Maternal inheritance of deltamethrin resistance in the salmon louse Lepeophtheirus salmonis (Krøyer) is associated with unique mtDNA haplotypes.
Parasitic infections by the salmon louse, Lepeophtheirus salmonis (Krøyer), cause huge economic damage in salmon farming in the northern hemisphere, with combined treatment costs and production losses in 2014 having been estimated at US$ 350 million for Norway (annual production 1.25 million tonnes). The control of L. salmonis relies significantly on medicinal treatments, supplemented by non-pharmacological approaches. However, efficacy losses have been reported for several delousing agents, including the pyrethroid deltamethrin. The aim of the present study was to analyse the genetic basis of deltamethrin resistance in L. salmonis. Deltamethrin median effective concentrations (EC50) were 0.28 μg L-1 in the drug susceptible L. salmonis strain IoA-00 and 40.1 μg L-1 in the pyrethroid resistant strain IoA-02. IoA-00 and IoA-02 were crossed to produce families spanning one parental and three filial generations (P0, F1-F3). In three families derived from P0 crosses between an IoA-00 sire and an IoA-02 dam, 98.8% of F2 parasites (n = 173) were resistant, i.e. remained unaffected after exposure to 2.0 μg L-1 deltamethrin. F3 parasites from these crosses showed a deltamethrin EC50 of 9.66 μg L-1. In two families of the inverse orientation at P0 (IoA-02 sire x IoA-00 dam), 16.7% of F2 parasites were resistant (n = 84), while the deltamethrin EC50 in F3 animals was 0.26 μg L-1. The results revealed a predominantly maternal inheritance of deltamethrin resistance. The 15,947-nt mitochondrial genome was sequenced and compared among six unrelated L. salmonis strains and parasites sampled from wild salmon in 2010. IoA-02 and three further deltamethrin resistant strains, established from isolates originating from different regions of Scotland, showed almost identical mitochondrial haplotypes. In contrast, the mitochondrial genome was variable among susceptible strains and L. salmonis from wild hosts. Deltamethrin caused toxicity and depletion of whole body ATP levels in IoA-00 but not IoA-02 parasites. The maternal inheritance of deltamethrin resistance and its association with mitochondrial haplotypes suggests that pyrethroid toxicity in L. salmonis may involve molecular targets encoded by mitochondrial genes.


Protein translocation in photoreceptor light adaptation: a common theme in vertebrate and invertebrate vision.
How do our eyes adjust to daily light levels that vary by almost 11 orders of magnitude? Research shows that, in both vertebrates and invertebrates, signaling proteins are translocated in a light-dependent manner between the photoreceptor cellular compartments where visual transduction takes place, and the rest of the photoreceptor cell. Protein translocation is likely to contribute to photoreceptor light adaptation by adjusting the sensitivity and speed of photoresponse to ever-changing conditions of ambient illumination.


Dimensions and volumetric BMD of the proximal femur and their relation to age among older U.S. men.
We measured femoral neck and shaft dimensions and volumetric BMD with QCT. Relations of these measures to age were quantified in a cross-sectional study among 3358 men 65-100 years old. Relations of femoral neck dimensions and vBMD to age differed from those in the shaft, indicating that patterns of bone modeling and remodeling in the neck and shaft are distinct. Little is known about population variation in dimensions and volumetric BMD of the proximal femur or the relation of these measures to age among older men. In a cross-sectional study, dimensions and volumetric BMD (vBMD) in the femoral neck and shaft were obtained from QCT scans among 3358 men 65-100 years of age in the Osteoporotic Fractures in Men cohort. Total bone size and size of the cortical and medullary compartments were measured with volumes in the femoral neck and with areas in the shaft. We quantified distributions of these measures and examined their relations to age with multivariable linear regression. Population variation in femoral neck and shaft dimensions and vBMD was substantial. In the femoral neck, total volume was minimally related to age, whereas cortical volume was 5% smaller and medullary volume was 10% larger (both p < 0.0001) in the oldest (85+ years) compared with the youngest (65-69 years) men. Across these ages, the percent of cortical bone declined from 46% to 42% (p < 0.0001). Integral and trabecular vBMD were 9% and 22% lower, whereas DXA femoral neck BMD was 4% lower, in the older men. Neck cortical vBMD was unrelated to age. In the shaft, cross-sectional area and medullary area were 9% and 22% larger, respectively, in the oldest men (both p < 0.0001), but cortical area was unchanged with age. The percent of cortical bone declined from 69% to 65% across these ages (p < 0.0001). Shaft cortical BMD was 4% lower in the older men (p < 0.0001). There is substantial diversity of femoral morphology and vBMD among older U.S. men. Patterns indicative of modeling and remodeling in the femoral neck were distinct from those in the shaft. Notably, changes in periosteal and endosteal dimensions that underlie cortical thinning appear to differ in the neck and shaft.


Evaluating the influence of implicit models of mental disorder on processes of shared decision making within community-based multi-disciplinary teams.
This paper reports findings from a qualitative study concerning the influence of implicit models of mental disorder on shared decision making within community-based mental health teams. One-hundred participants representing five distinct multi-agency groups: psychiatrists, community psychiatric nurses, approved social workers, patients and informal carers operating within Leicestershire, England were interviewed using a standard case vignette describing a person whose behaviour suggests he may have schizophrenia. The results showed that each of the study's multi-agency groups implicitly supports a complex range of model dimensions regarding the nature of schizophrenia, the appropriateness of specific forms of treatment and care, and their respective rights and obligations towards each other. The influence of these implicit model patterns on processes of shared decision making are discussed through evaluating their contribution to our understanding of the power relationships existing between various practitioner groups (including informal carers), and between practitioners and patients during clinical encounters.


Decoy Engineering: The Next Step in Resistance Breeding.
The recent finding that decoy engineering can expand the recognition specificity of a plant immune receptor opens a wealth of opportunities for resistance breeding. In this Spotlight we discuss which factors should be considered to successfully translate decoy engineering into crop species.


In vivo loss of slow potassium channel activity in individuals with benign familial neonatal epilepsy in remission.
Benign familial neonatal epilepsy is a neuronal channelopathy most commonly caused by mutations in KCNQ2, which encodes the K(v)7.2 subunit of the slow K(+) channel. K(v)7.2 is expressed in both central and peripheral nervous systems. Seizures occur in the neonatal period, often in clusters within the first few days of life, and usually remit by 12 months of age. The mechanism of involvement of K(v)7.2 mutations in the process of seizure generation has not been established in vivo. In peripheral axons, K(v)7.2 contributes to the nodal slow K(+) current. The present study aimed to determine whether axonal excitability studies could detect changes in peripheral nerve function related to dysfunction or loss of slow potassium channel activity. Nerve excitability studies were performed on eight adults with KCNQ2 mutations and a history of benign familial neonatal epilepsy, now in remission. Studies detected distinctive changes in peripheral nerve, indicating a reduction in slow K(+) current. Specifically, accommodation to long-lasting depolarizing currents was reduced in mutation carriers by 24% compared with normal controls, and the threshold undershoot after 100 ms depolarizing currents was reduced by 22%. Additional changes in excitability included a reduction in the relative refractory period, an increase in superexcitability and a tendency towards reduced sub-excitability. Modelling of the nerve excitability changes suggested that peripheral nerve hyperexcitability may have been ameliorated by upregulation of other potassium channels. We conclude that subclinical dysfunction of K(v)7.2 in peripheral axons can be reliably detected non-invasively in adulthood. Related alterations in neuronal excitability may contribute to epilepsy associated with KCNQ2 mutations.


Phylogeny of the serpin superfamily: implications of patterns of amino acid conservation for structure and function.
We present a comprehensive alignment and phylogenetic analysis of the serpins, a superfamily of proteins with known members in higher animals, nematodes, insects, plants, and viruses. We analyze, compare, and classify 219 proteins representative of eight major and eight minor subfamilies, using a novel technique of consensus analysis. Patterns of sequence conservation characterize the family as a whole, with a clear relationship to the mechanism of function. Variations of these patterns within phylogenetically distinct groups can be correlated with the divergence of structure and function. The goals of this work are to provide a carefully curated alignment of serpin sequences, to describe patterns of conservation and divergence, and to derive a phylogenetic tree expressing the relationships among the members of this family. We extend earlier studies by Huber and Carrell as well as by Marshall, after whose publication the serpin family has grown functionally, taxonomically, and structurally. We used gene and protein sequence data, crystal structures, and chromosomal location where available. The results illuminate structure-function relationships in serpins, suggesting roles for conserved residues in the mechanism of conformational change. The phylogeny provides a rational evolutionary framework to classify serpins and enables identification of conserved amino acids. Patterns of conservation also provide an initial point of comparison for genes identified by the various genome projects. New homologs emerging from sequencing projects can either take their place within the current classification or, if necessary, extend it.


