Why and how do nursing homes implement culture change practices? Insights from qualitative interviews in a mixed methods study.
To understand the process of instituting culture change (CC) practices in nursing homes (NHs). NH Directors of Nursing (DONs) and Administrators (NHAs) at 4,149 United States NHs were surveyed about CC practices. Follow-up interviews with 64 NHAs were conducted and analyzed by a multidisciplinary team which reconciled interpretations recorded in an audit trail. The themes include: (a) Reasons for implementing CC practices vary; (b) NH approaches to implementing CC practices are diverse; (c) NHs consider resident mix in deciding to implement practices; (d) NHAs note benefits and few costs to implementing CC practices; (e) Implementation of changes is challenging and strategies for change are tailored to the challenges encountered; (f) Education and communication efforts are vital ways to institute change; and (g) NHA and other staff leadership is key to implementing changes. Diverse strategies and leadership skills appear to help NHs implement reform practices, including CC innovations.


Immune phenotype of children with newly diagnosed and gluten-free diet-treated celiac disease.
Recent data suggest the involvement of both the adaptive and the innate immune system in celiac disease (CD). However, little is known about the immune phenotype of children with CD and its alteration upon dietary intervention. We characterized the prevalence of major interacting members of the adaptive and innate immune system in peripheral blood of newly diagnosed children with CD and tested its alteration with the improvement of clinical signs after the introduction of gluten-free diet (GFD). Peripheral blood was taken from ten children with biopsy-proven CD at the time of diagnosis and after the resolution of clinical symptoms following GFD. As controls, 15 children with functional abdominal pain were enrolled. The prevalence of the cells of adaptive and innate immunity was measured with labeled antibodies against surface markers and intracellular FoxP3 using a flow cytometer. Patients with CD were found to have lower T helper, Th1 and natural killer (NK), NKT and invariant NKT cell prevalence and with higher prevalence of activated CD4(+) cells, myeloid dendritic cells (DC) and Toll-like receptor (TLR) 2 and TLR-4 positive DCs and monocytes compared to controls. After resolution of symptoms on GFD, the majority of these changes normalized, although the prevalence of NK and NKT cell, DC and TLR-2 expressing DCs and monocytes remained abnormal. The immune phenotype in childhood CD indicates the implication of both adaptive and innate immune system. The normalization of immune abnormalities occurs on GFD, but the kinetics of this process probably differs among different cell types.


Novel mechanistic insights into physiological signaling pathways mediated by mycobacterial Ser/Thr protein kinases.
Protein phosphorylation is known to be one of the keystones of signal sensing and transduction in all living organisms. Once thought to be essentially confined to the eukaryotic kingdoms, reversible phosphorylation on serine, threonine, and tyrosine residues, has now been shown to play a major role in many prokaryotes, where the number of Ser/Thr protein kinases (STPKs) equals or even exceeds that of two-component systems. Mycobacterium tuberculosis, the etiological agent of tuberculosis, is one of the most studied organisms for the role of STPK-mediated signaling in bacteria. Driven by the interest and tractability of these enzymes as potential therapeutic targets, extensive studies revealed the remarkable conservation of protein kinases and their cognate phosphatases across evolution, and their involvement in bacterial physiology and virulence. Here, we present an overview of the current knowledge of mycobacterial STPK structures and kinase activation mechanisms, and we then focus on PknB and PknG, two well-characterized STPKs that are essential for the intracellular survival of the bacillus. We summarize the mechanistic evidence that links PknB to the regulation of peptidoglycan synthesis in cell division and morphogenesis, and the major findings that establish PknG as a master regulator of central carbon and nitrogen metabolism. Two decades after the discovery of STPKs in M. tuberculosis, the emerging landscape of O-phosphosignaling is starting to unveil how eukaryotic-like kinases can be engaged in unique, non-eukaryotic-like, signaling mechanisms in mycobacteria.


Millisecond timescale disinhibition mediates fast information transmission through an avian basal ganglia loop.
Avian song learning shares striking similarities with human speech acquisition and requires a basal ganglia (BG)-thalamo-cortical circuit. Information processing and transmission speed in the BG is thought to be limited by synaptic architecture of two serial inhibitory connections. Propagation speed may be critical in the avian BG circuit given the temporally precise control of musculature during vocalization. We used electrical stimulation of the cortical inputs to the BG to study, with fine time resolution, the functional connectivity within this network. We found that neurons in thalamic and cortical nuclei that are not directly connected with the stimulated area can respond to the stimulation with extremely short latencies. Through pharmacological manipulations, we trace this property back to the BG and show that the cortical stimulation triggers fast disinhibition of the thalamic neurons. Surprisingly, feedforward inhibition mediated by striatal inhibitory neurons onto BG output neurons sometimes precedes the monosynaptic excitatory drive from cortical afferents. The fast feedforward inhibition lengthens a single interspike interval in BG output neurons by just a few milliseconds. This short delay is sufficient to drive a strong, brief increase in firing probability in the target thalamic neurons, evoking short-latency responses. By blocking glutamate receptors in vivo, we show that thalamic responses do not appear to rely on excitatory drive, and we show in a theoretical model that they could be mediated by postinhibitory rebound properties. Such fast signaling through disinhibition and rebound may be a crucial specialization for learning of rapid and temporally precise motor acts such as vocal communication.


A programme evaluation of 'First Steps': A peer-conceived, developed and led self-management intervention for people after a Parkinson's diagnosis.
A diagnosis of Parkinson's often leads to uncertainty about the future and loss of perceived control. Peer support may offer a means to address these concerns and promote self-management. A programme evaluation of the feasibility and potential effects of 'First Steps', utilising a pragmatic step wedge approach. Comparing First Steps (intervention) to (control) conditions.Setting: In the community at four sites in southern England.Participants: Newly diagnosed (≤ 12months) people with Parkinson's.Intervention: First Steps was a 2-day peer-conceived, developed and led intervention to support self-management.Main measures: At 0, 12 and 24 weeks anxiety and depression (Hospital, Anxiety and Depression Scale, HADS), daily functioning (World Health Organisation Disability Assessment Schedule, WHODAS), physical activity, quality of life (EQ5D), carer strain and service utilisation were assessed. Between February 2018 and July 2019, 36 participants were enrolled into intervention and 21 to control conditions, all were included in statistical analysis. Lost to follow up was n = 1 (intervention) and n = 1 adverse event was reported (control, unrelated). Of the 36 allocated to the intervention n = 22 participants completed both days of First Steps during the study period. Completion of outcome measures was >95% at 24 weeks. Small effects favouring the intervention were found for HADS (odds ratio (OR) = 2.06, 95% confidence interval (CI) 0.24:17.84), Carer Strain Index (OR = 2.22, 95% CI 0.5:9.76) and vigorous (d = 0.42, 95% CI -0.12:0.97) and total physical activity (d = 0.41, 95% CI -0.13:0.95). EQ5D, WHOSDAS and service utilisation, was similar between groups. First Steps was feasible and safe and we found potential to benefit physical activity, mental health and carer strain. Further research with longer-term follow up is warranted.


The Human Fetus Preferentially Engages with Face-like Visual Stimuli.
In the third trimester of pregnancy, the human fetus has the capacity to process perceptual information [1-3]. With advances in 4D ultrasound technology, detailed assessment of fetal behavior [4] is now possible. Furthermore, modeling of intrauterine conditions has indicated a substantially greater luminance within the uterus than previously thought [5]. Consequently, light conveying perceptual content could be projected through the uterine wall and perceived by the fetus, dependent on how light interfaces with maternal tissue. We do know that human infants at birth show a preference to engage with a top-heavy, face-like stimulus when contrasted with all other forms of stimuli [6, 7]. However, the viability of performing such an experiment based on visual stimuli projected through the uterine wall with fetal participants is not currently known. We examined fetal head turns to visually presented upright and inverted face-like stimuli. Here we show that the fetus in the third trimester of pregnancy is more likely to engage with upright configural stimuli when contrasted to inverted visual stimuli, in a manner similar to results with newborn participants. The current study suggests that postnatal experience is not required for this preference. In addition, we describe a new method whereby it is possible to deliver specific visual stimuli to the fetus. This new technique provides an important new pathway for the assessment of prenatal visual perceptual capacities.


Spontaneous rescue from cystic fibrosis in a mouse model.
From the original CftrTgH(neoim)Hgu mutant mouse model with a divergent genetic background (129P2, C57BL/6, MF1) we have generated two inbred CftrTgH(neoim)Hgu mutant strains named CF/1-CftrTgH(neoim)Hgu and CF/3-CftrTgH(neoim)Hgu, which are fertile and show normal growth and lifespan. Initial genome wide scan analysis with microsatellite markers indicated that the two inbred strains differed on the genetic level. In order to further investigate whether these genetic differences have an impact on the disease phenotype of cystic fibrosis we characterised the phenotype of the two inbred strains. Reduced amounts, compared to wild type control animals, of correctly spliced Cftr mRNA were detected in the nasal epithelia, lungs and the intestine of both inbred CftrTgH(neoim)Hgu strains, with higher residual amount observed for CF/1-CftrTgH(neoim)Hgu than CF/3-CftrTgH(neoim)Hgu for every investigated tissue. Accordingly the amounts of wild type Cftr protein in the intestine were 9% for CF/1-CftrTgH(neoim)Hgu and 4% for CF/3-CftrTgH(neoim)Hgu. Unlike the apparent strain and/or tissue specific regulation of Cftr mRNA splicing, short circuit current measurements in the respiratory and intestinal epithelium revealed that both strains have ameliorated the basic defect of cystic fibrosis with a presentation of a normal electrophysiology in both tissues. Unlike the outbred CftrTgH(neoim)Hgu insertional mouse model, which displayed the electrophysiological defect in the gastrointestinal and respiratory tracts characteristic of cystic fibrosis, both inbred CftrTgH(neoim)Hgu strains have ameliorated the electrophysiological defect. On the basis of these findings both CF/1-CftrTgH(neoim)Hgu and CF/3-CftrTgH(neoim)Hgu offer an excellent model whereby determination of the minimal levels of protein required for the restoration of the basic defect of cystic fibrosis can be studied, along with the modulating factors which may affect this outcome.


