In vivo performance of hierarchical HRP-crosslinked silk fibroin/β-TCP scaffolds for osteochondral tissue regeneration

Background: Osteochondral defects (OCD) can affect the articular cartilage and subchondral bone tissues, which requires superior therapies for the simultaneous and full restoration of such structurally and biologically different tissues. Methods: Tissue engineered OC grafts were prepared using a horseradish peroxidase (HRP) approach to crosslink silk fibroin (HRP-SF) as the articular cartilage-like layer and an underlying HRP-SF/ZnSrTCP subchondral bone-like layer (HRP-SF/dTCP), through salt-leaching/freeze-drying methodologies. In vivo OC regeneration was assessed by implantating the hierarchical scaffolds in rabbit critical size OC defects, during 8 weeks. A comparative analysis was performed using hierarchical OC grafts made of pure β-TCP (HRP-SF/TCP). Results: The hierarchical scaffolds showed good integration into the host tissue and no signs of acute inflammatory reaction, after 8 weeks of implantation. The histological analyses revealed positive collagen type II and glycosaminoglycansâ formation in the articular cartilage-like layer. New bone ingrowthâ s and blood vessels infiltration were detected in the subchondral bone-like layers. Conclusions: The proposed hierarchical scaffolds presented an adequate in vivo response with cartilage tissue regeneration and calcified tissue formation specially promoted by the ionic incorporation into the subchondral bone layer, confirming the hierarchical structures as suitable for OCD regeneration.Portuguese Foundation for Science and Technology for the Hierarchitech project (M-era-Net/0001/2014), for the fellowships (SFRH/BD/99555/2014) and (SFRH/BPD/101952/2014), and for the distinctions attributed to JMO (IF/01285/2015) and SP (CEECIND/03673/2017). Also, financial support from FCT/MCTES (Fundação para a Ciência e a Tecnologia/ Ministério Da Ciência, Tecnologia, e Ensino Superior) and fundo social europeu através do programa operacional do capital humano (FSE/POCH), PD/59/2013, PD/BD/113806/201

Design Considerations for Massively Parallel Sequencing Studies of Complex Human Disease

Massively Parallel Sequencing (MPS) allows sequencing of entire exomes and genomes to now be done at reasonable cost, and its utility for identifying genes responsible for rare Mendelian disorders has been demonstrated. However, for a complex disease, study designs need to accommodate substantial degrees of locus, allelic, and phenotypic heterogeneity, as well as complex relationships between genotype and phenotype. Such considerations include careful selection of samples for sequencing and a well-developed strategy for identifying the few “true” disease susceptibility genes from among the many irrelevant genes that will be found to harbor rare variants. To examine these issues we have performed simulation-based analyses in order to compare several strategies for MPS sequencing in complex disease. Factors examined include genetic architecture, sample size, number and relationship of individuals selected for sequencing, and a variety of filters based on variant type, multiple observations of genes and concordance of genetic variants within pedigrees. A two-stage design was assumed where genes from the MPS analysis of high-risk families are evaluated in a secondary screening phase of a larger set of probands with more modest family histories. Designs were evaluated using a cost function that assumes the cost of sequencing the whole exome is 400 times that of sequencing a single candidate gene. Results indicate that while requiring variants to be identified in multiple pedigrees and/or in multiple individuals in the same pedigree are effective strategies for reducing false positives, there is a danger of over-filtering so that most true susceptibility genes are missed. In most cases, sequencing more than two individuals per pedigree results in reduced power without any benefit in terms of reduced overall cost. Further, our results suggest that although no single strategy is optimal, simulations can provide important guidelines for study design

Tracing Changes in Families Who Participated in the Home-Start Parenting Program: Parental Sense of Competence as Mechanism of Change

The present study aimed to (1) determine the long-term effectiveness of Home-Start, a preventive parenting program, and (2) test the hypothesis that changes in maternal sense of competence mediate the program’s effects. Participants were 124 mothers (n = 66 intervention, n = 58 comparison). Four assessments took place during a 1-year period. Latent growth modeling showed that Home-Start enhanced growth in maternal sense of competence and supportive parenting, and led to a decrease in the use of inept discipline. Results of mediational and cross-lagged analyses were consistent with the hypothesized model: Participation in Home-Start was related to the changes in maternal sense of competence, which in turn predicted changes in parenting. The results affirm the importance of directly targeting parental sense of competence in the context of prevention work with parents

GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers

We describe methods with enhanced power and specificity to identify genes targeted by somatic copy-number alterations (SCNAs) that drive cancer growth. By separating SCNA profiles into underlying arm-level and focal alterations, we improve the estimation of background rates for each category. We additionally describe a probabilistic method for defining the boundaries of selected-for SCNA regions with user-defined confidence. Here we detail this revised computational approach, GISTIC2.0, and validate its performance in real and simulated datasets

Next-generation sequencing

Next-generation sequencing (also known as massively parallel sequencing) technologies are revolutionising our ability to characterise cancers at the genomic, transcriptomic and epigenetic levels. Cataloguing all mutations, copy number aberrations and somatic rearrangements in an entire cancer genome at base pair resolution can now be performed in a matter of weeks. Furthermore, massively parallel sequencing can be used as a means for unbiased transcriptomic analysis of mRNAs, small RNAs and noncoding RNAs, genome-wide methylation assays and high-throughput chromatin immunoprecipitation assays. Here, I discuss the potential impact of this technology on breast cancer research and the challenges that come with this technological breakthrough

Social networks and implementation of evidence-based practices in public youth-serving systems: a mixed-methods study

<p>Abstract</p> <p>Background</p> <p>The present study examines the structure and operation of social networks of information and advice and their role in making decisions as to whether to adopt new evidence-based practices (EBPs) among agency directors and other program professionals in 12 California counties participating in a large randomized controlled trial.</p> <p>Methods</p> <p>Interviews were conducted with 38 directors, assistant directors, and program managers of county probation, mental health, and child welfare departments. Grounded-theory analytic methods were used to identify themes related to EBP adoption and network influences. A web-based survey collected additional quantitative information on members of information and advice networks of study participants. A mixed-methods approach to data analysis was used to create a sociometric data set (n = 176) for examination of associations between advice seeking and network structure.</p> <p>Results</p> <p>Systems leaders develop and maintain networks of information and advice based on roles, responsibility, geography, and friendship ties. Networks expose leaders to information about EBPs and opportunities to adopt EBPs; they also influence decisions to adopt EBPs. Individuals in counties at the same stage of implementation accounted for 83% of all network ties. Networks in counties that decided not to implement a specific EBP had no extra-county ties. Implementation of EBPs at the two-year follow-up was associated with the size of county, urban versus rural counties, and in-degree centrality. Collaboration was viewed as critical to implementing EBPs, especially in small, rural counties where agencies have limited resources on their own.</p> <p>Conclusions</p> <p>Successful implementation of EBPs requires consideration and utilization of existing social networks of high-status systems leaders that often cut across service organizations and their geographic jurisdictions.</p> <p>Trial Registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT00880126">NCT00880126</a></p

Nutrition aspects in children receiving maintenance hemodialysis: impact on outcome

Children with end-stage renal disease (ESRD) have rates of mortality estimated to be 30-times higher than expected for age compared with those of healthy children. Physical manifestations of under-nutrition, such as body mass index (BMI) and low height standard deviation score (SDS), have been associated with increased risk of mortality. Traditional measures, such as height, weight and serum albumin concentration, may not be accurate indicators to assess the nutritional status of children receiving maintenance hemodialysis. Normalized protein catabolic rate (nPCR) has emerged as a better marker of nutritional status of such children. Meeting the special nutritional needs of these children often requires nutritional supplementation, by either the enteral or the parenteral route. Recently, in children receiving maintenance hemodialysis who are malnourished, intradialytic parenteral nutrition (IDPN) has been utilized as a means to provide additional protein and calories. This article is a state-of-the-art review of malnutrition in children receiving maintenance hemodialysis, with special focus on outcome, nPCR and IDPN