S cysteine-rich (SCR) binding domain analysis of the Brassica self-incompatibility S-locus receptor kinase.
Brassica self-incompatibility, a highly discriminating outbreeding mechanism, has become a paradigm for the study of plant cell-cell communications. When self-pollen lands on a stigma, the male ligand S cysteine-rich (SCR), which is present in the pollen coat, is transmitted to the female receptor, S-locus receptor kinase (SRK). SRK is a membrane-spanning serine/threonine receptor kinase present in the stigmatic papillar cell membrane. Haplotype-specific binding of SCR to SRK brings about pollen rejection. The extracellular receptor domain of SRK (eSRK) is responsible for binding SCR. Based on sequence homology, eSRK can be divided into three subdomains: B lectin-like, hypervariable, and PAN. Biochemical analysis of these subdomains showed that the hypervariable subdomain is responsible for most of the SCR binding capacity of eSRK, whereas the B lectin-like and PAN domains have little, if any, affinity for SCR. Fine mapping of the SCR binding region of SRK using a peptide array revealed a region of the hypervariable subdomain that plays a key role in binding the SCR molecule. We show that residues within the hypervariable subdomain define SRK binding and are likely to be involved in defining haplotype specificity.


The NAPRESSIM trial: the use of low-dose, prophylactic naloxone infusion to prevent respiratory depression with intrathecally administered morphine in elective hepatobiliary surgery: a study protocol and statistical analysis plan for a randomised controlled trial.
Intrathecally administered morphine is effective as part of a postoperative analgesia regimen following major hepatopancreaticobiliary surgery. However, the potential for postoperative respiratory depression at the doses required for effective analgesia currently limits its clinical use. The use of a low-dose, prophylactic naloxone infusion following intrathecally administered morphine may significantly reduce postoperative respiratory depression. The NAPRESSIM trial aims to answer this question. 'The use of low-dose, prophylactic naloxone infusion to prevent respiratory depression with intrathecally administered morphine' trial is an investigator-led, single-centre, randomised, double-blind, placebo-controlled, double-arm comparator study. The trial will recruit 96 patients aged > 18 years, undergoing major open hepatopancreaticobiliary resections, who are receiving intrathecally administered morphine as part of a standard anaesthetic regimen. It aims to investigate whether the prophylactic administration of naloxone via intravenous infusion compared to placebo will reduce the proportion of episodes of respiratory depression in this cohort of patients. Trial patients will receive an infusion of naloxone or placebo, commenced within 1 h of postoperative extubation continued until the first postoperative morning. The primary outcome is the rate of respiratory depression in the intervention group as compared to the placebo group. Secondary outcomes include pain scores, rates of nausea and vomiting, pruritus, sedation scores and adverse outcomes. We will also employ a novel, non-invasive, respiratory minute volume monitor (ExSpiron 1Xi, Respiratory Motion, Inc., 411 Waverley Oaks Road, Building 1, Suite 150, Waltham, MA, USA) to assess the monitor's accuracy for detecting respiratory depression. The trial aims to provide a clear management plan to prevent respiratory depression after the intrathecal administration of morphine, and thereby improve patient safety. ClinicalTrials.gov, ID: NCT02885948 . Registered retrospectively on 4 July 2016. Protocol Version 2.0, 3 April 2017. Protocol identification (code or reference number): UCDCRC/15/006 EudraCT registration number: 2015-003504-22. Registered on 5 August 2015.


Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes.
Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR) = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.


The effect of fasting on PET Imaging of Hepatocellular Carcinoma.
The clinical utility of positron emission tomography (PET) imaging for liver cancer applications is not clearly defined either for diagnosis or treatment assessment. Previous clinical studies demonstrated that fluorodeoxyglucose (FDG) did not show uptake in some hepatocellular carcinoma (HCC) while acetate showed uptake. Pre-imaging fasting is required for clinical PET imaging with FDG. No studies were done to confirm the effect of fasting on acetate uptake in HCC for PET imaging. We investigated this situation with a woodchuck model of viral infection-induced HCC. Four tumor-bearing and one control woodchucks were involved in this study. They were first imaged by PET in fed state followed by another imaging session one week later when they were fasted over-night. Some animals also had FDG-PET scan that was acquired later on the same day. After imaging studies, animals were sacrificed, and their liver excised for histology. Standardized Uptake Value (SUV) was calculated using a region of interest (ROI) placed on each tumor with focal uptake. Acetate showed uptake in each HCC lesion when the animals were either fasted or fed with no significant difference in SUV values (p=0.177); some of the tumors were histologically confirmed as well-differentiated HCC while others were confirmed as moderately- or poorly-differentiated HCC; no focal uptake was found in the control animal. For the accompanying FDG scans, the uptake was detected only in animals that were fasted although the uptake pattern was different from that with acetate. This study provided a hint that fasting or not has little impact on PET imaging of HCC with acetate. It also confirmed prior finding regarding tumor heterogeneity that led to different tracer uptake pattern in the same tumor. Human studies are needed to validate the findings from this pre-clinical investigation.


Spatial modeling for air pollution monitoring network design: example of residential woodsmoke.
The purpose of this paper is to demonstrate how to develop an air pollution monitoring network to characterize small-area spatial contrasts in ambient air pollution concentrations. Using residential woodburning emissions as our case study, this paper reports on the first three stages of a four-stage protocol to measure, estimate, and validate ambient residential woodsmoke emissions in Vancouver, British Columbia. The first step is to develop an initial winter nighttime woodsmoke emissions surface using inverse-distance weighting of emissions information from consumer woodburning surveys and property assessment data. Second, fireplace density and a compound topographic index based on hydrological flow regimes are used to enhance the emissions surface. Third, the spatial variation of the surface is used in a location-allocation algorithm to design a network of samplers for the woodsmoke tracer compound levoglucosan and fine particulate matter. Measurements at these network sites are then used in the fourth stage of the protocol (not presented here): a mobile sampling campaign aimed at developing a high-resolution surface of woodsmoke concentrations for exposure assignment in health effects studies. Overall the results show that relatively simple data inputs and spatial analysis can be effective in capturing the spatial variability of ambient air pollution emissions and concentrations.


Absolute requirement of cholesterol binding for Hedgehog gradient formation in Drosophila.
How morphogen gradients are shaped is a major question in developmental biology, but remains poorly understood. Hedgehog (Hh) is a locally secreted ligand that reaches cells at a distance and acts as a morphogen to pattern the Drosophila wing and the vertebrate neural tube. The proper patterning of both structures relies on the precise control over the slope of Hh activity gradient. A number of hypotheses have been proposed to explain Hh movement and hence graded activity of Hh. A crux to all these models is that the covalent binding of cholesterol to Hh N-terminus is essential to achieve the correct slope of the activity gradient. Still, the behavior of cholesterol-free Hh (Hh-N) remains controversial: cholesterol has been shown to either increase or restrict Hh range depending on the experimental setting. Here, in fly embryos and wing imaginal discs, we show that cholesterol-free Hh diffuses at a long-range. This unrestricted diffusion of cholesterol-free Hh leads to an absence of gradient while Hh signaling strength remains uncompromised. These data support a model where cholesterol addition restricts Hh diffusion and can transform a leveled signaling activity into a gradient. In addition, our data indicate that the receptor Patched is not able to sequester cholesterol-free Hh. We propose that a morphogen gradient does not necessarily stem from the active transfer of a poorly diffusing molecule, but can be achieved by the restriction of a highly diffusible ligand.