Grazing animals drove domestication of grain crops.
In addition to large-seeded cereals, humans around the world during the mid-Holocene started to cultivate small-seeded species of herbaceous annuals for grain, including quinoa, amaranth, buckwheat, the millets and several lost crops domesticated in North America. The wild ancestors of these crops have small seeds with indigestible defences and do not germinate readily. Today, these wild plants exist in small fragmentary stands that are not appealing targets for foragers. This combination of traits has led many to argue that they must have been a food of last resort. We propose a new explanation: the domestication of small-seeded annuals involved a switch from endozoochoric dispersal (through animal ingestion) to human dispersal. Humans encountered these plants in dense stands created by grazing megafauna, making them easy to harvest. As humans began to cultivate these plants they took on the functional role of seed dispersers, and traits associated with endozoochory were lost or reduced. The earliest traits of domestication-thinning or loss of indigestible seed protections, loss of dormancy and increased seed size-can all be explained by the loss of the ruminant dispersal process and concomitant human management of wild stands. We demonstrate, by looking at rangeland ecology and herd animal herbivory patterns, that the progenitors of all of these species evolved to be dispersed by megafaunal ruminants and that heavy herbivory leads to dense homogenous clusters of endozoochoric plants. Hence, easily harvested stands on nitrogen hot spots near water sources would have existed in regions where these plants were domesticated. Future experimental and ecological studies could enhance our understanding of the relationships between specific crops and their possible ruminant dispersers.


Radiographic osteoarthritis of the hip and bone mineral density. The Study of Osteoporotic Fractures Research Group.
To examine the cross-sectional association between radiographic features of hip osteoarthritis (OA) and bone mineral density (BMD) of the hip, spine, and appendicular skeleton among Caucasian women ages 65 and older who were participating in the Study of Osteoporotic Fractures. Pelvis radiographs of 4,855 subjects were assessed for individual radiographic features of hip OA: osteophytes, joint space narrowing, subchondral sclerosis, cysts, and femoral head deformity. Hips were graded on a summary scale of 0 (no OA) to 4 (severe OA) based on the number of radiographic features present. Appendicular BMD was measured in all subjects, and hip and spine BMD in 84% of the group. We used linear regression to examine the association of BMD with hip OA, and to adjust for age, weight, and other determinants of bone mass. Three hundred fifty-one women (7.2%) had mild (grade 2) and 228 (4.7%) had moderate to severe (grade 3-4) radiographic evidence of hip OA. Women with grade 3-4 hip OA had a higher age-adjusted BMD at the femoral neck and Ward's triangle (9-10%; P < 0.0001), trochanter (4%; P < 0.01), lumbar spine (8%; P < 0.0001), and distal radius and calcaneus (5%; P < 0.0001 [for each comparison]) compared with those with grade 0-1 OA in the worse hip. Elevations in BMD were greatest in the femoral neck of hips with OA, in women with bilateral hip OA, and in women with hip osteophytes. These findings were essentially unchanged by adjustment for determinants of bone mass. Elderly Caucasian women with moderate to severe radiographic hip OA had higher BMD in the hip, spine, and appendicular skeleton than did women without hip OA. Our findings are consistent with a role of elevated BMD in the pathogenesis of hip OA.


A new blind source separation framework for signal analysis and artifact rejection in functional Near-Infrared Spectroscopy.
In the analysis of functional Near-Infrared Spectroscopy (fNIRS) signals from real-world scenarios, artifact rejection is essential. However, currently there exists no gold-standard. Although a plenitude of methodological approaches implicitly assume the presence of latent processes in the signals, elaborate Blind-Source-Separation methods have rarely been applied. A reason are challenging characteristics such as Non-instantaneous and non-constant coupling, correlated noise and statistical dependencies between signal components. We present a novel suitable BSS framework that tackles these issues by incorporating A) Independent Component Analysis methods that exploit both higher order statistics and sample dependency, B) multimodality, i.e., fNIRS with accelerometer signals, and C) Canonical-Correlation Analysis with temporal embedding. This enables analysis of signal components and rejection of motion-induced physiological hemodynamic artifacts that would otherwise be hard to identify. We implement a method for Blind Source Separation and Accelerometer based Artifact Rejection and Detection (BLISSA2RD). It allows the analysis of a novel n-back based cognitive workload paradigm in freely moving subjects, that is also presented in this manuscript. We evaluate on the corresponding data set and simulated ground truth data, making use of metrics based on 1st and 2nd order statistics and SNR and compare with three established methods: PCA, Spline and Wavelet-based artifact removal. Across 17 subjects, the method is shown to reduce movement induced artifacts by up to two orders of magnitude, improves the SNR of continuous hemodynamic signals in single channels by up to 10dB, and significantly outperforms conventional methods in the extraction of simulated Hemodynamic Response Functions from strongly contaminated data. The framework and methods presented can serve as an introduction to a new type of multivariate methods for the analysis of fNIRS signals and as a blueprint for artifact rejection in complex environments beyond the applied paradigm.


Acetabular cartilage delamination in femoroacetabular impingement. Risk factors and magnetic resonance imaging diagnosis.
Delamination of acetabular articular cartilage is a common abnormality in hips with femoroacetabular impingement. The purpose of the present study was to identify clinical and radiographic factors predisposing to delamination and to assess the diagnostic accuracy of magnetic resonance arthrography for the detection of these lesions. Following a retrospective review of records, we determined that acetabular cartilage delamination had been present in twenty-eight of sixty-four hips that had undergone a surgical dislocation procedure for the treatment of femoroacetabular impingement. Multivariable logistic regression was performed to assess the correlation of radiographic findings (i.e., magnetic resonance imaging and computerized tomography findings) with the status of delamination. The preoperative interpretations of the magnetic resonance arthrograms for twenty-seven hips that underwent surgical dislocation were reviewed to assess the accuracy of detecting delamination. At the time of surgery, nine of these twenty-seven hips were found to have delamination. Magnetic resonance arthrography interpretations that did not correlate with operative findings were subjected to conspicuity assessment and error analysis. The rate of delamination of the acetabular cartilage as noted at the time of surgical dislocation was 44% (twenty-eight of sixty-four). Delamination was strongly associated with male sex and femoral sided signs of impingement; however, it was not associated with acetabular overcoverage (center-edge angle, >40 degrees) (odds ratio = 0.16; p < 0.05). While there was no significant difference in the prevalence of labral lesions between groups, whenever labral and delamination lesions were found in the same hip, they were directly adjacent to one another. Preoperative magnetic resonance arthrography had a low sensitivity for delamination (22%) but had a high specificity (100%). Two-thirds of the delamination lesions were visible on retrospective review of these images when the reader was unblinded to the surgical findings. Delamination could most often be identified on the sagittal T1-weighted image and on the proton-density sequences with fat saturation. There should be a high level of suspicion for articular cartilage delamination in men and in patients with primarily cam-type femoroacetabular impingement. Acetabular overcoverage may be protective against delamination. Preoperative high-quality magnetic resonance arthrograms should be carefully analyzed for evidence of delamination in this patient population.


Performance measures for correlation filters.
Several performance criteria are described to enable a fair comparison among the various correlation filter designs: signal-to-noise ratio, peak sharpness, peak location, light efficiency, discriminability, and distortion invariance. The trade-offs resulting between some of these criteria are illustrated with the help of a new family of filters called fractional power filters (FPFs). The classical matched filter, phase-only filter (POF), and inverse filter are special cases of FPFs. Using examples, we show that the POF appears to provide a good compromise between noise tolerance and peak sharpness.


Pandora's Box: mitochondrial defects in ischaemic heart disease and stroke.
Ischaemic heart disease and stroke are vascular events with serious health consequences worldwide. Recent genetic and epigenetic techniques have revealed many genetic determinants of these vascular events and simplified the approaches to research focused on ischaemic heart disease and stroke. The pathogenetic mechanisms of ischaemic heart disease and stroke are complex, with mitochondrial involvement (partially or entirely) recently gaining substantial support. Not only can mitochondrial reactive oxygen species give rise to ischaemic heart disease and stroke by production of oxidised low-density lipoprotein and induction of apoptosis, but the impact on pericytes contributes directly to the pathogenesis. Over the past two decades, publications implicate the causative role of nuclear genes in the development of ischaemic heart disease and stroke, in contrast to the potential role of mitochondrial DNA (mtDNA) in the pathophysiology of the disorders, which is much less understood, although recent studies do demonstrate that the involvement of mitochondria and mtDNA in the development of ischaemic heart disease and stroke is likely to be larger than originally thought, with the novel discovery of links among mitochondria, mtDNA and vascular events. Here we explore the molecular events and mtDNA alterations in relation to the role of mitochondria in ischaemic heart disease and stroke.


A model predicting delivery of saquinavir in nanoparticles to human monocyte/macrophage (Mo/Mac) cells.
Modeling the influence of a technology such as nanoparticle systems on drug delivery is beneficial in rational formulation design. While there are many studies showing drug delivery enhancement by nanoparticles, the literature provides little guidance regarding when nanoparticles are useful for delivery of a given drug. A model was developed predicting intracellular drug concentration in cultured cells dosed with nanoparticles. The model considered drug release from nanoparticles as well as drug and nanoparticle uptake by the cells as the key system processes. Mathematical expressions for these key processes were determined using experiments in which each process occurred in isolation. In these experiments, intracellular delivery of saquinavir, a low solubility drug dosed as a formulation of poly(ethylene oxide)-modified poly(epsilon- caprolactone) (PEO-PCL) nanoparticles, was studied in THP-1 human monocyte/macrophage (Mo/Mac) cells. The model accurately predicted the enhancement in intracellular concentration when drug was administered in nanoparticles compared to aqueous solution. This simple model highlights the importance of relative kinetics of nanoparticle uptake and drug release in determining overall enhancement of intracellular drug concentration when dosing with nanoparticles.


