HIV treatment outcomes following antiretroviral therapy initiation and monitoring: A workplace program in Papua, Indonesia

Background Papua Province, Indonesia is experiencing an on-going epidemic of Human Immunodeficiency Virus (HIV) infection, with an estimated 9-fold greater prevalence than the overall national rate. This study reviewed the treatment outcomes of an HIV-infected cohort on Antiretroviral Therapy (ART) and the predictors in terms of immunological recovery and virological response. Methods ART-naive individuals in a workplace HIV program in southern Papua were retrospectively analyzed. Patients were assessed at 6, 12 and 36 months after ART initiation for treatment outcomes, and risk factors for virological suppression (viral load (VL) = 1 log decrease in VL at 6 months (OR 19.25, p<0.001). Higher baseline CD4 was significantly correlated with better immunological outcomes, and lower likelihood of experiencing immunological failure (p <0.001). Conclusion Virological response at six months after beginning ART is the strongest predictor of viral suppression at 12 and 36 months, and may help in identifying patients needing additional adherence therapy support. Higher baseline CD4 positively affects the immunological outcomes of patients. The findings indicate HIV control programs should prioritize the availability of VL testing and begin ART regardless of CD4 counts in infected patients

Indicadores de rendimiento defensivo en baloncesto en ganadores y perdedores

El objetivo de la presente investigación es analizar las diferencias en la utilización a lo largo del partido de algunos aspectos técnico-tácticos defensivos en baloncesto, entre equipos ganadores y perdedores. Se analizaron todas las fases de ataque (n=2305) llevadas a cabo a lo largo de 12 partidos de la etapa de playoff del campeonato chileno Dimayor jugado el año 2006. En cada fase de ataque se analizaron las siguientes variables en relación con el equipo defensor: (1) Tipo de defensa (individual, zonal, mixta, otras); (2) Presión en la transición ofensiva; (3) Cambios defensivos; (4) Ayudas defensivas; (5) Pases interiores; (6) Grado de oposición al lanzamiento (bajo, medio, alto); (7) Puntos recibidos; (8) Rebotes defensivos; (9) Resultado final del partido. Los resultados más significativos muestran que: a) a lo largo de todo el partido, los equipos ganadores alternan más entre la defensa individual y zonal, mientras que los perdedores alternan entre individual, zonal y mixta; b) las diferencias de puntos en el marcador se producen en el primer y tercer periodo de juego; c) los perdedores presionan más la transición ofensiva en los dos últimos periodos de juego; d) en el cuarto periodo, los equipos perdedores son mejores capturando rebotes defensivos en comparación con los ganadores; e) los cambios defensivos, ayudas sobre el hombre con balón y pases interiores permitidos, no diferencian a ganadores de perdedores en ningún period

Metabolic adaptations in skeletal muscle after 84 days of bed rest with and without concurrent flywheel resistance exercise

As metabolic changes in human skeletal muscle after long-term (simulated) spaceflight are not well understood, this study examined the effects of long-term microgravity, with and without concurrent resistance exercise, on skeletal muscle oxidative and glycolytic capacity. Twenty-one men were subjected to 84 days head-down tilt bed rest with (BRE; n = 9) or without (BR; n = 12) concurrent flywheel resistance exercise. Activity and gene expression of glycogen synthase, glycogen phosphorylase (GPh), hexokinase, phosphofructokinase-1 (PFK-1), and citrate synthase (CS), as well as gene expression of succinate dehydrogenase (SDH), vascular endothelial growth factor (VEFG), peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1α), and myostatin, were analyzed in samples from m. vastus lateralis collected before and after bed rest. Activity and gene expression of enzymes controlling oxidative metabolism (CS, SDH) decreased in BR but were partially maintained in BRE. Activity of enzymes regulating anaerobic glycolysis (GPh, PFK-1) was unchanged in BR. Resistance exercise increased the activity of GPh. PGC-1α and VEGF expression decreased in both BR and BRE. Myostatin increased in BR but decreased in BRE after bed rest. The analyses of these unique samples indicate that long-term microgravity induces marked alterations in the oxidative, but not the glycolytic, energy system. The proposed flywheel resistance exercise was effective in counteracting some of the metabolic alterations triggered by 84-day bed rest. Given the disparity between gene expression vs. enzyme activity in several key metabolic markers, posttranscriptional mechanisms should be explored to fully evaluate metabolic adaptations to long-term microgravity with/without exercise countermeasures in human skeletal muscle

