beta/delta mRNA abundance and DNA-binding activity compared with control subjects. Conclusions: Overall, these findings provide new mechanisms by which PPAR beta/delta and FGF21 regulate VLDLR levels and influence hepatic steatosis development. 2017 The Authors. Published by Elsevier GmbH.

Despite the advent of immunotherapy in urothelial cancer, there is still a need to find effective cytotoxic agents beyond first and second lines. Vinflunine is the only treatment approved in this setting by the European Medicines Agency and taxanes are also widely used in second line. Cabazitaxel is a taxane with activity in docetaxel-refractory cancers. A randomized study was conducted to compare its efficacy versus vinflunine.

Fibroblast growth factor 21 (FGF21), a peptide hormone with pleiotropic effects on carbohydrate and lipid metabolism, is considered a target for the treatment of diabetes. We investigated the role of peroxisome proliferator-activated receptor (PPAR) ß/d deficiency in hepatic FGF21 regulation. Increased Fgf21 expression was observed in the livers of PPARß/d-null mice and in mouse primary hepatocytes when this receptor was knocked down by small interfering RNA (siRNA). Increased Fgf21 was associated with enhanced protein levels in the heme-regulated eukaryotic translation initiation factor 2a (eIF2a) kinase (HRI). This increase caused enhanced levels of phosphorylated eIF2a and activating transcription factor (ATF) 4, which is essential for Fgf21-induced expression. siRNA analysis demonstrated that HRI regulates Fgf21 expression in primary hepatocytes. Enhanced Fgf21 expression attenuated tunicamycin-induced endoplasmic reticulum stress, as demonstrated by using a neutralizing antibody against FGF21. Of note, increased Fgf21 expression in mice fed a high-fat diet or hepatocytes exposed to palmitate was accompanied by reduced PPARß/d and activation of the HRI-eIF2a-ATF4 pathway. Moreover, pharmacological activation of HRI increased Fgf21 expression and reduced lipid-induced hepatic steatosis and glucose intolerance, but these effects were not observed in Fgf21-null mice. Overall, these findings suggest that HRI is a potential target for regulating hepatic FGF21 levels.

BACKGROUND: smoking. The purpose of the study was to use Conversational Analysis to enhance understanding of the process in Motivational Interviewing sessions carried out by primary care doctors and nurses to motivate their patients to quit smoking. The present study is a substudy of the Systematic Intervention on Smoking Habits in Primary Health Care Project (Spanish acronym: ISTAPS). interview sessions were conducted with two of the nine) in the ISTAPS study who were current smokers and scored fewer than 5 points on the Richmond test that measures motivation to quit smoking were videotaped and transcribed. A total of 11 interviews conducted by five primary health care professionals in Barcelona, Spain, were analysed. Qualitative Content Analysis was used to develop an analytical guide for coding transcriptions. Conversation Analysis allowed detailed study of the exchange of words during the interaction. on readiness to change, and summary. The interaction was constructed during an office visit, where interactional dilemmas arise and can be resolved in various ways. Some actions by professionals (use of reiterations, declarations, open-ended questions) helped to construct a framework of shared relationship; others inhibited this relationship (focusing on risks of smoking, clinging to the protocol, and prematurely emphasizing change). Some professionals tended to resolve interactional dilemmas (e.g., resistance) through a confrontational or directive style. Interactions that did not follow Motivational Interviewing principles predominated in seven of the interviews analysed. increases when a health professional encounters individuals with low motivation for change, and interactional dilemmas may occur that make it difficult to follow Motivational Interview principles. Incorporating different forms of expression during the Motivational Interviewing could help to build patient-centred health care relationships and, for patients with low motivation to stop smoking, offer an opportunity to reflect on tobacco use during the office visit. The study findings could be included in professional training to improve the quality of motivational interviewing. DDEUIT

Background: In contrast with HIV-1, information about drug resistance in HIV-2 is scarce and mainly derived from small series of patients failing antiretroviral therapy. Methods: The spectrum of changes in the reverse transcriptase (RT), protease (PR) and integrase (INT) genes was examined in HIV-2 individuals enrolled in the HIV-2 Spanish register. Results: From a total of 236 HIV-2-infected individuals registered in Spain from 1989 to June 2010, 53 PR, 44 RT and 8 INT sequences were obtained. Low plasma viraemia precluded collection of this information from most of the remaining cases. No major mutations associated with drug resistance in HIV-1 were recognized in 29 PR, 20 RT and 5 INT sequences from antiretroviral-naive HIV-2 individuals, although natural polymorphisms with potential effects on susceptibility to PR inhibitors were recognized at 10 positions (L10V/I, V32I, M36I, M46I, I47V, Q58E, A71V/I, G73A, V82I and L89I/V) and for nucleoside reverse transcriptase inhibitors at three positions (T69N, V75I and K219E). In 24 antiretroviral-experienced patients with virological failure the most frequent major RT resistance mutations were M184V (58%), Q151M (33%) and K65R (21%), which are rarely seen thymidine analogue mutations. In PR the most frequent major changes were V47A (17%), I54M (17%), I82F (13%), L90M (29%) and L99F (29%). Two of the three patients who failed on raltegravir had N155H in the INT region. Conclusions: Drug resistance mutations in HIV-2 are selected at the same positions as in HIV-1, although with different frequency. Polymorphisms in the RT and PR associated with drug resistance in HIV-1 as compensatory changes are common in untreated HIV-2 subjects. These findings highlight the need for specific guidelines for interpreting genotypic resistance patterns in HIV-2 infection. © The Author 2011. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