Coupling the advection-dispersion equation with fully kinetic reversible/irreversible sorption terms to model radiocesium soil profiles in Fukushima Prefecture.
Radiocesium is an important environmental contaminant in fallout from nuclear reactor accidents and atomic weapons testing. A modified Diffusion-Sorption-Fixation (mDSF) model, based on the advection-dispersion equation, is proposed to describe the vertical migration of radiocesium in soils following fallout. The model introduces kinetics for the reversible binding of radiocesium. We test the model by comparing its results to depth profiles measured in Fukushima Prefecture, Japan, since 2011. The results from the mDSF model are a better fit to the measurement data (as quantified by R2) than results from a simple diffusion model and the original DSF model. The introduction of reversible sorption kinetics means that the exponential-shape depth distribution can be reproduced immediately following fallout. The initial relaxation mass depth of the distribution is determined by the diffusion length, which depends on the distribution coefficient, sorption rate and dispersion coefficient. The mDSF model captures the long tails of the radiocesium distribution at large depths, which are caused by different rates for kinetic sorption and desorption. The mDSF model indicates that depth distributions displaying a peak in activity below the surface are possible for soils with high organic matter content at the surface. The mDSF equations thus offers a physical basis for various types of radiocesium depth profiles observed in contaminated environments.


Glucocorticoids and insulin promote plasminogen activator inhibitor 1 production by human adipose tissue.
Plasminogen activator inhibitor 1 (PAI-1) is likely to play a role in vascular disease, primarily in subjects with android obesity. It has been demonstrated that PAI-1 is overexpressed in adipose tissue from obese subjects and that visceral adipose tissue produced more PAI-1 than subcutaneous fat. In the present study, the effect of insulin and glucocorticoids, which are key mediators of adipose tissue metabolism, was examined in relation to PAI-1 synthesis by human adipose tissue explants (HAT), collagenase isolated human adipocytes (IHA), cultured human stromal cells (cSC), and differentiated adipocytes from the murine clonal cell line 3T3-F442A. A significant increase in PAI-1 antigen release (1.5-fold) from HAT was detectable after 16 h of treatment with insulin concentrations of at least 10(-8) mol/l. This was associated with a PAI-1 mRNA increase. Concomitant addition of insulin (10(-8) mol/l) to forskolin (5 x 10(-5) mol/l) reversed the decrease in PAI-1 antigen caused by forskolin alone. No effect on PAI-1 antigen was observed when insulin was incubated with IHA or cSC. 3T3 F442A cells were sensitive to insulin with a four- and twofold increase in PAI-1 antigen and mRNA levels, respectively, after 16 h of stimulation with 10(-8) mol/l. Dexamethasone (DXM) significantly enhanced PAI-1 antigen and mRNA expression by HAT (1.5- and 2.5-fold increase, respectively) at concentrations of at least 10(-8) mol/l. A higher stimulation was observed with IHA (sevenfold increase) and with the differentiated 3T3 F442 cell line. Cortisol was found to be less potent than DXM. No effect was observed when glucocorticoids were incubated with cSC. Coincubation of HAT with insulin (10(-7) mol/l) and DXM (10(-7) mol/l) led to an additive effect on PAI-1 synthesis. These results support the hypothesis that PAI-1 expression in human adipose tissue is controlled by insulin and glucocorticoids and may help to explain the increase in plasma PAI-1 levels observed in patients with android obesity.


Host suitability in soybean cultivars for the reniform nematode, 2000 tests.
In greenhouse pot experiments during summer 2000, 118 soybean cultivars were tested to determine their suitability as hosts for the reniform nematode, Rotylenchulus reniformis. The cultivars included 115 new entries into the Arkansas and Mississippi soybean variety testing programs and three entries submitted by an extension nematologist from Texas. Also included in the tests were the R. reniformis-resistant cultivars Forrest and Hartwig, the susceptible cultivar Braxton, and fallow R. reniformis-infested soil that served as controls. Total number of eggs and nematodes extracted from both the soil and roots from each pot and reproductive indices (Pf/Pi) were calculated for each cultivar. The ratio of the Pf/Pi of each cultivar to the Pf/Pi of Forrest (RF), and the log ratio[log(10) (RF + 1)], are reported. Cultivars with reproductive indices that were greater than the reproductive index on Forrest were considered to be suitable hosts for R. reniformis. These data will be useful in the selection of soybean cultivars to use in rotation with cotton or other susceptible crops to help control the reniform nematode.


Coupling of zygotic transcription to mitotic control at the Drosophila mid-blastula transition.
One of the most prominent features at the mid-blastula transition (MBT) observed in most embryos is a pause in cell cycle regulated by the nucleocytoplasmic (N/C) ratio. By using chromosome rearrangements to manipulate the DNA content of embryos, we determined that the threshold for this cell cycle pause in Drosophila is about 70% of the DNA content normally present at cycle 14. Embryos with DNA contents around this value show intermediate cell cycle behaviors. Some pause at cycle 14, some at cycle 15, and some form patches arrested in different mitotic cycles. A second feature at MBT is a massive increase in zygotic transcription and a parallel degradation of maternally supplied RNAs. To determine whether these changes in gene expression are governed by the same N/C ratio that controls cell cycle pause, we compared gene expression in haploid and diploid Drosophila embryos. We find that most maternal RNA degradation and most new transcription correlate with absolute time or developmental stage, and are timed independently of the N/C ratio. We identify a class of zygotically active genes whose expression depends on the N/C ratio and which are only expressed at cycle 15 in haploids. In embryos with patchy cell cycle behavior due to threshold DNA contents, the expression of these genes correlates tightly with the boundaries of the mitotic patches, suggesting either that the mechanism that pauses the mitotic cycle is the same as the one that measures the N/C ratio, or that it is tightly coupled to the mechanism controlling zygotic transcription of N/C ratio genes at the MBT.


Phylogeography of foot-and-mouth disease virus serotype O in Ecuador.
Foot-and-mouth disease virus (FMDV) is the causative agent of the most important disease of domestic cattle, foot-and-mouth disease. In Ecuador, FMDV is maintained at an endemic state, with sporadic outbreaks. To unravel the tempo and mode of FMDV spread within the country we conducted a Bayesian phylogeographic analysis using a continuous time Markov chain (CTMC) to model the diffusion of FMDV between Ecuadorian provinces. We implement this framework through Markov chain Monte Carlo available in the BEAST package to study 90 FMDV serotype O isolates from 17 provinces in the period 2002-2010. The Bayesian approach also allowed us to test hypotheses on the mechanisms of viral spread by incorporating environmental and epidemiological data in our prior distributions and perform Bayesian model selection. Our analyses suggest an intense flow of viral strains throughout the country that is possibly coupled to animal movements and ecological factors, since most of inferred viral spread routes were in Coast and Highland regions. Moreover, our results suggest that both short- and long-range spread occur within Ecuador. The province of Esmeraldas, in the border with Colombia and where most animal commerce is done, was found to be the most probable origin of the circulating strains, pointing to a transboundary behavior of FMDV in South America. These findings suggest that uncontrolled animal movements can create a favorable environment for FMDV maintenance and pose a serious threat to control programmes. Also, we show that phylogeographic modeling can be a powerful tool in unraveling the spatial dynamics of viruses and potentially in controlling the spread of these pathogens.


Acute first-time hamstring strains during high-speed running: a longitudinal study including clinical and magnetic resonance imaging findings.
Hamstring muscle strain is one of the most common injuries in sports. Still, knowledge is limited about the progression of clinical and magnetic resonance imaging characteristics and their association with recovery time in athletes. Knowing the anatomical location and extent of an acute first-time hamstring strain in athletes is critical for the prognosis of recovery time. Case series (prognosis); Level of evidence, 2. Eighteen elite sprinters with acute first-time hamstring strains were prospectively included in the study. All subjects were examined, clinically and with magnetic resonance imaging, on 4 occasions after injury: at day 2 to 4, 10, 21, and 42. The clinical follow-up period was 2 years. All sprinters were injured during competitive sprinting, and the primary injuries were all located in the long head of the biceps femoris muscle. There was an association between the time to return to pre-injury level (median, 16; range, 6-50 weeks) and the extent of the injury, as indicated by the magnetic resonance imaging parameters. Involvement of the proximal free tendon, as estimated by MRI, and proximity to the ischial tuberosity, as estimated both by palpation and magnetic resonance imaging, were associated with longer time to return to pre-injury level. Careful palpation during the first 3 weeks after injury and magnetic resonance imaging investigation performed during the first 6 weeks after injury provide valuable information that can be used to predict the time to return to pre-injury level of performance in elite sprinting.


Quality evaluation of colonoscopy reporting and colonoscopy performance in daily clinical practice.
Comprehensive monitoring of colonoscopy quality requires complete and accurate colonoscopy reporting. This study aimed to assess the compliance with colonoscopy reporting and to assess the quality of colonoscopy performance. Consecutive colonoscopy reports were reviewed by hand. Four hundred reports were included from each department. Daily clinical practice in 12 Dutch endoscopy departments. Consecutive patients undergoing scheduled colonoscopy procedures. Quality of reporting was assessed by using the American Society for Gastrointestinal Endoscopy criteria for colonoscopy reporting. Quality of colonoscopy performance was evaluated by using the cecal intubation rate and adenoma detection rate (ADR). A total of 4800 colonoscopies were performed by 116 endoscopists: 70% by gastroenterologists, 16% by gastroenterology fellows, 10% by internists, 3% by nurse-endoscopists, and 1% by surgeons. The mean age of the patients was 59 years (standard deviation 16), and 47% were male. Reports contained information on indication, sedation practice, and extent of the procedure in more than 90%. Only 62% of the reports mentioned the quality of bowel preparation (range between departments 7%-100%); photographic documentation of the cecal landmarks was present in 71% (range 22%-97%). The adjusted cecal intubation rate was 92% (range 84%-97%). The ADR was 24% (range 13%-32%). Dependent on reports, no intervention in endoscopic practice. No analysis for performance per endoscopist. Colonoscopy reporting varied significantly in clinical practice. Colonoscopy performance met the suggested standards; however, considerable variability between endoscopy departments was found. The results of this study underline the importance of the implementation of quality indicators and guidelines. Moreover, by continuous monitoring of quality parameters, the quality of both colonoscopy reporting and colonoscopy performance can easily be improved.