Metabolic adaptations in skeletal muscle after 84 days of bed rest with and without concurrent flywheel resistance exercise

As metabolic changes in human skeletal muscle after long-term (simulated) spaceflight are not well understood, this study examined the effects of long-term microgravity, with and without concurrent resistance exercise, on skeletal muscle oxidative and glycolytic capacity. Twenty-one men were subjected to 84 days head-down tilt bed rest with (BRE; n 9) or without (BR; n 12) concurrent flywheel resistance exercise. Activity and gene expression of glycogen synthase, glycogen phosphorylase (GPh), hexokinase, phosphofructokinase-1 (PFK-1), and citrate synthase (CS), as well as gene expression of succinate dehydrogenase (SDH), vascular endothelial growth factor (VEFG), peroxisome proliferator-activated receptor gamma coactivator- 1 (PGC-1 ), and myostatin, were analyzed in samples from m.vastus lateralis collected before and after bed rest. Activity and gene expression of enzymes controlling oxidative metabolism (CS, SDH) decreased in BR but were partially maintained in BRE. Activity of enzymes regulating anaerobic glycolysis (GPh, PFK-1) was unchanged in BR. Resistance exercise increased the activity of GPh. PGC-1 and VEGF expression decreased in both BR and BRE. Myostatin increased in BR but decreased in BRE after bed rest. The analyses of these unique samples indicate that long-term microgravity induces marked alterations in the oxidative, but not the glycolytic, energy system. The proposed flywheel resistance exercise was effective in counteracting some of the metabolic alterations triggered by 84-day bed rest. Given the disparity between gene expression vs. enzyme activity in several key metabolic markers, posttranscriptional mechanisms should be explored to fully evaluate metabolic adaptations to long-term microgravity with/without exercise countermeasures in human skeletal muscle

Knowledge, attitudes and preventive practices of primary health care professionals towards alcohol use: A national, cross-sectional study.

Introduction Primary care (PC) professionals' knowledge about alcohol use has been identified as one of the barriers PC providers face in their clinic. Both PC professionals’ level of training and attitude are crucial in the clinical practice regarding alcohol use. Objective To evaluate the knowledge, attitude, and preventive practices of Spanish PC physicians and nurses towards alcohol use. Design An observational, descriptive, cross-sectional, multi-center study. Methodology Location: PC centers of the Spanish National Health System (NHS). Participants: PC physicians and nurses selected randomly from health care centers, and by sending an e-mail to semFYC and SEMERGEN members. Healthcare providers completed an online survey on knowledge, attitude, and follow-up recommendations for reducing alcohol intake. A descriptive, bivariate, and multivariate statistical analysis was conducted (p<0.05). Results Participants: 1,760 healthcare providers completed the survey (75.6% [95% CI 73.5–77.6] family physicians; 11.4% [95% CI 9.9–12.9] medical residents; and 12.5% [95% CI 10.9–14.1] nurses), with a mean age of 44.7 (SD 11.24, range: 26–64, 95% CI: 47.2–48.2). Knowledge was higher in family physicians (p<0.001), older professionals (Spearman's r = 0.11, p<0.001), and resident trainers (p<0.001). The PC professional most likely to provide advice for reducing alcohol use was: a nurse (p <0.001), female (p = 0.010), between 46 and 55 years old (p <0.001). Conclusions PC providers’ knowledge and preventive practices regarding alcohol use are scarce, hence specific training strategies to increase their knowledge and improve their attitude and skills with regard to this health problem should be considered a healthcare policy priority.post-print507 K

Brief Report: CYP27B1 rs10877012 T Allele Was Linked to Non-AIDS Progression in ART-Naïve HIV-Infected Patients: A Retrospective Study.