The aim of this study was to establish the test-retest reliability of a knee extensor and flexor muscle fatigue protocol using a biodex system 3 isokinetic dynamometer.Three-outpatient Rehabilitation Departments undertook the study. Fatigue was evaluated in the dominant knee of 90 healthy female volunteers, non-sportswomen, aged between 20 and 40. They performed 40 consecutive concentric knee flexions and extensions, at 120 degrees /s, on a Biodex 3 isokinetic dynamometer. Two evaluations were done over a period of seven days. Analysed variables were: maximal repetition of total work, maximal work repetition number, work to body weight ratio, total work, work during first and last third of the protocol, fatigue ratio, work fatigue. Statistical analysis determined mean values, medians and box-plots. Intraclass Correlation Coefficients (ICC) (confidence interval 95 %), t-test and one-way analysis of variance (ANOVA) evaluated reliability. Difference of means (di), standard error of measurement (SEM) and 95% of interval confidence (IC di) were also calculated (P0.05).All participants completed the study. Reliability data were excellent (ICC0.75) for total work (0.85), work during first third (0.80) and last third (0.80) in extension, and for total work in flexion. Reliability data were fair to good (ICC 0.4-0.75) for the rest of the variables. Median varied less than 20% in all cases during test-retest.This knee fatigue protocol is reliable for flexion and extension, above all when using the total work as a variable. The desirability of multicentre studies in rehabilitation and standardisation of protocols is emphasised.

Background: Strength training has been proposed by several authors to treat Lateral Epicondylitis. However, there is still a lack of information concerning muscle weakness and its relationship to imbalances and fatigability of forearm muscles during dynamic conditions in subjects after epicondylitis recovery. Aim: To analyze the relationship between lateral humeral epicondylitis, and forearm muscle strength and fatigue. Setting: Rehabilitation specialized center Population: Cross-sectional study in eight former epicondylitis men free of symptoms and actively working at the moment of the evaluation and eight healthy men volunteers. Methods: Isokinetic tests were performed at different velocities in order to assess strength in concentric and eccentric contractions. Additionally, a long-term concentric test was carried out in order to analyze strength during endurance. The following variables were analyzed: Average torque of dorsal and palmar flexors of the wrist and ratio of agonist/antagonist for non-endurance contractions; length of initial and final plateaus and the slope of average torque decay during the endurance test. Results: In both groups, average torque produced by palmar flexor muscles was higher than that produced by dorsal flexor muscles. Patients showed higher strength in palmar flexor muscles, whereas dorsal flexor strength was similar for both populations. Palmar flexor vs. dorsal flexor ratio was significantly higher in patients for eccentric contractions. Regarding fatigue, results showed that torque decreased earlier in patients. Conclusions and clinical rehabilitation impact: Both palmar flexor force and palmar/dorsal ratio in eccentric exercise were significantly higher in patients. This finding indicates a muscular imbalance in patients underlying the epicondylitis condition. Additionally, former patients fatigued earlier. Findings indicate that muscle imbalances and fatigability might be related to lateral epicondylitis. […]

Hipercolesterolèmia familiar; Aterosclerosi; Puntuació de risc genètic Familial hypercholesterolemia; Atherosclerosis; Genetic risk scores Hipercolesterolemia familiar; Aterosclerosis; Puntuaciones de riesgo genético Familial hypercholesterolemia (FH) is associated with mutations in the low-density lipoprotein (LDL) receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) genes. A pathological variant has not been identified in 30–70% of clinically diagnosed FH patients, and a burden of LDL cholesterol (LDL-c)-raising alleles has been hypothesized as a potential cause of hypercholesterolemia in these patients. Our aim was to study the distribution of weighted LDL-c-raising single-nucleotide polymorphism (SNP) scores (weighted gene scores or wGS) in a population recruited in a clinical setting in Catalonia. The study included 670 consecutive patients with a clinical diagnosis of FH and a prior genetic study involving 250 mutation-positive (FH/M+) and 420 mutation-negative (FH/M−) patients. Three wGSs based on LDL-c-raising variants were calculated to evaluate their distribution among FH patients and compared with 503 European samples from the 1000 Genomes Project. The FH/M− patients had significantly higher wGSs than the FH/M+ and control populations, with sensitivities ranging from 42% to 47%. A wGS based only on the SNPs significantly associated with FH (wGS8) showed a higher area under the receiver operating characteristic curve, and higher diagnostic specificity and sensitivity, with 46.4% of the subjects in the top quartile. wGS8 would allow for the assignment of a genetic cause to 66.4% of the patients if those with polygenic FH are added to the 37.3% of patients with monogenic FH. Our data indicate that a score based on 8 SNPs and the75th percentile cutoff point may identify patients with polygenic FH in Catalonia, although with limited diagnostic sensitivity and specificity This research was funded by the Instituto de Salud Carlos III (ISCIII), and Fondo Europeo de DesarrolloRegional (FEDER) “Una manera de hacer Europa”, grants PI14/01648 (to F.B.-V. and J.M.M.-C.) and PI18/00164(to F.B.-V.), as well as by Fundacióla Maratóde TV3 grant 20152431 (to F.B.-V.), Centro de Investigación Biomédicaen Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), and Centro de Investigación Biomédicaen Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN). CIBERDEM and CIBEROBN are ISCIII projects