Hypomorphic function and somatic reversion of DOCK8 cause combined immunodeficiency without hyper-IgE.
Loss-of-function mutations in DOCK8 are linked to hyper-IgE syndrome. Patients typically present with recurrent sinopulmonary infections, severe cutaneous viral infections, food allergies and elevated serum IgE. Although patients may present with a spectrum of disease-related symptoms, molecular mechanisms explaining phenotypic variability in patients are poorly defined. Here we characterized a novel compound heterozygous mutation in DOCK8 in a patient diagnosed with primary combined immunodeficiency which was not typical of classical DOCK8 deficiency. In contrast to previously identified mutations in DOCK8 which result in complete loss of function, the newly identified single nucleotide insertion results in expression of a truncated DOCK8 protein. Functional evaluation of the truncated DOCK8 protein revealed its hypomorphic function. In addition we found somatic reversion of DOCK8 predominantly in T cells. The combination of somatic reversion and hypomorphic DOCK8 function explains the milder and atypical phenotype of the patient and further broadens the spectrum of DOCK8-associated disease.


A palladacyclic N-heterocyclic carbene system used to probe the donating abilities of monoanionic chelators.
A series of NHC-containing [C^N]- or [C^C']-type palladacyclic complexes of the general formula [PdBr(iPr2-bimy)(L^X)] (5-8, 11, 12, iPr2-bimy = 1,3-diisopropylbenzimidazolin-2-ylidene) have been synthesized and fully characterized. Using these complexes, the donating abilities of monoanionic chelators were probed for the first time. The [C^N]-type palladacycles 5-8 were prepared from acetato-bridged dipalladium complexes [Pd(μ-CH3COO)(C^N)]2 (1-4) and iPr2-bimy·H+Br-as precursors. In the case of the [C^C']-type NHC palladacycles (11, 12), the hetero-bis(NHC) complexes trans-[PdBr2(iPr2-bimy)(trz)] (8, 9, trz = 1,2,3-triazolin-5-ylidene) containing the iPr2-bimy probe were first prepared followed by acetate-assisted cyclopalladations. The 13Ccarbene NMR signals of the iPr2-bimy ligands in all complexes (i.e. HEP and HEP2 values) are found to rationally reflect the donating abilities of the incorporated trz or [L^X]-type chelators with the exception of the Bzpy ligand (Bzpy = 2-(2-pyridinylmethyl)phenyl-C,N). This has been attributed to its larger bite angle, the resulting varied coordination geometry and the lack of electronic delocalization between the two donor units. The donicities of [L^X]-type chelators studied in this work were found to surpass those of all other bidentate ligands evaluated by HEP2 thus far.


Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel.
New data and antiretroviral regimens expand treatment choices in resource-rich settings and warrant an update of recommendations to treat adults infected with human immunodeficiency virus (HIV). To provide updated treatment recommendations for adults with HIV, emphasizing when to start treatment; what treatment to start; the use of laboratory monitoring tools; and managing treatment failure, switches, and simplification. An International Antiviral Society-USA panel of experts in HIV research and patient care considered previous data and reviewed new data since the 2012 update with literature searches in PubMed and EMBASE through June 2014. Recommendations and ratings were based on the quality of evidence and consensus. Antiretroviral therapy is recommended for all adults with HIV infection. Evidence for benefits of treatment and quality of available data increase at lower CD4 cell counts. Recommended initial regimens include 2 nucleoside reverse transcriptase inhibitors (NRTIs; abacavir/lamivudine or tenofovir disoproxil fumarate/emtricitabine) and a third single or boosted drug, which should be an integrase strand transfer inhibitor (dolutegravir, elvitegravir, or raltegravir), a nonnucleoside reverse transcriptase inhibitor (efavirenz or rilpivirine) or a boosted protease inhibitor (darunavir or atazanavir). Alternative regimens are available. Boosted protease inhibitor monotherapy is generally not recommended, but NRTI-sparing approaches may be considered. New guidance for optimal timing of monitoring of laboratory parameters is provided. Suspected treatment failure warrants rapid confirmation, performance of resistance testing while the patient is receiving the failing regimen, and evaluation of reasons for failure before consideration of switching therapy. Regimen switches for adverse effects, convenience, or to reduce costs should not jeopardize antiretroviral potency. After confirmed diagnosis of HIV infection, antiretroviral therapy should be initiated in all individuals who are willing and ready to start treatment. Regimens should be selected or changed based on resistance test results with consideration of dosing frequency, pill burden, adverse toxic effect profiles, comorbidities, and drug interactions.


T-cell-independent resistance to infection and generation of immunity to Francisella tularensis.
The intraperitoneal 50% lethal dose (LD50) for Francisella tularensis LVS in both normal control heterozygote BALB/c nu/+ mice and BALB/c nu/nu mice was 2 x 10(0). Both nu/+ and nu/nu mice given 10(7) LVS bacteria or more intradermally (i.d.) died, with a mean time to death of about 7 to 8 days. On the other hand, nu/+ mice given 10(6) LVS bacteria or less survived for more than 60 days and cleared systemic bacteria, while nu/nu mice given 10(6) LVS bacteria or less survived for more than 10 days but died between days 25 and 30. Thus, the short-term (i.e., < 10-day) i.d. LD50 of both nu/nu and nu/+ mice was 3 x 10(6), but the long-term (i.e., > 10-day) i.d. LD50 of nu/nu mice was less than 7 x 10(0). The short-term survival of i.d. infection was dependent on tumor necrosis factor and gamma interferon: treatment of nu/nu mice with anti-tumor necrosis factor or anti-gamma interferon at the time of i.d. infection resulted in death from infection 7 to 8 days later, whereas control infected nu/nu mice survived for 26 days. nu/nu mice infected with LVS i.d. generated LVS-specific serum antibodies, which were predominantly immunoglobulin M: titers peaked 7 days after i.d. infection but declined sharply by day 21, after which mice died. Surprisingly, nu/nu mice given 10(3) LVS bacteria i.d. became resistant to a lethal challenge (5,000 LD50s) of LVS intraperitoneally within 2 days after i.d. infection; nu/nu mice similarly infected with LVS i.d. and challenged with Salmonella typhimurium (10 LD50s) were not protected. nu/nu mice given nu/+ spleen cells intravenously as a source of mature T cells survived i.d. infection for more than 60 days and cleared bacteria. Taken together, these studies demonstrate that i.d. infection of nu/nu mice with LVS rapidly generates T-cell-independent, short-term, specific protective immunity against lethal challenge, but T lymphocytes are essential for long-term survival.


Mannitol 1-phosphate metabolism is required for sporulation in planta of the wheat pathogen Stagonospora nodorum.
An expressed sequence tag encoding a putative mannitol 1-phosphate dehydrogenase (Mpd1) has been characterized from the fungal wheat pathogen Stagonospora nodorum. Mpd1 was disrupted by insertional mutagenesis, and the resulting mpd1 strains lacked all detectable NAD-linked mannitol 1-phosphate dehydrogenase activity (EC 184.108.40.206). The growth rates, sporulation, and spore viability of the mutant strains in vitro were not significantly different from the wild type. The viability of the mpd1 spores when subjected to heat stress was comparable to wild type. Characterization of the sugar alcohol content by nuclear magnetic resonance spectroscopy revealed that, when grown on glucose, the mutant strains contained significantly less mannitol, less arabitol, but more trehalose than the wild-type strains. The mannitol content of fructose-grown cultures was normal. No secreted mannitol could be detected in wild type or mutants. Pathogenicity assays revealed the disruption of Mpd1 did not affect lesion development, however the mutants were unable to sporulate. These results throw new light on the role of mannitol in fungal plant interactions, suggesting a role in metabolic and redox regulation during the critical process of sporulation on senescing leaf material.


Eccentric hamstring strength and hamstring injury risk in Australian footballers.
Are eccentric hamstring strength and between-limb imbalance in eccentric strength, measured during the Nordic hamstring exercise, risk factors for hamstring strain injury (HSI)? Elite Australian footballers (n = 210) from five different teams participated. Eccentric hamstring strength during the Nordic exercise was obtained at the commencement and conclusion of preseason training and at the midpoint of the season. Injury history and demographic data were also collected. Reports on prospectively occurring HSI were completed by the team medical staff. Relative risk (RR) was determined for univariate data, and logistic regression was employed for multivariate data. Twenty-eight new HSI were recorded. Eccentric hamstring strength below 256 N at the start of the preseason and 279 N at the end of the preseason increased the risk of future HSI 2.7-fold (RR, 2.7; 95% confidence interval, 1.3 to 5.5; P = 0.006) and 4.3-fold (RR, 4.3; 95% confidence interval, 1.7 to 11.0; P = 0.002), respectively. Between-limb imbalance in strength of greater than 10% did not increase the risk of future HSI. Univariate analysis did not reveal a significantly greater RR for future HSI in athletes who had sustained a lower limb injury of any kind within the last 12 months. Logistic regression revealed interactions between both athlete age and history of HSI with eccentric hamstring strength, whereby the likelihood of future HSI in older athletes or athletes with a history of HSI was reduced if an athlete had high levels of eccentric strength. Low levels of eccentric hamstring strength increased the risk of future HSI. Interaction effects suggest that the additional risk of future HSI associated with advancing age or previous injury was mitigated by higher levels of eccentric hamstring strength.


Nondiffractive subwavelength wave beams in a medium with externally controlled anisotropy.
We predict and experimentally demonstrate that in a medium with externally induced anisotropy, a wave source of a sufficiently small size can excite practically nondiffractive wave beams with stable subwavelength transverse aperture. The direction of beam propagation is controlled by rotating the induced anisotropy axis. Nondiffractive wave beam propagation, reflection, and scattering, as well as beam steering have been directly observed by optically probing dipolar spin waves in yttrium iron garnet films, where the uniaxial anisotropy was created by an in-plane bias magnetic field.


MMP-2-Controlled Transforming Micelles for Heterogeneic Targeting and Programmable Cancer Therapy.
Herein, through the active-peptide-functionalization, we developed a nanoscale micelles system (named HEKM) which consists of tumor microenvironment-regulated shape-changing with specific recognition abilities for enhanced cellular targeting, internalization and therapy of heterogeneic tumors. As a result, HEKMs could recognize and bind the tumor heterogeneity marker EGFR-HER2 complex, which led to an enhanced tumor targeting effect. In particular, HEKMs could self-assemble into nanorods under normal physiological conditions while transform into nanospheres in the tumor extracellular microenvironment by a sensitive response to matrix metalloproteinase-2 (MMP-2). The nanorods could prolong the blood circulation time while the nanospheres could accelerate tissue penetration in tumors. In vivo dual-modal targeted imaging was realized by FRET-fluorophore conjugation and gadolinium loading in HEKMs. Tumor cell apoptosis was achieved by proapoptotic element integration. The in vitro and in vivo studies both demonstrated that these rationally designed, shape-changing and targeting micelles could achieve maximized drug efficacy and minimum side effects.