HIV/AIDS progression is linked to vitamin D, which is regulated by several key cytochromes P450 (CYP). Single nucleotide polymorphisms (SNPs) in CYP genes influence vitamin D metabolism and serum levels. The objective of this study was to evaluate the association between CYP SNPs and the clinical AIDS progression in antiretroviral treatment (ART)-naïve HIV-infected patients. We performed a retrospective study in 661 ART-naïve HIV-infected patients who were stratified by their AIDS progression pattern [181 long-term nonprogressors (LTNPs), 332 moderate progressors, and 148 rapid progressors (RPs)]. Four CYP SNPs (CYP2R1 rs10500804, CYP2R1 rs1993116, CYP27B1 rs10877012, and CYP24A1 rs6013897) were genotyped using Agena Bioscience's MassARRAY platform. Correction for multiple testing was performed using the false discovery rate (Benjamini-Hochberg procedure). The adjusted regression showed a significant association only for CYP27B1 rs10877012 SNP. When analyzing all HIV patients, the rs10877012 T allele was protective against AIDS progression (ordinal outcome) under the dominant [adjusted odds ratio (aOR) = 0.69; P = 0.021) and additive (aOR) = 0.75; P = 0.025] inheritance models. When analyzing LTNPs versus RPs, the rs10877012 T allele also showed a significant protective association under the dominant (aOR = 0.45; P = 0.004) and additive (aOR = 0.54; P = 0.008) inheritance models. P values remained significant after correcting by multiple comparisons only for the comparison of LTNPs versus RPs (extreme phenotypes). The CYP27B1 rs10877012 T allele was linked to non-AIDS progression in ART-naïve HIV-infected patients. The rs10877012 SNP seems to have an impact on the clinical AIDS progression, possibly modifying vitamin D levels, which could be relevant for the pathogenesis of HIV infection.This work has been (partially) funded by the RD16/0025/0019 and RD16CIII/0002/0002, projects as part of Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (2013-2016) and cofinanced by Instituto de Salud Carlos III (ISCIII-Subdirección General de Evaluación) and Fondo Europeo de Desarrollo Regional (FEDER), RETIC PT17/0015/0042, Fondo de Investigación Sanitaria (FIS) (grant number PI16/01863, PI17/01115, PI17CIII/00003), EPIICAL Project and Comunidad de Madrid (B2017/BMD-3703). CIBER-BBN is an initiative funded by the VINational R&D&i Plan 2008-2011, Iniciativa Ingenio 2010, the Consolider Program, and CIBER Actions and financed by ISCIII with assistance from the European Regional Development Fund. This work has been supported partially by a EUROPARTNER: Strengthening and spreading international partnership activities of the Faculty of Biology and Environmental Protection for interdisciplinary research and innovation of the University of Lodz Programme: NAWA International Academic Partnership Programme. This article/publication is based upon work from COST Action CA 17140 "Cancer Nanomedicine from the Bench to the Bedside" supported by COST (European Cooperation in Science and Technology). AFR and MAJS are supported by “Instituto de Salud Carlos III” [grant number CP14/0010and CP17CIII/00007, respectivelly].Programa de Investigación de la Consejería de Sanidad de la Comunidad de Madrid to JLJ.S

RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer

Colorectal cancer; Predictive markers; Tumour biomarkersCáncer colorrectal; Marcadores predictivos; Biomarcadores tumoralesCàncer colorrectal; Marcadors predictius; Biomarcadors tumoralsAnti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAFV600E colorectal cancer (mCRCBRAF-V600E). However, a large fraction of patients do not respond, underscoring the need to identify molecular determinants of treatment response. Using whole-exome sequencing in a discovery cohort of patients with mCRCBRAF-V600E treated with anti-BRAF/EGFR therapy, we found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with microsatellite-stable (MSS) tumors. Analysis of an independent validation cohort confirmed the relevance of RNF43 mutations to predicting clinical benefit (72.7% versus 30.8%; P = 0.03), as well as longer progression-free survival (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.12–0.75; P = 0.01) and overall survival (HR, 0.26; 95% CI, 0.10–0.71; P = 0.008), in patients with MSS-RNF43mutated versus MSS-RNF43wild-type tumors. Microsatellite-instable tumors invariably carried a wild-type-like RNF43 genotype encoding p.G659fs and presented an intermediate response profile. We found no association of RNF43 mutations with patient outcomes in a control cohort of patients with MSS-mCRCBRAF-V600E tumors not exposed to anti-BRAF targeted therapies. Overall, our findings suggest a cross-talk between the MAPK and WNT pathways that may modulate the antitumor activity of anti-BRAF/EGFR therapy and uncover predictive biomarkers to optimize the clinical management of these patients.VHIO would like to acknowledge the Cellex Foundation for providing research facilities and equipment, the FERO Foundation for their funding support, the Consorcio Centro de Investigación Biomédica en Red de Cáncer (CIBERONC, CB16/12/00259) from the Institute of Health Carlos III (ISCIII), Ministry of Science and Innovation, and the Department of Health (Generalitat de Catalunya, SLT008/18/00198 and SLT008/18/00205) for their support on this research. Authors acknowledge financial support from the State Agency for Research (Agencia Estatal de Investigación) (CEX2020-001024-S / AEI / 10.13039 /501100011033). This research is funded by the SCITRON program; Novartis funded the genomics characterization by WES of samples from 28 patients from the discovery cohort and had no influence on data analysis/interpretation or writing of the paper (3003145512 to R.A.T.). S.Li. is financially supported by a Chinese Scholarship Council PhD fellowship (201909370083 to S. Li). R.P.-L. is supported by a CRIS Foundation Talent Award (TALENT19-05), the FERO Foundation, the Instituto de Salud Carlos III-Investigación en Salud (PI18/01395 and PI21/01019 to R.P.-L.) and the Prostate Cancer Foundation (Young Investigator Award). This work was supported by the Miguel Servet-I Research Award from ISCIII of the Ministry of Economy (CP17/00199 to R.A.T.), the Olga Torres Foundation Award to emerging researchers (2601 to R.A.T.), the ISCIII-FEDER (PI17/00947 and PI20/00968 to E.E.), and the Fundación AECC (CLSEN19001ELEZ to E.E.) and Ministry of Science and Innovation (Europa Redes y Gestores, ECT2020-000827 to E.E.)

Design and manufacture of a bed supported tidal turbine model for blade and shaft load measurement in turbulent flow and waves

Laboratory testing of tidal turbine models is an essential tool to investigate hydrodynamic interactions between turbines and the flow. Such tests can be used to calibrate numerical models and to estimate rotor loading and wake development to inform the design of full scale machines and array layout. The details of the design and manufacturing techniques used to develop a highly instrumented turbine model are presented. The model has a 1.2 m diameter, three bladed horizontal axis rotor and is bottom mounted. Particular attention is given to the instrumentation which can measure streamwise root bending moment for each blade and torque and thrust for the overall rotor. The model is mainly designed to investigate blade and shaft loads due to both turbulence and waves. Initial results from tests in a 2 m deep by 4 m wide flume are also presented

Integration of contractile forces during tissue invagination

Contractile forces generated by the actomyosin cytoskeleton within individual cells collectively generate tissue-level force during epithelial morphogenesis. During Drosophila mesoderm invagination, pulsed actomyosin meshwork contractions and a ratchet-like stabilization of cell shape drive apical constriction. Here, we investigate how contractile forces are integrated across the tissue. Reducing adherens junction (AJ) levels or ablating actomyosin meshworks causes tissue-wide epithelial tears, which release tension that is predominantly oriented along the anterior–posterior (a-p) embryonic axis. Epithelial tears allow cells normally elongated along the a-p axis to constrict isotropically, which suggests that apical constriction generates anisotropic epithelial tension that feeds back to control cell shape. Epithelial tension requires the transcription factor Twist, which stabilizes apical myosin II, promoting the formation of a supracellular actomyosin meshwork in which radial actomyosin fibers are joined end-to-end at spot AJs. Thus, pulsed actomyosin contractions require a supracellular, tensile meshwork to transmit cellular forces to the tissue level during morphogenesis.American Cancer Society (grant PF-06-143-01-DDC)National Institutes of Health (U.S.) (NIH/NIGMS, P50 grant GM071508)National Institutes of Health (U.S.) (NIH/NIGMS, R01 grant GM079340)Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (grant 5R37HD15587)Howard Hughes Medical Institute (Investigator