Higher Incidence of Clostridium difficile Infection Among Individuals With Inflammatory Bowel Disease.
Studies of Clostridium difficile infections (CDIs) among individuals with inflammatory bowel disease (IBD) have used data from single centers or CDI administrative data codes of limited diagnostic accuracy. We determined the incidence, risk factors, and outcomes after CDI in a population-based cohort of patients with IBD and laboratory confirmation diagnoses of CDI. We searched the University of Manitoba IBD Epidemiology Database and Manitoba Health CDI databases to identify individuals with CDI, with or without IBD, from July 1, 2005 through March 31, 2014. Time trends of incidence were assessed using joinpoint regression. Multivariable Cox regression analyses were performed to assess differences in CDI incidence rates and mortality after CDI between individuals with and without IBD. Conditional logistic regression was performed to determine predictors of CDI among individuals with IBD. Individuals with IBD had a 4.8-fold increase in risk of CDI than individuals without IBD; we found no difference between individuals with ulcerative colitis vs Crohn's disease. There was no increase in CDI incidence over the study time period in either group. Among individuals with IBD, exposure to corticosteroids, infliximab or adalimumab, metronidazole, hospitalizations, higher ambulatory care visits, shorter duration of IBD, and higher comorbidities were associated with an increased risk of CDI. Although CDI increased mortality among individuals with and without IBD, there was lower mortality after CDI among individuals with IBD than without IBD (hazard ratio, 0.65; 95% confidence interval, 0.44-0.96). CDI incidence is no longer increasing among individuals with IBD. We identified unique risk factors for CDI in patients with IBD. CDI is associated with a greater increase in mortality among individuals without IBD than with IBD.


Estimated Residential Exposure to Agricultural Chemicals and Premature Mortality by Parkinson's Disease in Washington State.
The aim of this study was to examine the relationship between estimated residential exposure to agricultural chemical application and premature mortality from Parkinson's disease (PD) in Washington State. Washington State mortality records for 2011⁻2015 were geocoded using residential addresses, and classified as having exposure to agricultural land-use within 1000 meters. Generalized linear models were used to explore the association between land-use associated with agricultural chemical application and premature mortality from PD. Individuals exposed to land-use associated with glyphosate had 33% higher odds of premature mortality than those that were not exposed (Odds Ratio (OR) = 1.33, 95% Confidence Intervals (CI) = 1.06⁻1.67). Exposure to cropland associated with all pesticide application (OR = 1.19, 95% CI = 0.98⁻1.44) or Paraquat application (OR = 1.22, 95% CI = 0.99⁻1.51) was not significantly associated with premature mortality from PD, but the effect size was in the hypothesized direction. No significant associations were observed between exposure to Atrazine (OR = 1.21, 95% CI = 0.84⁻1.74) or Diazinon (OR = 1.07, 95% CI = 0.85⁻1.34), and premature mortality from PD. The relationship between pesticide exposure and premature mortality aligns with previous biological, toxicological, and epidemiological findings. Glyphosate, the world's most heavily applied herbicide, and an active ingredient in Roundup® and Paraquat, a toxic herbicide, has shown to be associated with the odds of premature mortality from PD.


Mutations in FGFR3 gene associated with maxillary retrognathism.
Understanding the role of fibroblast growth factor receptor (FGFR) in the regulation of bone development and disease will ultimately lead to better prevention and treatment of related bone deformities and disorders. To evaluate the role of gene FGFR3 in individuals with retrognathic maxilla by polymerase chain reaction (PCR) technique at molecular level and evaluate the significance of the same. Hospital based fundamental research involving individuals having maxillary retrognathism. A total of 62 individuals (30M and32F) who were willing to take part in the study were selected from cephalometric measurements of N I A and the length PNS to ANS. The institution based basic genetic research study involved collection of fresh blood samples, DNA extraction, PCR analysis, and amplification using the specifically designed forward and reverse primers for targeting the commonly occurring mutations in FGFR3 gene. Further the products were sequenced to evaluate the presence of any novel mutations. The targeted single-nucleotide polymorphisms, at position 1138 in exon 10 of the FGFR3 gene were not identified in the analyzed blood samples. The detailed sequencing of full gene revealed the presence of 2 novel mutations, Exon 3: A213G and Exon 3: A223A/G in one individual. The present study indicated 2 novel mutations in gene FGFR3 in individual with maxillary retrognathism. The genetic-environmental interactions might have played a significant role in the expression of retrognathic maxilla.


Analysis of protein-DNA and protein-protein interactions of centromere protein B (CENP-B) and properties of the DNA-CENP-B complex in the cell cycle.
We previously reported that centromere protein B (CENP-B) forms a stable complex (designated complex A) containing two alphoid DNAs in vitro. Domains in the CENP-B polypeptide involved in the formation of complex A were determined in the present study with truncated derivatives expressed in Escherichia coli and in rabbit reticulocyte lysates. It was revealed by gel mobility shift analyses that polypeptides containing the NH2-terminal DNA-binding domain bind a DNA molecule as a monomer, while dimerizing at a novel hydrophobic domain in the COOH-terminal region of 59 amino acid residues. This polypeptide dimerization activity at the COOH-terminal region was also confirmed with the two-hybrid system in Saccharomyces cerevisiae cells. The results thus proved that CENP-B polypeptides form a homodimer at the COOH-terminal hydrophobic domain, each binding a DNA strand at their NH2-terminal domains. The dimerization and DNA-binding domains fall into two of the three completely conserved sequences found in human and mouse CENP-B, and complex A-forming activity was also detected in nuclear extracts of mouse cells. Metaphase-specific phosphorylation of CENP-B was also detected, but this had no effect on its complex A-forming activity. On the basis of the present results, we propose that CENP-B plays an important role in the assembly of specific centromere structures by forming unique DNA-protein complexes at the sites of CENP-B boxes on the centromeric repetitive DNA both in interphase nuclei and on mitotic chromosomes.


Recombination confounds interpretations of Wolbachia evolution.
Wolbachia are vertically transmitted bacteria known from arthropods and nematode worms, which are maintained in host populations because they either physiologically benefit infected individuals or parasitically manipulate their reproduction. The different manipulation phenotypes are scattered across the Wolbachia phylogeny, suggesting that there have been multiple evolutions of similar phenotypes. This conclusion relies on the assumption of an absence of recombination between bacterial strains, so that the gene used to reconstruct the phylogeny reflects the evolutionary history of the genes involved in the trait. We tested for recombination by reconstructing the phylogeny of two Wolbachia genes from seven B-subdivision strains. The two genes produced mutually incompatible topologies, indicating that these lineages are subject to genetic recombination. This means that many evolutionary patterns inferred from Wolbachia phylogenies must be re-evaluated. Furthermore, recombination may be an important feature both in the evolution of the manipulation phenotypes and avoidance of Müller's ratchet. Finally, we discuss the implications of recombination for attempts to genetically engineer Wolbachia for use in the control of crop pests and human pathogens.


Simple heuristic for the viscosity of polydisperse hard spheres.
We build on the work of Mooney [Colloids Sci. 6, 162 (1951)] to obtain an heuristic analytic approximation to the viscosity of a suspension any size distribution of hard spheres in a Newtonian solvent. The result agrees reasonably well with rheological data on monodispserse and bidisperse hard spheres, and also provides an approximation to the random close packing fraction of polydisperse spheres. The implied packing fraction is less accurate than that obtained by Farr and Groot [J. Chem. Phys. 131(24), 244104 (2009)], but has the advantage of being quick and simple to evaluate.


Thermal nociceptive properties of trigeminal afferent neurons in rats.
Although nociceptive afferents innervating the body have been heavily studied form many years, much less attention has been paid to trigeminal afferent biology. In particular, very little is known concerning trigeminal nociceptor responses to heat, and almost nothing in the rat. This study uses a highly controlled and reproducible diode laser stimulator to investigate the activation of trigeminal afferents to noxious skin heating. The results of this experiment demonstrate that trigeminal thermonociceptors are distinct from themonociceptors innervating the limbs. Trigeminal nociceptors have considerably slower action potential conduction velocities and lower temperature thresholds than somatic afferent neurons. On the other hand, nociceptors innervating both tissue areas separate into those that respond to short pulse, high rate skin heating and those that respond to long pulse, low rate skin heating. This paper provides the first description in the literature of the in vivo properties of thermonociceptors in rats. These finding of two separate populations aligns with the separation between C and A-delta thermonociceptors innervating the paw, but have significant differences in terms of temperature threshold and average conduction velocities. An understanding of the temperature response properties of afferent neurons innervating the paw skin have been critical in many mechanistic discoveries, some leading to new pain therapies. A clear understanding of trigeminal nociceptors may be similarly useful in the investigation of trigeminal pain mechanisms and potential therapies.