Haplotype analysis of the HSD17B1 gene and risk of breast cancer: a comprehensive approach to multicenter analyses of prospective cohort studies.
The 17beta-hydroxysteroid dehydrogenase 1 gene (HSD17B1) encodes 17HSD1, which catalyzes the final step of estradiol biosynthesis. Despite the important role of HSD17B1 in hormone metabolism, few epidemiologic studies of HSD17B1 and breast cancer have been conducted. This study includes 5,370 breast cancer cases and 7,480 matched controls from five large cohorts in the Breast and Prostate Cancer Cohort Consortium. We characterized variation in HSD17B1 by resequencing and dense genotyping a multiethnic sample and identified haplotype-tagging single nucleotide polymorphisms (htSNP) that capture common variation within a 33.3-kb region around HSD17B1. Four htSNPs, including the previously studied SNP rs605059 (S312G), were genotyped to tag five common haplotypes in all cases and controls. Conditional logistic regression was used to estimate odds ratios (OR) for disease. We found no evidence of association between common HSD17B1 haplotypes or htSNPs and overall risk of breast cancer. The OR for each haplotype relative to the most common haplotype ranged from 0.98 to 1.07 (omnibus test for association: X2 = 3.77, P = 0.58, 5 degrees of freedom). When cases were subdivided by estrogen receptor (ER) status, two common haplotypes were associated with ER-negative tumors (test for trend, Ps = 0.0009 and 0.0076; n = 353 cases). HSD17B1 variants that are common in Caucasians are not associated with overall risk of breast cancer; however, there was an association among the subset of ER-negative tumors. Although the probability that these ER-negative findings are false-positive results is high, these findings were consistent across each cohort examined and warrant further study.


An evaluation of the effectiveness of diploma-level training in cognitive behaviour therapy.
As part of the UK government's initiative to Increase Access to Psychological Therapies (see http://www.iapt.nhs.uk/for full details of the IAPT programme) there has been an expansion in the provision of post-graduate Diploma training in cognitive behaviour therapy (CBT). Previous evaluations of such training programmes have yielded mixed results but have been limited by small sample sizes and/or limited assessment measures. To evaluate the impact of a long-standing Diploma in CBT training programme on a variety of measures of CBT competence. Trainees' levels of CBT skill are compared at the beginning and end of CBT training. The effect of therapist factors such as age, professional background and gender on the development of CBT competence is also examined. Results show that trainees demonstrate higher levels of CBT skills after completing the training than they did before, with the majority achieving pre-determined criteria for competence. Trainees' gender was not related to their performance but trainees' age showed a negative association with CBT skill (older trainees performed worse). Trainees' professional background also had an impact on their level of CBT competence, with trainees who were clinical psychologists demonstrating the highest levels of competence across a range of measures. CBT Diploma training leads to increases in the level of trainees' CBT competence, with the majority achieving the levels demonstrated in research trials by the end of training. Thus, this training is likely to lead to improved outcomes for patients. Further research is needed to determine the most efficient ways of enhancing CBT skills.


Volume change of segments II and III of the liver after gastrectomy in patients with gastric cancer.
We aimed to evaluate the relationship between gastrectomy and the volume of liver segments II and III in patients with gastric cancer. Computed tomography images of 54 patients who underwent curative gastrectomy for gastric adenocarcinoma were retrospectively evaluated by two blinded observers. Volumes of the total liver and segments II and III were measured. The difference between preoperative and postoperative volume measurements was compared. Total liver volumes measured by both observers in the preoperative and postoperative scans were similar (P > 0.05). High correlation was found between both observers (preoperative r=0.99; postoperative r=0.98). Total liver volumes showed a mean reduction of 13.4% after gastrectomy (P = 0.977). The mean volume of segments II and III showed similar decrease in measurements of both observers (38.4% vs. 36.4%, P = 0.363); the correlation between the observers were high (preoperative r=0.97, P < 0.001; postoperative r=0.99, P < 0.001). Volume decrease in the rest of the liver was not different between the observers (8.2% vs. 9.1%, P = 0.388). Time had poor correlation with volume change of segments II and III and the total liver for each observer (observer 1, rseg2/3=0.32, rtotal=0.13; observer 2, rseg2/3=0.37, rtotal=0.16). Segments II and III of the liver showed significant atrophy compared with the rest of the liver and the total liver after gastrectomy. Volume reduction had poor correlation with time.


A high-throughput in vitro drug screen in a genetically engineered mouse model of diffuse intrinsic pontine glioma identifies BMS-754807 as a promising therapeutic agent.
Diffuse intrinsic pontine gliomas (DIPGs) represent a particularly lethal type of pediatric brain cancer with no effective therapeutic options. Our laboratory has previously reported the development of genetically engineered DIPG mouse models using the RCAS/tv-a system, including a model driven by PDGF-B, H3.3K27M, and p53 loss. These models can serve as a platform in which to test novel therapeutics prior to the initiation of human clinical trials. In this study, an in vitro high-throughput drug screen as part of the DIPG preclinical consortium using cell-lines derived from our DIPG models identified BMS-754807 as a drug of interest in DIPG. BMS-754807 is a potent and reversible small molecule multi-kinase inhibitor with many targets including IGF-1R, IR, MET, TRKA, TRKB, AURKA, AURKB. In vitro evaluation showed significant cytotoxic effects with an IC50 of 0.13 μM, significant inhibition of proliferation at a concentration of 1.5 μM, as well as inhibition of AKT activation. Interestingly, IGF-1R signaling was absent in serum-free cultures from the PDGF-B; H3.3K27M; p53 deficient model suggesting that the antitumor activity of BMS-754807 in this model is independent of IGF-1R. In vivo, systemic administration of BMS-754807 to DIPG-bearing mice did not prolong survival. Pharmacokinetic analysis demonstrated that tumor tissue drug concentrations of BMS-754807 were well below the identified IC50, suggesting that inadequate drug delivery may limit in vivo efficacy. In summary, an unbiased in vitro drug screen identified BMS-754807 as a potential therapeutic agent in DIPG, but BMS-754807 treatment in vivo by systemic delivery did not significantly prolong survival of DIPG-bearing mice.


Influence of Different Sewer Biofilms on Transformation Rates of Drugs.
To estimate drug consumption more reliably, wastewater-based epidemiology would benefit from a better understanding of drug residue stability during in-sewer transport. We conducted batch experiments with real, fresh wastewater and sewer biofilms. Experimental conditions mimic small to medium-sized gravity sewers with a relevant ratio of biofilm surface area to wastewater volume (33 m2 m-3). The influences of biological, chemical, and physical processes on the transformation of 30 illicit drug and pharmaceutical residues were quantified. Rates varied among locations and over time. Three substances were not stable-that is, >20% transformation, mainly due to biological processes-at least for one type of tested biofilm for a residence time ≤2 h: amphetamine, 6-acetylcodeine, and 6-monoacetylmorphine. Cocaine, ecgonine methyl ester, norcocaine, cocaethylene, and mephedrone were mainly transformed by chemical hydrolysis and, hence, also unstable in sewers. In contrast, ketamine, norketamine, O-desmethyltramadol, diclofenac, carbamazepine, and methoxetamine were not substantially affected by in-sewer processes under all tested conditions and residence times up to 12 h. Our transformation rates include careful quantification of uncertainty and can be used to identify situations in which specific compounds are not stable. This will improve accuracy and uncertainty estimates of drug consumption when applied to the back-calculation.


The orphan nuclear receptor NR4A1 (Nur77) regulates oxidative and endoplasmic reticulum stress in pancreatic cancer cells.
NR4A1 (Nur77, TR3) is an orphan nuclear receptor that is overexpressed in pancreatic cancer and exhibits pro-oncogenic activity. RNA interference of NR4A1 expression in Panc-1 cells induced apoptosis and subsequent proteomic analysis revealed the induction of several markers of endoplasmic reticulum stress, including glucose-related protein 78 (GRP78), CCAAT/enhancer-binding protein-homologous protein (CHOP), and activating transcription factor-4 (ATF-4). Treatment of pancreatic cancer cells with the NR4A1 antagonist 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) gave similar results. Moreover, both NR4A1 knockdown and DIM-C-pPhOH induced reactive oxygen species (ROS), and induction of ROS and endoplasmic reticulum stress by these agents was attenuated after cotreatment with antioxidants. Manipulation of NR4A1 expression coupled with gene expression profiling identified a number of ROS metabolism transcripts regulated by NR4A1. Knockdown of one of these transcripts, thioredoxin domain containing 5 (TXNDC5), recapitulated the elevated ROS and endoplasmic reticulum stress; thus, demonstrating that NR4A1 regulates levels of endoplasmic reticulum stress and ROS in pancreatic cancer cells to facilitate cell proliferation and survival. Finally, inactivation of NR4A1 by knockdown or DIM-C-pPhOH decreased TXNDC5, resulting in activation of the ROS/endoplasmic reticulum stress and proapoptotic pathways. The NR4A1 receptor is pro-oncogenic, regulates the ROS/endoplasmic reticulum stress pathways, and inactivation of the receptor represents a novel pathway for inducing cell death in pancreatic cancer.


The bovine CD1 family contains group 1 CD1 proteins, but no functional CD1d.
The CD1 family of proteins presents lipid Ags to T cells. Human CD1a, CD1b, and CD1c have been shown in humans to present mycobacterial lipid Ags. Cattle, like humans, are a natural host of several mycobacterial pathogens. In this study, we describe the CD1 family of genes in cattle (Bos taurus) and provide evidence that B. taurus expresses CD1a, CD1e, and multiple CD1b molecules, but no CD1c and CD1d molecules. In mice and humans, CD1d is known to present Ag to NKT cells, a T cell lineage that is characterized by a limited TCR repertoire, capable of rapidly secreting large amounts of IFN-gamma and IL-4. In cattle, two CD1D pseudogenes were found and no intact CD1D genes. Consistent with this, we found complete lack of reactivity to a potent, cross-reactive Ag for NKT cells in mice and humans, alpha-galactosylceramide. Our data suggest the absence of NKT cells in cattle. It remains open whether other cells with the NKT-like phenotype and functions are present in this species. With its functional CD1A and CD1B genes, B. taurus is well equipped to present Ags to CD1-restricted T cells other than NKT cells. Cattle can be used as a model to study group 1 CD1-restricted T cell immunity, including its role in the defense against mycobacterial infections that occur naturally in this species.