Prevalence and progression of visual impairment in patients newly diagnosed with clinical type 2 diabetes: a 6-year follow up study

<p>Abstract</p> <p>Background</p> <p>Many diabetic patients fear visual loss as the worst consequence of diabetes. In most studies the main eye pathology is assigned as the cause of visual impairment. This study analysed a broad range of possible ocular and non-ocular predictors of visual impairment prospectively in patients newly diagnosed with clinical type 2 diabetes.</p> <p>Methods</p> <p>Data were from a population-based cohort of 1,241 persons newly diagnosed with clinical, often symptomatic type 2 diabetes aged ≥ 40 years. After 6 years, 807 patients were followed up. Standard eye examinations were done by practising ophthalmologists.</p> <p>Results</p> <p>At diabetes diagnosis median age was 65.5 years. Over 6 years, the prevalence of blindness (visual acuity of best seeing eye ≤ 0.1) rose from 0.9% (11/1,241) to 2.4% (19/807) and the prevalence of moderate visual impairment (> 0.1; < 0.5) rose from 5.4% (67/1,241) to 6.7% (54/807). The incidence (95% confidence interval) of blindness was 40.2 (25.3-63.8) per 10,000 patient-years. Baseline predictors of level of visual acuity (age, age-related macular degeneration (AMD), cataract, living alone, low self-rated health, and sedentary life-style) and speed of continued visual loss (age, AMD, diabetic retinopathy (DR), cataract, living alone, and high fasting triglycerides) were identified.</p> <p>Conclusions</p> <p>In a comprehensive assessment of predictors of visual impairment, even in a health care system allowing self-referral to free eye examinations, treatable eye pathologies such as DR and cataract emerge together with age as the most notable predictors of continued visual loss after diabetes diagnosis. Our results underline the importance of eliminating barriers to efficient eye care by increasing patients' and primary care practitioners' awareness of the necessity of regular eye examinations and timely surgical treatment.</p

Actos Now for the prevention of diabetes (ACT NOW) study

Abstract Background Impaired glucose tolerance (IGT) is a prediabetic state. If IGT can be prevented from progressing to overt diabetes, hyperglycemia-related complications can be avoided. The purpose of the present study was to examine whether pioglitazone (ACTOS®) can prevent progression of IGT to type 2 diabetes mellitus (T2DM) in a prospective randomized, double blind, placebo controlled trial. Methods/Design 602 IGT subjects were identified with OGTT (2-hour plasma glucose = 140–199 mg/dl). In addition, IGT subjects were required to have FPG = 95–125 mg/dl and at least one other high risk characteristic. Prior to randomization all subjects had measurement of ankle-arm blood pressure, systolic/diastolic blood pressure, HbA1C, lipid profile and a subset had frequently sampled intravenous glucose tolerance test (FSIVGTT), DEXA, and ultrasound determination of carotid intima-media thickness (IMT). Following this, subjects were randomized to receive pioglitazone (45 mg/day) or placebo, and returned every 2–3 months for FPG determination and annually for OGTT. Repeat carotid IMT measurement was performed at 18 months and study end. Recruitment took place over 24 months, and subjects were followed for an additional 24 months. At study end (48 months) or at time of diagnosis of diabetes the OGTT, FSIVGTT, DEXA, carotid IMT, and all other measurements were repeated. Primary endpoint is conversion of IGT to T2DM based upon FPG ≥ 126 or 2-hour PG ≥ 200 mg/dl. Secondary endpoints include whether pioglitazone can: (i) improve glycemic control (ii) enhance insulin sensitivity, (iii) augment beta cell function, (iv) improve risk factors for cardiovascular disease, (v) cause regression/slow progression of carotid IMT, (vi) revert newly diagnosed diabetes to normal glucose tolerance. Conclusion ACT NOW is designed to determine if pioglitazone can prevent/delay progression to diabetes in high risk IGT subjects, and to define the mechanisms (improved insulin sensitivity and/or enhanced beta cell function) via which pioglitazone exerts its beneficial effect on glucose metabolism to prevent/delay onset of T2DM. Trial Registration clinical trials.gov identifier: NCT0022096