Walnut Consumption for Two Years and Leukocyte Telomere Attrition in Mediterranean Elders: Results of a Randomized Controlled Trial.
Randomized controlled trials on diet and shortening of leukocyte telomere length (LTL) mostly focus on marine-derived n-3 polyunsaturated fatty acids (PUFA). Walnuts are a sustainable source of n-3 PUFA. We investigated whether inclusion of walnuts (15% of energy) in the diet for 2 years would maintain LTL in cognitively healthy elders (63⁻79 years old) compared to a control group (habitual diet, abstaining from walnuts). This opportunistic sub-study was conducted within the Walnuts and Healthy Aging study, a dual-centre (Barcelona, Spain and Loma Linda University, California) parallel trial. A sub-set of the Barcelona site participants were randomly assigned to the walnut (n = 80) or control group (n = 69). We assessed LTL at baseline and at 2 years and we conducted repeated-measures ANCOVA with 2 factors: time (baseline, 2 years) and group (control, walnut) and their interaction. Adjusted means (95% confidence interval) of LTL (in kb) in controls were 7.360 (7.084,7.636) at baseline and 7.061 (6.835,7.288) after 2 years; corresponding values in the walnut group were 7.064 (6.807,7.320) and 7.074 (6.864,7.284). The time × intervention interaction was nearly significant (p = 0.079), suggestive of a trend of walnut consumption in preserving LTL. This exploratory research finding should be confirmed in trials with adequate statistical power.


Novel, biocompatible, and disease modifying VIP nanomedicine for rheumatoid arthritis.
Despite advances in rheumatoid arthritis (RA) treatment, efficacious and safe disease-modifying therapy still represents an unmet medical need. Here, we describe an innovative strategy to treat RA by targeting low doses of vasoactive intestinal peptide (VIP) self-associated with sterically stabilized micelles (SSMs). This spontaneous interaction of VIP with SSM protects the peptide from degradation or inactivation in biological fluids and prolongs circulation half-life. Treatment with targeted low doses of nanosized SSM-VIP but not free VIP in buffer significantly reduced the incidence and severity of arthritis in an experimental model, completely abrogating joint swelling and destruction of cartilage and bone. In addition, SSM associated VIP, unlike free VIP, had no side-effects on the systemic functions due to selective targeting to inflamed joints. Finally, low doses of VIP in SSM successfully downregulated both inflammatory and autoimmune components of RA. Collectively, our data clearly indicate that VIP-SSM should be developed to be used as a novel nanomedicine for the treatment of RA.


Family Satisfaction in a Medical College Multidisciplinary Intensive Care Unit (ICU)-How Can We Improve?
In recent years, patient and family-centered implications are being recognized as important outcome measures and one of the quality indicators of health care system worldwide. Most of the Intensive Care Unit patients cannot make decisions themselves, accordingly family members are surrogate decision-makers and judges of care quality. This study was conducted as a prospective observational study using Family Satisfaction-Intensive Care Unit questionnaire to ascertain the level of family satisfaction of care and their involvement in the decision making process of their patient's treatment. The study was conducted over 3 months with 100 family members by FS-ICU questionnaire survey method. After 48 hours of ICU admission, the questionnaire was administered to an eligible family member by a resident who was not involved in the treatment of the patient, in a language understood by them (English/Kannada). Each question was scored using 5 point Likert response Scale and the scores were transformed into 0 (least satisfied) to100 (most satisfied) scale. Satisfaction with overall care was 65.31±23.62 (FS-ICU/Care). Satisfaction with decision making process was 73.06±22.154 (FS-ICU/ DM). Individual factors which contributed to lower scores were management of pain and agitation of the patient, waiting room atmosphere and emotional support. This study identified the individual factors which contributed to the high and low satisfaction scores. With this baseline data as reference, there is scope to enhance the aspects of quality care for patients and their family members. JanardhanIyengar SM, Srinivasan R et al. Family Satisfaction in a Medical College Multidisciplinary Intensive Care Unit (ICU)-How Can We Improve? Indian J of Crit Care Med 2019;23(2):83-88.


Plant-wide (BSM2) evaluation of reject water treatment with a SHARON-Anammox process.
In wastewater treatment plants (WWTPs) equipped with sludge digestion and dewatering systems, the reject water originating from these facilities contributes significantly to the nitrogen load of the activated sludge tanks, to which it is typically recycled. In this paper, the impact of reject water streams on the performance of a WWTP is assessed in a simulation study, using the Benchmark Simulation Model no. 2 (BSM2), that includes the processes describing sludge treatment and in this way allows for plant-wide evaluation. Comparison of performance of a WWTP without reject water with a WWTP where reject water is recycled to the primary clarifier, i.e. the BSM2 plant, shows that the ammonium load of the influent to the primary clarifier is 28% higher in the case of reject water recycling. This results in violation of the effluent total nitrogen limit. In order to relieve the main wastewater treatment plant, reject water treatment with a combined SHARON-Anammox process seems a promising option. The simulation results indicate that significant improvements of the effluent quality of the main wastewater treatment plant can be realized. An economic evaluation of the different scenarios is performed using an Operating Cost Index (OCI).


Nitric oxide synthase inhibitor and lipopolysaccharide effects on reactivity of guinea pig airways.
The in vivo and in vitro effects of nitric oxide (NO) synthase inhibitors and lipopolysaccharide (LPS) on reactivity of guinea pig airways were examined. In isolated, perfused tracheas from untreated animals, the NO synthase inhibitors, N omega-nitro-L-arginine methyl ester (L-NAME; 10(-4)M), NG-methyl-L-arginine (L-NMMA; 10(-4) M) and aminoguanidine (10(-4) M) had no effect or inhibited reactivity to extraluminally (EL) or intraluminally (IL) applied methacholine and histamine. L-NMMA (10(-4) M) did not appreciably contract resting or metacholine-contracted preparations (+/- 3 x 10(-4) M L-arginine) and L-arginine only weakly relaxed contracted tracheas (+/- L-NMMA). Sodium nitroprusside and S-nitroso-N-penicillamine elicited relaxant responses and were more potent extraluminally than intraluminally. Methylene blue (10(-5) M) antagonized relaxation to sodium nitroprusside. Incubation with Escherichia coli LPS (10 micrograms/ml; 30 min incubation) alone in the EL and IL baths depressed methacholine and histamine concentration-response curves. In the presence of LPS, L-NAME potentiated responses to intraluminally applied methacholine but did not affect responses to extraluminally added methacholine. Four days after i.p. injection of animals with LPS (4 mg/kg), L-NAME potentiated responses to IL methacholine, and L-arginine acquired greater relaxant activity. LPS injection increased sensitivity to intraluminally added but not extraluminally added isoproterenol. LPS given by i.p. injection or by inhalation did not affect basal specific airway resistance of conscious animals or reactivity to methacholine aerosol during a postexposure period of 6 to 72 h. NO seems to have little role in regulating reactivity of guinea pig airways to bronchoconstrictor agonists, except after in vitro or in vivo exposure to LPS. After LPS injection the in vitro changes suggestive of NO synthase induction are not associated with altered airway reactivity to inhaled methacholine.


Clinical Aspects of Foot Health in Individuals with Alzheimer's Disease.
Alzheimer's disease (AD) shows a marked presence of physiologic changes and the start or aggravation of underlying diseases such as physical frailty in diverse anatomical regions. It is believed to have a particularly harmful effect on the health of the foot. We examined the foot health status in older persons with AD, with a specific focus on the extent to which people with AD may be using inadequate footwear in old age. Seventy-three community-dwelling people with probable, mild to moderate AD aged 65-95 years were recruited from a center of excellence for AD. A single trained physician evaluated health status and foot conditions. Current shoe and foot length and width measurements were taken using a calibrated Brannock device. The results indicate that sixty-five participants (89.04%) suffered from feet problems. Also, only twenty-two subjects (30.14%) used the correct shoes in width and size related with the morphology of their feet. Fifty-one participants (69.86%) were using incorrect shoes in length or width. The present study revealed that peoples with AD had a high presence of foot health problems. Also, the use of inappropriate shoes revealed measurable differences of association between shoe size and the morphology of the foot.


Work and technological innovation in organic agriculture.
Organic agriculture is a sustainable cultivation ecologically, economically and socially. Several researches in organic agriculture have been made from technical perspectives, economic traits or related to ecological aspects. There are practically no investigations into the nature of the technology used in organic agriculture, especially from an ergonomic perspective. From the activity analysis, this study aimed to map the technology used in the production of organic vegetables. Properties producing organic vegetables were selected representing the State of São Paulo. It was applied an instrument (questionnaire and semi-structured interview) with their managers and it was made visual records to identify adaptations, innovations and technological demands that simultaneously minimize the workload and the difficulties in performing the tasks and increase work productivity. For some of the technological innovations a digital scanner was used to generate a virtual solid model to facilitate its redesign and virtual prototyping. The main results show that organic farmers have little technology in product form. The main innovations that enable competitive advantage or allow higher labor productivity occur in the form of processes, organization and marketing.