Is early ischemic lesion volume on diffusion-weighted imaging an independent predictor of stroke outcome? A multivariable analysis.
The heterogeneity of stroke makes outcome prediction difficult. Neuroimaging parameters may improve the predictive value of clinical measures such as the National Institutes of Health Stroke Scale (NIHSS). We investigated whether the volume of early ischemic brain lesions assessed with diffusion-weighted imaging (DWI) was an independent predictor of functional outcome. We retrospectively selected patients with nonlacunar ischemic stroke in the anterior circulation from 4 prospective Stanford Stroke Center studies evaluating early MRI. The baseline NIHSS score and ischemic stroke risk factors were assessed. A DWI MRI was performed within 48 hours of symptom onset. Clinical characteristics and early lesion volume on DWI were compared between patients with an independent outcome (Barthel Index score >/=85) and a dependent outcome (Barthel Index score <85) at 1 month. A logistic regression model was performed with factors that were significantly different between the 2 groups in univariate analysis. Sixty-three patients fulfilled the entry criteria. One month after symptom onset, 24 patients had a Barthel Index score <85 and 39 had a Barthel Index score >/=85. In univariate analysis, patients with independent outcome were younger, had lower baseline NIHSS scores, and had smaller lesion volumes on DWI. In a logistic regression model, DWI volume was an independent predictor of outcome, together with age and NIHSS score, after correction for imbalances in the delay between symptom onset and MRI. DWI lesion volume measured within 48 hours of symptom onset is an independent risk factor for functional independence. This finding could have implications for the design of acute stroke trials.


Patients with Disorders of Consciousness in India: Preliminary Results from a Pilot Survey.
The epidemiological data of Indian patients with disorders of consciousness (DOC), specifically vegetative state and minimally conscious state, have not been investigated. The present study sought to explore the current state of the art in India for patients with DOC promoting a pilot survey. An ad hoc questionnaire was sent to a total of 400 Indian professionals who are affiliated to various centers; 59 professionals completed the questionnaire and 52 of them declared that their centers hospitalized patients with DOC in the last year for rehabilitation/medical treatments. The majority of the professionals were from Maharashtra region. The main preliminary findings showed that the prevalence rates of traumatic and nontraumatic etiologies were equally distributed, that the rate of use of the coma recovery scale-revised was low, and that the rehospitalization was always or frequently possible in neurological and rehabilitation units. The extrapolated estimated rate of patients with DOC hospitalized in the centers involved in 2017 was equal to 4 per million of population in Maharashtra region. More than 50% of the professionals declared that there were neither sufficient nor adequate services for caregivers' support. Even if the present pilot survey has some limitations, the present article offers the first preliminary data on patients with DOC in Indian country.


An Incremental Shuttle Wheel Test for Wheelchair Tennis Players.
To determine the relationship between outcomes of the shuttle wheel test (SWT) and peak oxygen uptake (VO2peak) during that test and whether SWT and VO2peak can discriminate between different skill levels of wheelchair tennis players. Fifteen wheelchair tennis players performed an SWT on a tennis court while VO2 was measured continuously. Outcome measures were VO2peak and achieved stage. Relations between outcomes and Dutch wheelchair tennis ranking were calculated with Spearman correlation. Independent t tests were used to test for differences between national and international players. Moderate correlations were found between VO2peak and SWT outcome (r = .40-.47). The tennis ranking correlated weakly with VO2peak (r = -.35) and strongly with SWT outcome (r = -.80). A significant difference was found between national and international players for achieved stage (P = .027) and VO2peak (P = .027). The SWT outcome only explained a small part of the variance in VO2peak among players, so it cannot be considered a valid test for aerobic capacity. However, SWT outcomes are related to the skill level of the player and give a good indication of the overall peak wheelchair performance.


Evaluation of the visual prostate symptom score in a male population with great language diversity and limited education: a study from Namibia.
A visual prostate symptom score (VPSS) using pictograms was developed to assess the force of the urinary stream, urinary frequency, nocturia and quality of life (QoL). To compare the VPSS with the international prostate symptom score (IPSS) and maximum (Qmax) and average (Qave) urinary flow rates in men from diverse language groups with limited schooling. Men with lower urinary tract symptoms admitted to the urology ward at Windhoek Central Hospital, Namibia, were evaluated. Patients who were unable to complete the questionnaires alone were assisted by a doctor or nurse. Local ethics committee approval was obtained. Statistical analysis was performed using Student's t-test and Spearman's rank correlation test. One hundred men (mean age 56.3 years, range 20.1 - 95.4) were evaluated over a period of one year. All the men understood one or more of 15 languages, and 30 were illiterate; 32 had <5 years of schooling, 34 had 5 - 9 years and 34 had >9 years. The VPSS took significantly less time to complete than the IPSS. There were statistically significant correlations between the total VPSS and IPSS scores, between the four VPSS questions and the corresponding IPSS questions, and between Qmax and Qave and the VPSS total and VPSS questions on the force of the urinary stream and QoL. The VPSS pictograms depicting the force of the urinary stream and QoL correlated significantly with Qmax and Qave, indicating that they can be used as single-item questions to rapidly assess bladder outflow obstruction in men with limited education.


The influence of specific physical health conditions on retirement decisions.
Physical health has consistently been shown to strongly influence the retirement decision-making process. Unfortunately, "physical health" is typically operationalized in global terms. As a result, we know little about the specific aspects of physical health that influence the decision to retire. Therefore, in the present study, data from three waves of the Americans' Changing Lives (ACL) data set was examined to determine which specific health conditions are associated with retirement, continued work in the same job, or continued work but in a different job. The major health conditions most strongly related to retirement were lung disease and cancer, while only lung disease was predictive of job change at older ages. In contrast, arthritis and diabetes were the minor health conditions most strongly related to both changing jobs and retiring over an eight-year period. The results are discussed in terms of the importance of better understanding why specific health factors are associated with retirement and job changes during one's late career.


Factors associated with farm-level infection of porcine epidemic diarrhea during the early phase of the epidemic in Japan in 2013 and 2014.
The objective of this study was to investigate factors that caused rapid spread during the early phase of the porcine epidemic diarrhea (PED) epidemic in Japan in 2013 and 2014. Anonymized datasets from all pig farms were provided by Kagoshima (709 farms) and Miyazaki Prefectures (506 farms). Semi-parametric survival analysis was conducted using the first 180 days from the first case on December 3, 2013 in Kagoshima Prefecture. To compare the hazard between different farm management types, univariable survival analysis was conducted. As farm sizes varied among different farm types, bivariable survival analysis was conducted for farm size categories and farm density per km2 for each management type. A case-control study using a postal questionnaire survey was conducted in September 2014, and risk factor analysis was performed using generalized linear models with binomial errors. The hazard was significantly higher in farrow-to-finish farms than fattening farms [hazard ratio (HR) = 1.6, p < 0.01], but was not significantly different between reproduction and fattening farms (HR = 1.3, p = 0.16). In separate bivariable survival analyses for each farm type, large- and middle-scale farms had higher hazard than small-scale farms in fattening (HR = 5.8 and 2.6, respectively, both p < 0.01) and reproduction farms (HR = 4.0 and 3.6, respectively, both p < 0.01). In farrow-to-finish farms, large-scale farms had higher hazard than small-scale farms (HR = 2.8, p < 0.01), and higher farm density per km2 was also a risk factor (HR = 7.6, p < 0.01). In the case-control study, questionnaires were returned from 78 PED virus-infected and 91 non-infected farms. The overall response rate was 34%. Risk factors of the final model were occurrence of porcine reproductive and respiratory syndrome in the past 5 years [odds ratio (OR) = 1.97, 95% confidence interval (CI): 0.97-4.00, p = 0.054], use of a common compost station (OR = 2.51, 95%CI: 1.08-5.83, p = 0.03), and use of a pig excrement disposal service (OR = 2.64, 95%CI: 1.05-6.63, p = 0.04). High hazard in farrow-to-finish farms suggested transmission from slaughterhouses to susceptible suckling piglets. Hazard associated with large-scale farms and high density might be due to frequent vehicle entrance and transmission by roads. Improvement of farm hygiene management and avoidance of risky practices associated with contact with pig excrement were keys in preventing invasion of PED virus to a farm.


Musculoskeletal care pathways for adults with hip and knee pain at the interface between primary and secondary care: protocol for a systematic review.
Musculoskeletal (MSK) conditions are the most frequently reported chronic conditions and one of the biggest causes of disability in the UK. Given the ageing population and the impact of these problems, the demand for MSK treatment will rise. Despite reduced waiting times, MSK pathways have remained variable and inconsistent and need to be improved to meet patient needs. The aim of this systematic review is to understand the evidence for the effectiveness of current models of service delivery and care pathways for adult hip/knee pain patients accessing secondary care for specialist opinions. MEDLINE, MEDLINE In-Process, CINAHL, Embase, PEDro, PubMed, Web of Science, Cochrane Central and HMIC databases will be searched without language restrictions for papers published from 1990 onward. Websites will be reviewed for grey literature including care pathways, policy documents and unpublished MSK research. Additionally, reference lists will be checked and citations tracked for included studies. The following evidence will be included: research considering care pathways at the intersection between primary and secondary care for adults with hip and/or knee pain in countries with an established clinical pathway. Studies considering generalised inflammatory arthropathy and post-surgical care pathways will be excluded. Screening for included data will be conducted independently by two reviewers. After benchmarking, quality assessment and data extraction will be conducted by one reviewer and checked by a second. A mixed method analysis will be conducted. This systematic review will be used as part of a programme of research to identify best practice for MSK hip and knee pain care pathways. It will provide recommendations for pathway re-design to meet patient needs and ensure efficient streamlining of the patient journey. The review will combine a wide range of information sources including patient and clinician opinion, clinical guidelines, health service delivery research and stakeholder requirements. This should result in a pathway that provides better patient experience and outcomes, whilst meeting the demands placed on the NHS for high-quality evidence-based interventions with efficient use of resources. PROSPERO CRD42016035510.


