Estimating risk of encapsulating peritoneal sclerosis accounting for the competing risk of death

Background: Risk of Encapsulating Peritoneal Sclerosis (EPS) is strongly associated with the duration of peritoneal dialysis (PD), such that patients who have been on PD for some time may consider elective transfer to haemodialysis to mitigate risk of EPS. There is a need to determine this risk to better inform clinical decision-making, but previous studies have not allowed for the competing risk of death. Methods: This study included new adult PD patients in either Australia and New Zealand (ANZ 1990-2010) or Scotland (2000-2008) followed until 2012. Age, time on PD, primary renal disease, gender, dataset and diabetic status were evaluated as predictors at start of PD, then at three and five years after starting PD using flexible parametric competing risks models. Results: In 17,396 patients (16,162 ANZ, 1,234 Scotland), EPS was observed in 99 (0.57%) patients less frequently in ANZ patients (n=65, 0.4%) than in Scottish patients (n=34, 2.8%). The estimated risk of EPS was much lower when the competing risk of death was taken into account (1-KM=0.0126, CIF=0.0054). Strong predictors of EPS included age, primary renal disease and time on PD. The risk of EPS was reasonably discriminated at the start of PD (C-statistic = 0.74 to 0.79) and this improved at 3 and 5 years after starting PD (C-statistic = 0.81 to 0.92). Conclusions: EPS risk estimates are lower when calculated using competing risk of death analyses. A patient’s estimated risk of EPS is country-specific, and can be predicted using age, primary renal disease and duration of PD

CAR-T cell. the long and winding road to solid tumors

Adoptive cell therapy of solid tumors with reprogrammed T cells can be considered the "next generation" of cancer hallmarks. CAR-T cells fail to be as effective as in liquid tumors for the inability to reach and survive in the microenvironment surrounding the neoplastic foci. The intricate net of cross-interactions occurring between tumor components, stromal and immune cells leads to an ineffective anergic status favoring the evasion from the host's defenses. Our goal is hereby to trace the road imposed by solid tumors to CAR-T cells, highlighting pitfalls and strategies to be developed and refined to possibly overcome these hurdles

DAZL Relieves miRNA-Mediated Repression of Germline mRNAs by Controlling Poly(A) Tail Length in Zebrafish

BACKGROUND:During zebrafish embryogenesis, microRNA (miRNA) miR-430 contributes to restrict Nanos1 and TDRD7 to primordial germ cells (PGCs) by inducing mRNA deadenylation, mRNA degradation, and translational repression of nanos1 and tdrd7 mRNAs in somatic cells. The nanos1 and tdrd7 3'UTRs include cis-acting elements that allow activity in PGCs even in the presence of miRNA-mediated repression. METHODOLOGY/PRINCIPAL FINDINGS:Using a GFP reporter mRNA that was fused with tdrd7 3'UTR, we show that a germline-specific RNA-binding protein DAZ-like (DAZL) can relieve the miR-430-mediated repression of tdrd7 mRNA by inducing poly(A) tail elongation (polyadenylation) in zebrafish. We also show that DAZL enhances protein synthesis via the 3'UTR of dazl mRNA, another germline mRNA targeted by miR-430. CONCLUSIONS/SIGNIFICANCE:Our present study indicated that DAZL acts as an "anti-miRNA factor" during vertebrate germ cell development. Our data also suggested that miRNA-mediated regulation can be modulated on specific target mRNAs through the poly(A) tail control

α-thalassaemia

Alpha-thalassaemia is inherited as an autosomal recessive disorder characterised by a microcytic hypochromic anaemia, and a clinical phenotype varying from almost asymptomatic to a lethal haemolytic anaemia

Living Well with Diabetes: a randomized controlled trial of a telephone-delivered intervention for maintenance of weight loss, physical activity and glycaemic control in adults with type 2 diabetes

Background By 2025, it is estimated that approximately 1.8 million Australian adults (approximately 8.4% of the adult population) will have diabetes, with the majority having type 2 diabetes. Weight management via improved physical activity and diet is the cornerstone of type 2 diabetes management. However, the majority of weight loss trials in diabetes have evaluated short-term, intensive clinic-based interventions that, while producing short-term outcomes, have failed to address issues of maintenance and broad population reach. Telephone-delivered interventions have the potential to address these gaps. Methods/Design Using a two-arm randomised controlled design, this study will evaluate an 18-month, telephone-delivered, behavioural weight loss intervention focussing on physical activity, diet and behavioural therapy, versus usual care, with follow-up at 24 months. Three-hundred adult participants, aged 20-75 years, with type 2 diabetes, will be recruited from 10 general practices via electronic medical records search. The Social-Cognitive Theory driven intervention involves a six-month intensive phase (4 weekly calls and 11 fortnightly calls) and a 12-month maintenance phase (one call per month). Primary outcomes, assessed at 6, 18 and 24 months, are: weight loss, physical activity, and glycaemic control (HbA1c), with weight loss and physical activity also measured at 12 months. Incremental cost-effectiveness will also be examined. Study recruitment began in February 2009, with final data collection expected by February 2013. Discussion This is the first study to evaluate the telephone as the primary method of delivering a behavioural weight loss intervention in type 2 diabetes. The evaluation of maintenance outcomes (6 months following the end of intervention), the use of accelerometers to objectively measure physical activity, and the inclusion of a cost-effectiveness analysis will advance the science of broad reach approaches to weight control and health behaviour change, and will build the evidence base needed to advocate for the translation of this work into population health practice

GoLoco motif proteins binding to Gαi1: insights from molecular simulations

Molecular dynamics simulations, computational alanine scanning and sequence analysis were used to investigate the structural properties of the Gαi1/GoLoco peptide complex. Using these methodologies, binding of the GoLoco motif peptide to the Gαi1 subunit was found to restrict the relative movement of the helical and catalytic domains in the Gαi1 subunit, which is in agreement with a proposed mechanism of GDP dissociation inhibition by GoLoco motif proteins. In addition, the results provide further insights into the role of the “Switch IV” region located within the helical domain of Gα, the conformation of which might be important for interactions with various Gα partners

Extent, intensity and drivers of mammal defaunation:a continental-scale analysis across the Neotropics

Neotropical mammal diversity is currently threatened by several chronic human-induced pressures. We compiled 1,029 contemporary mammal assemblages surveyed across the Neotropics to quantify the continental-scale extent and intensity of defaunation and understand their determinants based on environmental covariates. We calculated a local defaunation index for all assemblages—adjusted by a false-absence ratio—which was examined using structural equation models. We propose a hunting index based on socioenvironmental co-variables that either intensify or inhibit hunting, which we used as an additional predictor of defaunation. Mammal defaunation intensity across the Neotropics on average erased 56.5% of the local source fauna, with ungulates comprising the most ubiquitous losses. The extent of defaunation is widespread, but more incipient in hitherto relatively intact major biomes that are rapidly succumbing to encroaching deforestation frontiers. Assemblage-wide mammal body mass distribution was greatly reduced from a historical 95th-percentile of ~ 14 kg to only ~ 4 kg in modern assemblages. Defaunation and depletion of large-bodied species were primarily driven by hunting pressure and remaining habitat area. Our findings can inform guidelines to design transnational conservation policies to safeguard native vertebrates, and ensure that the “empty ecosystem” syndrome will be deterred from reaching much of the New World tropics