TERRA: telomeric repeat-containing RNA.
Telomeres, the physical ends of eukaryotic chromosomes, consist of tandem arrays of short DNA repeats and a large set of specialized proteins. A recent analysis has identified telomeric repeat-containing RNA (TERRA), a large non-coding RNA in animals and fungi, which forms an integral component of telomeric heterochromatin. TERRA transcription occurs at most or all chromosome ends and it is regulated by RNA surveillance factors and in response to changes in telomere length. TERRA functions that are emerging suggest important roles in the regulation of telomerase and in orchestrating chromatin remodelling throughout development and cellular differentiation. The accumulation of TERRA at telomeres can also interfere with telomere replication, leading to a sudden loss of telomere tracts. Such a phenotype can be observed upon impairment of the RNA surveillance machinery or in cells from ICF (Immunodeficiency, Centromeric region instability, Facial anomalies) patients, in which TERRA is upregulated because of DNA methylation defects in the subtelomeric region. Thus, TERRA may mediate several crucial functions at the telomeres, a region of the genome that had been considered to be transcriptionally silent.


A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the Spine Oncology Study Group.
Systematic review and modified Delphi technique. To use an evidence-based medicine process using the best available literature and expert opinion consensus to develop a comprehensive classification system to diagnose neoplastic spinal instability. Spinal instability is poorly defined in the literature and presently there is a lack of guidelines available to aid in defining the degree of spinal instability in the setting of neoplastic spinal disease. The concept of spinal instability remains important in the clinical decision-making process for patients with spine tumors. We have integrated the evidence provided by systematic reviews through a modified Delphi technique to generate a consensus of best evidence and expert opinion to develop a classification system to define neoplastic spinal instability. A comprehensive classification system based on patient symptoms and radiographic criteria of the spine was developed to aid in predicting spine stability of neoplastic lesions. The classification system includes global spinal location of the tumor, type and presence of pain, bone lesion quality, spinal alignment, extent of vertebral body collapse, and posterolateral spinal element involvement. Qualitative scores were assigned based on relative importance of particular factors gleaned from the literature and refined by expert consensus. The Spine Instability Neoplastic Score is a comprehensive classification system with content validity that can guide clinicians in identifying when patients with neoplastic disease of the spine may benefit from surgical consultation. It can also aid surgeons in assessing the key components of spinal instability due to neoplasia and may become a prognostic tool for surgical decision-making when put in context with other key elements such as neurologic symptoms, extent of disease, prognosis, patient health factors, oncologic subtype, and radiosensitivity of the tumor.


How does the presence of a conspecific individual change the behavioral game that a predator plays with its prey?
Behavioral games predators play among themselves may have profound effects on behavioral games predators play with their prey. We studied the behavioral game between predators and prey within the framework of social foraging among predators. We tested how conspecific interactions among predators (little egret) change the predator-prey behavioral game and foraging success. To do so, we examined foraging behavior of egrets alone and in pairs (male and female) in a specially designed aviary consisting of three equally spaced pools with identical initial prey (comet goldfish) densities. Each pool was comprised of a risky microhabitat, rich with food, and a safe microhabitat with no food, forcing the fish to trade off food and safety. When faced with two versus one egret, we found that fish significantly reduced activity in the risky habitat. Egrets in pairs suffered reduced foraging success (negative intraspecific density dependence) and responded to fish behavior and to their conspecific by changing their visiting regime at the different pools-having shorter, more frequent visits. The time egret spent on each visit allowed them to match their long-term capture success rate across the environment to their capture success rate in the pool, which satisfies one aspect of optimality. Overall, egrets in pairs allocated more time for foraging and changed their foraging tactics to focus more on fish under cover and fish 'peeping' out from their shelter. These results suggest that both prey and predator show behavioral flexibility and can adjust to changing conditions as needed in this foraging game.


Nurses' perception of time availability in patient communication in Hong Kong.
To explore nurses' perceptions of their patient communication in practice and to identify their ways of communicating. Nurse theorists and clinicians are aware of the importance of nurse-patient communication in providing patient-centred care. However, barriers remain that prevent nurses from implementing quality/effective communication, and time is often viewed as a critical variable. Continuous emphasis on efficiency contravenes patient-centred care, warranting a re-examination of nurses' perception of time in nurse-patient communication. Focus group interviews were adopted. Thirty-nine registered nurses participated. Interviews were tape-recorded, transcribed and translated, and data were analysed using thematic analysis to identify codes, categories and themes/patterns. Three themes were identified regarding nurses' perception of communication with time: (1) Patterns of communication. (2) Routine scheduled communication vs. meeting individuals' needs. (3) Saving time through communication. Patterns of communication, based on participants' criteria such as the purpose, who initiated it, the nature of communication, expectation to perform, therapeutic value and relation with time were explicated. By integrating communication into routines as intended actions, nurses demonstrate that communication and relationship building with patients take no extra time. Good communication and good relationships help nurses save time. Nurses' communication behaviour is closely related to their perception of communication. This study suggests the need for a paradigm shift in thinking about communication as requiring time. Additionally, nurses should recognise the value of short, iterative interaction and chit-chat as quality communication for knowing their patients and providing patient-centred care. Nurses should think beyond time in the discourse of effective nurse-patient communication, as it often relates to manpower. An understanding of how nurses perceive their time availability for nurse-patient communication and their use of time for this aspect contribute to the discourse regarding how to improve patient-centred care.


Reversible morphological changes of assembled supramolecular amphiphiles triggered by pH-modulated host-guest interactions.
Reversible template-directed micellar-size and shape modulation by virtue of host-guest reversible docking of molecular templates at the micellar-solvent interface was achieved in water. By combining a π-electron deficient bipyridinium-based gemini amphiphile which is capable of binding and aligning with a π-electron rich tri(ethylene glycol)-disubstituted 1,5-diaminonaphthalene, a switchable detergent system which operates through the pH-responsive formation of bisammonium dications was realised. The binding of the 1,5-diaminonaphthalene guest to the bipyridinium-based micellar aggregate superstructure can be actuated by the addition of acid and base. Upon the addition of acid, protonation of the guest forming the dication deactivates molecular recognition with the charged head groups of the micellar aggregate by Coulombic repulsion. This process is completely reversible upon the addition of base, whereby the guest reintercalates into the superstructure -again forming donor-acceptor π-π stacks at the micellar-solvent interface amongst contiguous surfactant head groups. Synchrotron small angle X-ray scattering and dynamic laser light scattering confirm that this form of reversible directionally-templated micellisation results in an oblate spheroid-to-lamellar micelle morphological transition with a stabilising net decrease in the free energy of micellisation of 1.4 kcal mol(-1) per hydrophobic tail.


Employment status and use of respiratory protection among metalworkers, solderers and welders.
Reported associations of self-employment with occupational injury and cerebrovascular disease suggest that worker safety and health precautions may vary by occupational status. The authors assessed the extent to which use of respiratory protection and ventilation equipment is associated with self-employed versus employee status among adults in an international study. The European Community Respiratory Health Survey II (ECRHS II) is a follow-up study conducted in a population-based random sample of adult ECRHS I participants. Men and women enrolled in the ECRHS II completed interviewer-administered questionnaires to provide information about their occupational status and job history during the 9-year ECRHS follow-up period. Respondents in selected occupational groups completed supplemental questionnaires about their jobs and use of respiratory protection and ventilation equipment on-the-job. The authors assessed self-reported use of respiratory and ventilation equipment among 72 self-employed and 371 employed adults in metalworking, soldering and welding occupations. Local exhaust ventilation (fixed extraction: OR 0.37, 95% CI 0.17 to 0.80; mobile extraction: OR 0.23, 95% CI 0.09 to 0.60; on-tool extraction: OR 0.39, 95% CI 0.18 to 0.88) was reported less frequently among self-employed respondents than among employed respondents. The magnitude of the negative association between self-employment status and any of the three types of local exhaust ventilation was not attenuated by adjustment for duration of work per day or week or asthma and/or wheezing symptoms. Respiratory protection was not associated with employment status in these data. More limited use of local exhaust ventilation among self-employed workers compared to employees suggests the need to promote occupational safety among self-employed workers.