Factors associated with wasting among children under five years old in South Asia: Implications for action.
South Asia continues to carry the greatest share and number of wasted children worldwide. Understanding the determinants of wasting is important as policymakers renew efforts to tackle this persistent public health and development problem. Using data from national surveys in Bangladesh, India, the Maldives, Nepal, Pakistan and Afghanistan, this analysis explores factors associated with wasting among children aged 0 to 59 months (n = 252,797). We conducted multivariate mixed logistic regression and backwards stepwise methods to identify parsimonious models for each country separately (all p values <0.05). Younger children (0 to 5 months), and those whose mothers had a low body mass index (<18.5 kg/m2) had greater odds of being wasted in all countries. Later birth order, being male, maternal illiteracy, short maternal stature, lack of improved water source, and household poverty were also associated with wasting in various countries, but not systematically in all. Seasonality was also not consistently associated with wasting in the final models. These findings suggest that pre-conception (adolescence), pregnancy and early postpartum, represent windows of opportunity for tackling child wasting, not only stunting. Our analysis suggests that the underlying determinants of wasting and stunting in South Asia are similar, but not universal across geographies. Cost-effective interventions to prevent both stunting and wasting, and to treat severe wasting, need to be scaled up urgently. Separating these two manifestations of child undernutrition in conceptual and programmatic terms may unnecessarily impair progress to reach the Sustainable Development Goals targets aimed at addressing both child stunting and wasting.


Alfaxalone versus propofol in dogs: a randomised trial to assess effects on peri-induction tear production, intraocular pressure and globe position.
The purpose of this randomised trial was to compare the effects of alfaxalone and propofol on tear production (STT-1), intraocular pressure (IOP) and globe position (GP) in healthy dogs. Fourteen Beagles were randomly divided into two groups; dogs in one group received alfaxalone (3 mg/kg) (n=7) and dogs in the other group received propofol (6 mg/kg) (n=7), both administered intravenously. IOP and GP were evaluated at basal time (Tb) and T2,5,10,15,20,25&30 (minutes after complete drug administration). STT-1 was evaluated at Tb and T10,20&30. STT-1 and IOP results were analysed using analysis of variance and GP was analysed using the likelihood ratio χ(2) test. Dogs in the alfaxalone group showed a significant reduction in STT-1 at T10&20 (P<0.05), while the propofol group did not show statistically significant differences in this parameter over time. Both anaesthetic drugs produced a transient elevation of IOP at T2 (P>0.05), which then decreased (P<0.01). While alfaxalone caused a ventral globe deviation that lasted from T2 to T10 (P<0.05) and was fully recovered at T30, propofol induced a ventral globe deviation from T2 to T5 (P<0.05), being restored at T20. These results suggest that both alfaxalone and propofol can be safely used for intraocular surgery, as they significantly reduce IOP. Furthermore, anaesthetic induction with propofol would be especially recommended for dogs with tear deficiencies.


Mammalian phylogenetic diversity-area relationships at a continental scale.
In analogy to the species-area relationship (SAR), one of the few laws in ecology, the phylogenetic diversity-area relationship (PDAR) describes the tendency of phylogenetic diversity (PD) to increase with area. Although investigating PDAR has the potential to unravel the underlying processes shaping assemblages across spatial scales and to predict PD loss through habitat reduction, it has been little investigated so far. Focusing on PD has noticeable advantages compared to species richness (SR), since PD also gives insights on processes such as speciation/extinction, assembly rules and ecosystem functioning. Here we investigate the universality and pervasiveness of the PDAR at continental scale using terrestrial mammals as study case. We define the relative robustness of PD (compared to SR) to habitat loss as the area between the standardized PDAR and standardized SAR (i.e., standardized by the diversity of the largest spatial window) divided by the area under the standardized SAR only. This metric quantifies the relative increase of PD robustness compared to SR robustness. We show that PD robustness is higher than SR robustness but that it varies among continents. We further use a null model approach to disentangle the relative effect of phylogenetic tree shape and nonrandom spatial distribution of evolutionary history on the PDAR. We find that, for most spatial scales and for all continents except Eurasia, PDARs are not different from expected by a model using only the observed SAR and the shape of the phylogenetic tree at continental scale. Interestingly, we detect a strong phylogenetic structure of the Eurasian PDAR that can be predicted by a model that specifically account for a finer biogeographical delineation of this continent. In conclusion, the relative robustness of PD to habitat loss compared to species richness is determined by the phylogenetic tree shape but also depends on the spatial structure of PD.


Direct short-term effects of EBP teaching: change in knowledge, not in attitude; a cross-cultural comparison among students from European and Asian medical schools.
We report about the direct short-term effects of a Clinical Epidemiology and Evidence-based Medicine (CE-EBM) module on the knowledge, attitude, and behavior of students in the University Medical Center Utrecht (UMCU), Universitas Indonesia (UI), and University of Malaya (UM). We used an adapted version of a 26-item validated questionnaire, including four subscales: knowledge, attitude, behavior, and future use of evidence-based practice (EBP). The four components were compared among the students in the three medical schools before the module using one-way ANOVA. At the end of the module, we measured only knowledge and attitudes. We computed Cronbach's α to assess the reliability of the responses in our population. To assess the change in knowledge and attitudes, we used the paired t-test in the comparison of scores before and after the module. In total, 526 students (224 UI, 202 UM, and 100 UMCU) completed the questionnaires. In the three medical schools, Cronbach's α for the pre-module total score and the four subscale scores always exceeded 0.62. UMCU students achieved the highest pre-module scores in all subscales compared to UI and UM with the comparison of average (SD) score as the following: knowledge 5.04 (0.4) vs. 4.73 (0.69) and 4.24 (0.74), p<0.001; attitude 4.52 (0.64) vs. 3.85 (0.68) and 3.55 (0.63), p<0.001; behavior 2.62 (0.55) vs. 2.35 (0.71) and 2.39 (0.92), p=0.016; and future use of EBP 4.32 (0.59) vs. 4.08 (0.62) and 3.7 (0.71), p<0.01. The CE-EBM module increased the knowledge of the UMCU (from average 5.04±0.4 to 5.35±0.51; p<0.001) and UM students (from average 4.24±0.74 to 4.53±0.72; p<0.001) but not UI. The post-module scores for attitude did not change in the three medical schools. EBP teaching had direct short-term effects on knowledge, not on attitude. Differences in pre-module scores are most likely related to differences in the system and infrastructure of both medical schools and their curriculum.


An indigenous approach to explore health-related experiences among Māori parents: the Pukapuka Hauora asthma study.
The prevalence of asthma for Indigenous New Zealand Māori is amongst the highest in the world. Recent evidence shows ethnic differences in asthma symptom prevalence in New Zealand have widened, with asthma symptoms and hospitalisation rates consistently higher for Māori across all age-groups, especially children and adolescents. This paper: outlines our qualitative, longitudinal research exploring the practical issues Māori children and their families face trying to achieve optimum asthma outcomes; details the research methods used within this study; and discusses the process evaluation findings of the features that made this approach successful in engaging and retaining participants in the study. Thirty-two Māori families were recruited using a Kaupapa Māori (Māori way) Research approach. Each participated in a series of four in-depth interviews that were carried out at seasonal intervals over the course of one year. Families also took part in an interviewer-administered questionnaire and participated in a Photovoice exercise. All interviews were digitally recorded, transcribed verbatim and independently coded by two researchers. The research team then conducted the analysis and theme development. The questionnaires were analysed separately, with explanations for findings explored within the qualitative data. The methodology produced a 100 percent retention rate of the participating families over the course of the follow-up. This was attributed to the research collaboration, the respectful research relationships established with families, and the families' judgement that the methods used enabled them to tell their stories. The acceptability of the methodology will add to the validity and trustworthiness of the findings. Given the extent and persistence of ethnic disparities in childhood asthma management, it is imperative that an indigenous approach be taken to understanding the core issues facing Māori families. By conducting community-partnership research underpinned by an indigenous methodology, and employing a range of appropriate methods, we have successfully recruited and retained a cohort of Māori families with experiences of childhood asthma. We aim to make their voices heard in order to develop a series of culturally relevant interventions aimed at remediating these disparities.


Assessing the Utility of Hydrogen, Carbon and Nitrogen Stable Isotopes in Estimating Consumer Allochthony in Two Shallow Eutrophic Lakes.
Hydrogen stable isotopes (δ2H) have recently been used to complement δ13C and δ15N in food web studies due to their potentially greater power to separate sources of organic matter in aquatic food webs. However, uncertainties remain regarding the use of δ2H, since little is known about the potential variation in the amount of exchangeable hydrogen (Hex) among common sample materials or the patterns of δ2H when entire food webs are considered. We assessed differences in Hex among the typical sample materials in freshwater studies and used δ2H, δ13C and δ15N to compare their effectiveness in tracing allochthonous matter in food webs of two small temperate lakes. Our results showed higher average amounts of Hex in animal tissues (27% in fish and macroinvertebrates, 19% in zooplankton) compared to most plant material (15% in terrestrial plants and 8% in seston/periphyton), with the exception of aquatic vascular plants (23%, referred to as macrophytes). The amount of Hex correlated strongly with sample lipid content (inferred from C:N ratios) in fish and zooplankton samples. Overall, the three isotopes provided good separation of sources (seston, periphyton, macrophytes and allochthonous organic matter), particularly the δ2H followed by δ13C. Aquatic macrophytes revealed unexpectedly high δ2H values, having more elevated δ2H values than terrestrial organic matter with direct implications for estimating consumer allochthony. Organic matter from macrophytes significantly contributed to the food webs in both lakes highlighting the need to include macrophytes as a potential source when using stable isotopes to estimate trophic structures and contributions from allochthonous sources.


Skeletal muscle stem cell birth and properties.
Development and maintenance of an abundant tissue such as skeletal muscle poses several challenges. Curiously, not all skeletal muscle stem cells are born alike, since diverse genetic pathways can specify their birth. Stem and progenitor cells that establish the tissue during development, those that maintain its homeostasis, as well as participate in its regeneration have generated considerable interest. The ability to distinguish stem cells from more committed progenitors throughout prenatal and postnatal life has guided researchers to identify stem cell properties and characterise their niche. These properties include markers that influence cell behaviour and mode of division during normal development, after trauma and cell transplantations. This review addresses these issues from a developmental perspective.


Preferences for redistribution are sensitive to perceived luck, social homogeneity, war and scarcity.
Many human societies feature institutions for redistributing resources from some individuals to others, but preferred levels of redistribution vary greatly within and between populations. We postulate that support for redistribution is the output of a structured cognitive system that is sensitive to features of the social situation. We developed an experimental approach in which participants prescribe appropriate redistribution for hypothetical villages whose features vary. Over seven experiments involving 2400 adults from the UK, we show that participants shift their redistribution preferences systematically as situational features change. Higher levels of redistribution are favoured when luck is more important in the initial distribution of resources; when social groups are more homogeneous; when the group is at war; and when resources are abundant rather than scarce. Judgements about the right level of redistribution carry moderate or high levels of moral conviction. Participants have systematic intuitions about when the implementation of redistribution will prove problematic, distinct from their intuitions about when it is desirable. Individuals are only weakly consistent in the level of redistribution they prefer, and political orientation explains rather little variation in preferred redistribution for a given situation. We argue that people have divergent views on redistribution at least in part because they have different appraisals of the features of their societies. Understanding the operating principles of the psychology of redistribution may help explain variation and change in support for, and hence existence of, redistributive institutions across societies and over time.


Parenting interventions for the prevention of unintentional injuries in childhood.
Parent education and training programmes can improve maternal psychosocial health, child behavioural problems and parenting practices. This review assesses the effects of parenting interventions for reducing child injury. To assess the effects of parenting interventions for preventing unintentional injury in children aged under 18 years and for increasing possession and use of safety equipment and safety practices by parents. We searched CENTRAL, MEDLINE, EMBASE, BIOSIS Preview, PsycINFO, Sociological Abstracts, Social Science Citation Index, CINAHL, ProQuest Dissertations and Theses, ERIC, DARE, ASSIA, Web of Science, SIGLE and ZETOC. We also handsearched abstracts from the World Conferences on Injury Prevention & Control and the journal Injury Prevention. The searches were conducted in January 2011. We included randomised controlled trials (RCTs), non-randomised controlled trials (non-RCTs) and controlled before and after studies (CBAs), which evaluated parenting interventions administered to parents of children aged 18 years and under, and reported outcome data on injuries for children (unintentional or unspecified intent), possession and use of safety equipment or safety practices (including the Home Observation for Measurement of the Environment (HOME) scale which contained an assessment of home safety) by parents. Parenting interventions were defined as those with a specified protocol, manual or curriculum aimed at changing knowledge, attitudes or skills covering a range of parenting topics. Studies were selected, data were extracted and quality appraised independently by two authors. Pooled relative risks (RR) were estimated using random effect models. Twenty two studies were included in the review: 16 RCTs, two non-RCTs, one partially randomised trial which contained two randomised intervention arms and one non-randomised control arm, two CBA studies and one quasi randomised controlled trial. Seventeen studies provided interventions comprising parenting education and other support services; 15 of which were home visiting programmes and two of which were paediatric practice-based interventions. Two provided solely educational interventions. Nineteen studies recruited families who were from socio-economically disadvantaged populations, were at risk of adverse child outcomes or people who may benefit from extra support, such as single mothers, teenage mothers, first time mothers and mothers with learning difficulties. Ten RCTs involving 5074 participants were included in the meta-analysis, which indicated that intervention families had a statistically significant lower risk of injury than control families (RR 0.83, 95% CI 0.73 to 0.94). Sensitivity analyses undertaken including only RCTs at low risk of various sources of bias found the findings to be robust to including only those studies at low risk of detection bias in terms of blinded outcome assessment and attrition bias in terms of follow up of fewer than 80% of participants in each arm. When analyses were restricted to studies at low risk of selection bias in terms of inadequate allocation concealment the effect size was no longer statistically significant. Several studies found statistically significant fewer home hazards or a greater number of safety practices in intervention families. Of ten studies reporting scores on the HOME scale, data from three RCTs were included in a meta-analysis which found no evidence of a difference in quality of the home environment between treatment arms (mean difference 0.57, 95% CI -0.59 to 1.72). Most of the studies reporting home safety practices, home hazards or composite home safety scores found statistically significant effects favouring intervention arm families. Overall, using GRADE, the quality of the evidence was rated as moderate. Parenting interventions, most commonly provided within the home using multi-faceted interventions are effective in reducing child injury. There is fairly consistent evidence that they also improve home safety. The evidence relates mainly to interventions provided to families from disadvantaged populations, who are at risk of adverse child health outcomes or whose families may benefit from extra support. Further research is required to explore mechanisms by which these interventions may reduce injury, the features of parenting interventions that are necessary or sufficient to reduce injury and the generalisability to different population groups.


The role of ecological factors in shaping bat cone opsin evolution.
Bats represent one of the largest and most striking nocturnal mammalian radiations, exhibiting many visual system specializations for performance in light-limited environments. Despite representing the greatest ecological diversity and species richness in Chiroptera, Neotropical lineages have been undersampled in molecular studies, limiting the potential for identifying signatures of selection on visual genes associated with differences in bat ecology. Here, we investigated how diverse ecological pressures mediate long-term shifts in selection upon long-wavelength (Lws) and short-wavelength (Sws1) opsins, photosensitive cone pigments that form the basis of colour vision in most mammals, including bats. We used codon-based likelihood clade models to test whether ecological variables associated with reliance on visual information (e.g. echolocation ability and diet) or exposure to varying light environments (e.g. roosting behaviour and foraging habitat) mediated shifts in evolutionary rates in bat cone opsin genes. Using additional cone opsin sequences from newly sequenced eye transcriptomes of six Neotropical bat species, we found significant evidence for different ecological pressures influencing the evolution of the cone opsins. While Lws is evolving under significantly lower constraint in highly specialized high-duty cycle echolocating lineages, which have enhanced sonar ability to detect and track targets, variation in Sws1 constraint was significantly associated with foraging habitat, exhibiting elevated rates of evolution in species that forage among vegetation. This suggests that increased reliance on echolocation as well as the spectral environment experienced by foraging bats may differentially influence the evolution of different cone opsins. Our study demonstrates that different ecological variables may underlie contrasting evolutionary patterns in bat visual opsins, and highlights the suitability of clade models for testing ecological hypotheses of visual evolution.


Comparative effectiveness of early versus conventional timing of dialysis initiation in advanced CKD.
Previous observational studies examining outcomes associated with the timing of dialysis therapy initiation in the United States have often been limited by lead time and survivor bias. Retrospective cohort study comparing the effectiveness of early versus later (conventional) dialysis therapy initiation in advanced chronic kidney disease (CKD). The analysis used inverse probability weighting to account for an individual's contribution to different exposure groups over time in a pooled logistic regression model. Patients contributed risk to both exposure categories (early and later initiation) until there was a clear treatment strategy (ie, dialysis therapy was initiated early or estimated glomerular filtration rate [eGFR] decreased to <10mL/min/1.73m(2)). Patients with CKD who had at least one face-to-face outpatient encounter with a Cleveland Clinic health care provider as of January 1, 2005, and at least 3 eGFRs in the range of 20-30mL/min/1.73m(2) measured at least 180 days apart. Timing of dialysis therapy initiation as determined using model-based interpolation of eGFR trajectories over time. Timing was defined as early (interpolated eGFR at dialysis therapy initiation≥10mL/min/1.73m(2)) or later (eGFR < 10mL/min/1.73m(2)) and was time-varying. Death from any cause occurring from the time that eGFR was equal to 20mL/min/1.73m(2) through September 15, 2009. The study population consisted of 652 patients meeting inclusion criteria. Most (71.3%) of the study population did not initiate dialysis therapy during follow-up. Patients who did not initiate dialysis therapy (n=465) were older, more likely to be white, and had more favorable laboratory profiles than those who started dialysis therapy. Overall, 146 initiated dialysis early and 80 had eGFRs decrease to <10mL/min/1.73m(2). Many participants (n=426) were censored prior to attaining a clear treatment strategy and were considered undeclared. There was no statistically significant survival difference for the early compared with later initiation strategy (OR, 0.85; 95% CI, 0.65-1.11). Interpolated eGFR, moderate sample size, and likely unmeasured confounders. In patients with advanced CKD, timing of dialysis therapy initiation was not associated with mortality when accounting for lead time bias and survivor bias.


19-Nor-deoxycorticosterone production from aldosterone-producing adenomas.
19-Nor-deoxycorticosterone (19-nor-DOC), a hypertensinogenic mineralocorticoid, equipotent with aldosterone and independent of the renin-angiotensin system, is synthesized in the kidney and excreted in excess in the urine of patients with aldosterone-producing adenomas. This current study evaluated the adrenal and renal venous levels of aldosterone and 19-nor-DOC after adrenal and renal venous catheterization and blood sampling in five patients with aldosterone-producing adenomas. Aldosterone (mean +/- SEM) in the adrenal vein ipsilateral to the tumor (469 +/- 293 ng/dl) was higher than in the contralateral vein (70 +/- 59 ng/dl). 19-Nor-DOC (mean +/- SEM) was also higher in the ipsilateral (548 +/- 286 ng/dl) than in the contralateral (51 +/- 14 ng/dl) adrenal vein. In the renal veins, ipsilateral aldosterone (2.2 +/- 0.8 ng/dl) and 19-nor-DOC (12.2 +/- 2.4 ng/dl) were respectively similar to contralateral aldosterone (1.5 +/- 0.5 ng/dl) and 19-nor-DOC (14.6 +/- 1.3 ng/dl), whereas 19-nor-DOC was higher than aldosterone in each renal vein. The present study demonstrates that 19-nor-DOC is produced, not only from the kidneys, but also from the ipsilateral adrenal of patients with aldosterone-producing adenomas. The ipsilateral adrenal 19-nor-DOC production is comparable to that of aldosterone, suggesting that 19-nor-DOC may be contributing to the hypertension and hypokalemia in this disease. In the contralateral adrenal, aldosterone is suppressed to a greater extent than 19-nor-DOC, suggesting that these two steroids are under the influence of two different regulatory mechanisms.