Description of Phytomonas oxycareni n. sp. from the Salivary Glands of Oxycarenus lavaterae.
Phytomonas spp. (phytomonads) are a diverse and globally distributed group of unicellular eukaryotes that parasitize a wide range of plants and are transmitted by insect hosts. Here we report the discovery and characterisation of a new species of Phytomonas, named Phytomonas oxycareni n. sp., which was obtained from the salivary glands of the invasive species of true bug Oxycarenus lavaterae (Heteroptera). The new Phytomonas species exhibits a long slender promastigote morphology and can be found both within the lumen of the insect host's salivary glands as well as within the cells of the salivary gland itself. Sampling multiple individuals from the same population post-winter hibernation on two consecutive years revealed that infection was persistent over time. Finally, phylogenetic analyses of small subunit ribosomal RNA genes revealed that this species is sister to other species within the genus Phytomonas, providing new insight into the evolutionary history of the clade.


Overexpression of POLQ confers a poor prognosis in early breast cancer patients.
Depletion of POLQ (DNA polymerase theta) has recently been shown to render tumour cells more sensitive to radiotherapy whilst having little or no effect on normal tissues. This finding led us to investigate whether tumours that overexpress POLQ are associated with an adverse outcome. We therefore correlated the clinical outcomes of two retrospective series of patients with early breast cancer with the expression levels of POLQ, as determined by microarray gene expression analysis. We found that a significant number of tumours overexpressed POLQ and that overexpression was correlated with ER negative disease (p=0.047) and high tumour grade (p=0.004), both of which are associated with poor clinical outcomes. POLQ overexpression was associated with poor relapse free survival rates on both univariate (HR 5.80; 95% CI, 2.220 to 15.159; p<0.001) and multivariate analysis (HR 8.086; 95% CI 2.340 to 27.948 p=0.001). Analysis of other published clinical series confirmed that POLQ overexpression is associated with adverse clinical outcomes. The poor prognosis associated with POLQ is independent of other clinical or pathological features. The mechanism that causes this adverse outcome remains to be elucidated but may in part arise from resistance to adjuvant treatment. These findings, combined with the limited normal tissue expression of POLQ, make it a very appealing target for possible clinical exploitation.


SLC26A11 (KBAT) in Purkinje Cells Is Critical for Inhibitory Transmission and Contributes to Locomotor Coordination.
Chloride homeostasis determines the impact of inhibitory synaptic transmission and thereby mediates the excitability of neurons. Even though cerebellar Purkinje cells (PCs) receive a pronounced inhibitory GABAergic input from stellate and basket cells, the role of chloride homeostasis in these neurons is largely unknown. Here we studied at both the cellular and systems physiological level the function of a recently discovered chloride channel, SLC26A11 or kidney brain anion transporter (KBAT), which is prominently expressed in PCs. Using perforated patch clamp recordings of PCs, we found that a lack of KBAT channel in PC-specific KBAT KO mice (L7-KBAT KOs) induces a negative shift in the reversal potential of chloride as reflected in the GABAA-receptor-evoked currents, indicating a decrease in intracellular chloride concentration. Surprisingly, both in vitro and in vivo PCs in L7-KBAT KOs showed a significantly increased action potential firing frequency of simple spikes, which correlated with impaired motor performance on the Erasmus Ladder. Our findings support an important role for SLC26A11 in moderating chloride homeostasis and neuronal activity in the cerebellum.


Focus on Quality: Investigating Residents' Learning Climate Perceptions.
A department's learning climate is known to contribute to the quality of postgraduate medical education and, as such, to the quality of patient care provided by residents. However, it is unclear how the learning climate is perceived over time. This study investigated whether the learning climate perceptions of residents changed over time. The context for this study was residency training in the Netherlands. Between January 2012 and December 2014, residents from 223 training programs in 39 hospitals filled out the web-based Dutch Residency Educational Climate Test (D-RECT) to evaluate their clinical department's learning climate. Residents had to fill out 35 validated questions using a five point Likert-scale. We analyzed data using generalized linear mixed (growth) models. Overall, 3982 D-RECT evaluations were available to investigate our aim. The overall mean D-RECT score was 3.9 (SD = 0.3). The growth model showed an increase in D-RECT scores over time (b = 0.03; 95% CI: 0.01-0.06; p < 0.05). The observed increase in D-RECT scores implied that residents perceived an improvement in the learning climate over time. Future research could focus on factors that facilitate or hinder learning climate improvement, and investigate the roles that hospital governing committees play in safeguarding and improving the learning climate.


Degradation of nuclear matrix and DNA cleavage in apoptotic thymocytes.
In dexamethasone-treated thymocyte cultures an increase in nuclear proteolytic activity paralleled chromatin fragmentation and the appearance of small apoptotic cells. The elevation of nuclear proteolytic activity was accompanied by site-specific degradation of nuclear mitotic apparatus protein and lamin B, two essential components of the nuclear matrix. Nuclear mitotic apparatus protein phosphorylation and cleavage into 200 and 48 kDa fragments occurred within 30 minutes of dexamethasone treatment. Cleavage of lamin B, which generated a fragment of 46 kDa consistent with the central rod domain of the protein, was also detected after 30 minutes of exposure to the steroid hormone. The level of lamin B phosphorylation did not change as a result of the dexamethasone treatment and the lamina did not solubilize until the later stages of apoptosis. Initial DNA breaks, detected by the terminal transferase-mediated dUTP-biotin nick end labeling assay, occurred throughout the nuclei and solubilization of lamina was not required for this process to commence. The data presented in this paper support a model of apoptotic nuclear destruction brought about by the site-specific proteolysis of key structural proteins. Both the nuclear mitotic apparatus protein and lamin B were specifically targeted by protease(s) at early stages of the cell death pathway, which possibly initiate the cascade of degradative events in apoptosis.


The role of spurious feature familiarity in recognition memory.
In two experiments, we investigated the role of perceptual information in spurious recognition judgments. Participants viewed lists of words in various unusual fonts. The frequency with which each font was presented was manipulated at study: Each font was presented with 1 or 12 different words in Experiment 1 and with 1 or 20 words in Experiment 2. Although the participants were instructed in a word recognition test to judge only on the basis of the word, regardless of font, there were significantly more false alarms for new words seen in a previously presented font than for new words presented in a novel (not seen at study) font in Experiment 1. In Experiment 2, the participants were significantly more likely to make a false alarm to a new word seen in a font that had been used to present 20 words during study than to a font that had been used to present only 1 word during study. The data show a mirror effect, in which words tested in low-frequency fonts produced more hits and fewer false alarms than did words tested in high-frequency fonts. These results show that irrelevant perceptual information plays a role in recognition judgments by providing spurious sources of familiarity and, thus, provide evidence that perceptual information is represented and processed in the same way as semantic information.


Vestibular impact of Friedreich ataxia in early onset patients.
Friedreich ataxia (FRDA) is the most frequent form of inherited ataxias. Vestibular and auditory assessments are not commonly part of the check up for these patients despite hearing and balance complaints. Screening of vestibular and auditory function was performed in a large group of young patients with genetically confirmed FRDA. Our study included 43 patients (7-24 years of age). A complete vestibular assessment was performed including the canals function evaluation at 3 head velocities (bithermal caloric test, earth vertical axis rotation (EVAR) and head impulse test (HIT)) and otolith function evaluation (cervical vestibular evoked myogenic potentials). Information regarding the hearing evaluation of the patients were also retrieved including impedance tympanometry, distortion product otoacoustic emissions (DPOAEs), air and bone conduction audiometry and auditory brainstem response (ABR). Vestibular responses were impaired for canal responses (only at high and middle head velocities) and vestibulospinal otolithic responses. Abnormal neural conduction in the central auditory pathways was frequently observed. Oculomotor abnormalities were frequent, mostly hypermetric saccades and gaze instability. Inhibition of the vestibulo-ocular reflex by fixation was normal. We show that Friedreich ataxia, even at onset, frequently associate saccadic intrusions, abnormal ABRs and decreased vestibulo-ocular and vestibulospinal responses progressing over time. These sensory impairments combined with ataxia further impair patient's autonomy. These vestibular, auditory and visual impairments could be used as markers of the severity and progression of the disease. Adding vestibular and auditory testing to Friedreich patient's evaluation may help physicians improve patient's management.


Large-Area Epitaxial Monolayer MoS2.
Two-dimensional semiconductors such as MoS2 are an emerging material family with wide-ranging potential applications in electronics, optoelectronics, and energy harvesting. Large-area growth methods are needed to open the way to applications. Control over lattice orientation during growth remains a challenge. This is needed to minimize or even avoid the formation of grain boundaries, detrimental to electrical, optical, and mechanical properties of MoS2 and other 2D semiconductors. Here, we report on the growth of high-quality monolayer MoS2 with control over lattice orientation. We show that the monolayer film is composed of coalescing single islands with limited numbers of lattice orientation due to an epitaxial growth mechanism. Optical absorbance spectra acquired over large areas show significant absorbance in the high-energy part of the spectrum, indicating that MoS2 could also be interesting for harvesting this region of the solar spectrum and fabrication of UV-sensitive photodetectors. Even though the interaction between the growth substrate and MoS2 is strong enough to induce lattice alignment via van der Waals interaction, we can easily transfer the grown material and fabricate devices. Local potential mapping along channels in field-effect transistors shows that the single-crystal MoS2 grains in our film are well connected, with interfaces that do not degrade the electrical conductivity. This is also confirmed by the relatively large and length-independent mobility in devices with a channel length reaching 80 μm.


Diabetes Device Use in Adults With Type 1 Diabetes: Barriers to Uptake and Potential Intervention Targets.
Diabetes devices (insulin pumps, continuous glucose monitors [CGMs]) are associated with benefits for glycemic control, yet uptake of these devices continues to be low. Some barriers to device uptake may be modifiable through psychosocial intervention, but little is known about which barriers and which patients to target. We surveyed 1,503 adult T1D Exchange participants (mean age 35.3 [SD 14.8] years, mean diagnosis duration 20.4 [SD 12.5] years) to investigate barriers to device uptake, understand profiles of device users versus nonusers, and explore differences by age and sex. Scales used were the Diabetes Distress Scale, Technology Use Attitudes (General and Diabetes-Specific), and Barriers to Device Use and Reasons for Discontinuing Devices. Most commonly endorsed modifiable barriers were related to the hassle of wearing devices (47%) and disliking devices on one's body (35%). CGM users (37%) were older than nonusers (mean 38.3 vs. 33.5 years), had diabetes for longer (22.9 vs. 18.8 years), had more positive technology attitudes (22.6-26.0 vs. 21.4-24.8), and reported fewer barriers to using diabetes technology than nonusers (3.3 vs. 4.3). The youngest age-group (18-25 years) had the lowest CGM (26% vs. 40-48%) and insulin pump (64% vs. 69-77%) uptake, highest diabetes distress (2.2 vs. 1.8-2.1), and highest HbA1c levels (8.3% [67 mmol/mol] vs. 7.2-7.4% [55-57 mmol/mol]). Efforts to increase device use need to target physical barriers to wearing devices. Because young adults had the lowest device uptake rates, highest distress, and highest HbA1c compared with older age-groups, they should be the focus of future interventions to increase device use.


American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) Mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy.
An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO) offers timely clinical direction to ASCO's membership following publication or presentation of potentially practice-changing data from major studies. This PCO addresses the clinical utility of using epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small-cell lung cancer (NSCLC) to predict the benefit of taking a first-line EGFR tyrosine kinase inhibitor (TKI). Patients with EGFR-mutated NSCLC have a significantly higher rate of partial responses to the EGFR TKIs gefitinib and erlotinib. In the United States, approximately 15% of patients with adenocarcinoma of the lung harbor activating EGFR mutations. EGFR mutation testing is widespread at academic medical centers and in some locales in community practice. As of yet, there is no evidence of an overall survival (OS) benefit from selecting treatment based on performing this testing. One large phase III trial (the Iressa Pan-Asia Study [IPASS] trial), three smaller phase III randomized controlled trials using progression-free survival as the primary end point, and one small phase III trial with OS as the primary end point, all involving first-line EGFR TKIs and chemotherapy doublets, form the basis of this PCO. On the basis of the results of five phase III randomized controlled trials, patients with NSCLC who are being considered for first-line therapy with an EGFR TKI (patients who have not previously received chemotherapy or an EGFR TKI) should have their tumor tested for EGFR mutations to determine whether an EGFR TKI or chemotherapy is the appropriate first-line therapy. NOTE. ASCO's provisional clinical opinions (PCOs) reflect expert consensus based on clinical evidence and literature available at the time they are written and are intended to assist physicians in clinical decision making and identify questions and settings for further research. Because of the rapid flow of scientific information in oncology, new evidence may have emerged since the time a PCO was submitted for publication. PCOs are not continually updated and may not reflect the most recent evidence. PCOs cannot account for individual variation among patients and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine the best course of treatment for the patient. Accordingly, adherence to any PCO is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances. ASCO PCOs describe the use of procedures and therapies in clinical practice and cannot be assumed to apply to the use of these interventions in the context of clinical trials. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCO's PCOs, or for any errors or omissions.


Astronaut Cardiovascular Health and Risk Modification (Astro-CHARM) Coronary Calcium Atherosclerotic Cardiovascular Disease Risk Calculator.
Coronary artery calcium (CAC) is a powerful novel risk indicator for atherosclerotic cardiovascular disease (ASCVD). Currently, there is no available ASCVD risk prediction tool that integrates traditional risk factors and CAC. To develop a CAC ASCVD risk tool for younger individuals in the general population, subjects aged 40 to 65 without prior cardiovascular disease from 3 population-based cohorts were included. Cox proportional hazards models were developed incorporating age, sex, systolic blood pressure, total and high-density lipoprotein cholesterol, smoking, diabetes mellitus, hypertension treatment, family history of myocardial infarction, high-sensitivity C-reactive protein, and CAC scores (Astro-CHARM model [Astronaut Cardiovascular Health and Risk Modification]) as dependent variables and ASCVD (nonfatal/fatal myocardial infarction or stroke) as the outcome. Model performance was assessed internally, and validated externally in a fourth cohort. The derivation study comprised 7382 individuals with a mean age 51 years, 45% women, and 55% nonwhite. The median CAC was 0 (25th, 75th [0,9]), and 304 ASCVD events occurred in a median 10.9 years of follow-up. The c-statistic was 0.784 for the risk factor model, and 0.817 for Astro-CHARM ( P<0.0001). In comparison with the risk factor model, the Astro-CHARM model resulted in integrated discrimination improvement (0.0252), and net reclassification improvement (0.121; P<0.0001), as well. The Astro-CHARM model demonstrated good discrimination (c=0.78) and calibration (Nam-D'Agostino χ2, 13.2; P=0.16) in the validation cohort (n=2057; 55 events). A mobile application and web-based tool were developed to facilitate clinical application of this tool ( www.AstroCHARM.org ). The Astro-CHARM tool is the first integrated ASCVD risk calculator to incorporate risk factors, including high-sensitivity C-reactive protein and family history, and CAC data. It improves risk prediction in comparison with traditional risk factor equations and could be useful in risk-based decision making for cardiovascular disease prevention in the middle-aged general population.


First report of an intravenous and oral glycoprotein IIb/IIIa inhibitor (RPR 109891) in patients with recent acute coronary syndromes: results of the TIMI 15A and 15B trials.
RPR 109891 is a modified tetrapeptide glycoprotein IIb/IIIa inhibitor available in intravenous and oral formulations. Two phase II dose-ranging studies were performed to investigate pharmacodynamics and safety in acute coronary syndromes. The Thrombolysis In Myocardial Infarction (TIMI) 15A trial was a randomized, open-label, study of RPR 109891 administered intravenously for 24 to 96 hours in 91 patients. TIMI 15B was a randomized, double-blind comparison of intravenous RPR 109891 plus 4 weeks of oral RPR 109891 (n = 142) compared with placebo (n = 50). Intravenous RPR 109891 exhibited a dose-response inhibition of platelet aggregation; mean inhibition after a bolus ranged from 53% to 92%, and at steady state 49% to 98%. Oral RPR 109891 demonstrated less platelet inhibition (peaks, range 48% to 59%; troughs, range 18% to 39%). Mean glycoprotein IIb/IIIa receptor occupancy and platelet inhibition were highly correlated (r = 0.82, 95% confidence interval 0.74-0.88). There were trends for increased major hemorrhage (10% vs 6%, P =.57), thrombocytopenia <90,000 cells/mm(3) (13% vs 4%, P =.11), and profound thrombocytopenia <20, 000 (3.5% vs 0%, P =.33) with intravenous plus oral RPR 109891 compared with placebo. In 3 of 5 cases of profound thrombocytopenia, RPR 109891 had been interrupted because of bypass surgery, and a precipitous fall in platelet count occurred after the first postoperative oral dose. Intravenous RPR 109891 is a potent, predictable, dose-related platelet inhibitor. Oral RPR 109891 (</=600 mg/d) achieves moderate platelet inhibition. Interrupted glycoprotein IIb/IIIa blockade may be associated with a higher risk of profound thrombocytopenia and deserves closer examination in future studies.


Chronic eccentric arm cycling improves maximum upper-body strength and power.
Eccentric leg cycling (cycle ergometry adapted to impose muscle lengthening contractions) offers an effective exercise for restoring lower-body muscular function, maintaining health, and improving performance in clinical and athletic populations. We extended this model to the upper body and evaluated the effectiveness of a 7-week eccentric arm cycling (ECCarm) intervention to improve upper-body muscular function. We also explored whether ECCarm would alter arterial function. Participants performed ECCarm (n = 9) or concentric arm cycling (CONarm; n = 8) 3×/week while training intensity increased (5-20 min, 60-70% upper-body peak heart rate). Maximum elbow extensor strength, upper-body concentric power, and peripheral and central arterial stiffness were assessed before and after training. During training, heart rates and perceived exertion did not differ between groups (~68% upper-body peak heart rate, ~12 Borg units, both P > 0.05), whereas power during ECCarm was ~2× that for CONarm (122 ± 43 vs. 59 ± 20 W, P < 0.01). Muscle soreness for ECCarm was greater than CONarm (P = 0.02), however, soreness was minimal for both groups (<0.50 cm). Following training, ECCarm exhibited greater changes in elbow extensor strength (16 ± 10 vs. 1 ± 9%, P = 0.01) and upper-body power (6 ± 8 vs. -3 ± 7%, P < 0.01) compared to CONarm. Peripheral and central arterial stiffness did not change for either group (both P > 0.05). Upper-body eccentric exercise improved dynamic muscular function while training at low exertion levels. Results occurred with minimal soreness and without compromising arterial function. ECCarm findings parallel eccentric leg cycling findings and indicate that eccentric cycle ergometry offers a robust model for enhancing upper-body muscular function. ECCarm could have applications in rehabilitation and sport training.


Lovastatin as treatment for neurocognitive deficits in neurofibromatosis type 1: phase I study.
In a neurofibromatosis type 1 murine model, treatment with lovastatin reversed cognitive disabilities. We report on a phase I study examining the safety and tolerability of lovastatin in children with neurofibromatosis type 1. Twenty-four children with neurofibromatosis type 1 underwent a dose-escalation protocol for 3 months to identify the maximum tolerated dose and potential toxicity. Minimal side effects were evident, and no child experienced dose-limiting toxicity. Cognitive evaluations were completed before and after treatment, and the results suggested improvement in areas of verbal and nonverbal memory. Additional analyses, using reliable change indices, indicated improvements exceeding those of test-retest or practice effects in some participants. These observations may be analogous to the improvements observed in a neurofibromatosis type 1 murine model treated with lovastatin, although further study and replication are required. The safety and preliminary cognitive results support the need for a larger phase II trial in this population.


Longitudinal changes in resting-state fMRI from age 5 to age 6years covary with language development.
Resting-state functional magnetic resonance imaging is a powerful technique to study the whole-brain neural connectivity that underlies cognitive systems. The present study aimed to define the changes in neural connectivity in their relation to language development. Longitudinal resting-state functional data were acquired from a cohort of preschool children at age 5 and one year later, and changes in functional connectivity were correlated with language performance in sentence comprehension. For this, degree centrality, a voxel-based network measure, was used to assess age-related differences in connectivity at the whole-brain level. Increases in connectivity with age were found selectively in a cluster within the left posterior superior temporal gyrus and sulcus (STG/STS). In order to further specify the connection changes, a secondary seed-based functional connectivity analysis on this very cluster was performed. The correlations between resting-state functional connectivity (RSFC) and language performance revealed developmental effects with age and, importantly, also dependent on the advancement in sentence comprehension ability over time. In children with greater advancement in language abilities, the behavioral improvement was positively correlated with RSFC increase between left posterior STG/STS and other regions of the language network, i.e., left and right inferior frontal cortex. The age-related changes observed in this study provide evidence for alterations in the language network as language develops and demonstrates the viability of this approach for the investigation of normal and aberrant language development.


NAT2 variation and idiopathic talipes equinovarus (clubfoot).
Idiopathic talipes equinovarus (ITEV), or isolated clubfoot, is a common developmental anomaly that is characterized by a rigid foot, adducted forefoot, cavus midfoot, equinovarus of the hindfoot, and hypoplastic calf musculature. The etiology of this common birth defect is largely unknown, but genetic factors have been implicated in population and family studies and maternal smoking during pregnancy has been identified as an environmental risk factor. The biotransformation of exogenous substances, such as tobacco smoke, is modulated by numerous genes including N-acetylation genes, NAT1 and NAT2. Functional variants of these genes exist and can be distinguished by genotyping. We hypothesized that variation in NAT1 and NAT2 genes might be associated with ITEV. To test this hypothesis, NAT1 and NAT2 were genotyped in a sample of 56 multiplex ITEV families, 57 trios with a positive family history and 160 simplex trios with ITEV. The results detected a slight decrease in the expected number of homozygotes for the NAT2 normal allele in the Hispanic simplex trios. In addition, in a pilot case-control study of ITEV, there were significantly more slow NAT2 acetylators among the cases. This suggests that slow acetylation may be a risk factor for ITEV. This study is the first to find evidence suggesting a role for a biotransformation candidate gene in the etiology of ITEV and provides a scientific foundation to further explore the contributions of other tobacco metabolism genes in the etiology of clubfoot.


Systems analysis of cerebrovascular pressure transmission: an observational study in head-injured patients.
In an observational study in head-injured patients, cerebrovascular pressure transmission was investigated using a systems analysis approach whereby the blood pressure (BP) waveform was used as a measure of an input stimulus to the cerebrovascular bed (CVB) and the intracranial pressure (ICP) waveform as the response to that stimulus. The transfer function is a measure of how much pressure is transmitted through the CVB at a given frequency and is calculated using Fourier analysis of the pressure waveforms. The transfer function allows quantification of the pressure transmission performance of the CVB, thus providing a basis for comparison between normal and abnormal function. Fifteen hundred samples of ICP and BP waveforms were collected from 30 head-injured patients via microcomputer. Off-line spectral analysis of the waveform database revealed four main classes of transfer function: those with an overall flat transfer function (curve type 1); those with an elevated low-frequency response (curve type 2); those with an elevated high-frequency response (curve type 3); and those exhibiting both an elevated low- and high-frequency response (curve type 4). Curve types 2 and 4 were most often associated with raised ICP (greater than 20 mm Hg), whereas curve types 1 and 3 were most often affiliated with ICP less than 15 mm Hg. Studies of this type may provide insight into the pathophysiology of the CVB and ultimately aid in the prediction and treatment of raised ICP.


Combined rhinoplasty and genioplasty: long-term follow-up.
Long-term follow-up reference for experienced clinicians dedicated to profileplasty. To evaluate the long-term results and complications of combined rhinoplasty and genioplasty. Retrospective study including objective and subjective evaluation before and after 3 years of undergoing simultaneous open rhinoplasty and genioplasty among a cohort of 90 patients. SETTING Academic medical center. A total of 90 cases of combined rhinoplasty and genioplasty performed from January 2002 through January 2004 were reviewed to evaluate the stability of the esthetic result. Long-term stability of the esthetic outcome of the simultaneous open rhinoplasty and genioplasty. Soft-tissue Pogonion projection to the true vertical line and mandibular height (mandibular incisor tip to menton) were recorded. As far as reduction genioplasty patients are concerned, 45.6% of the patient population had a 100% stability after 3 years (<0.25 mm resorption measured at the menton). On the other hand, if augmentation genioplasty patients are considered, 52.4% (22 patients with a vertical augmentation range from 4-6 mm; mean, 5.3 mm; and 25 patients with a sagittal augmentation from 6-8 mm; mean, 7.2 mm) had 100% stability after 3 years. The chin was stable with no more than 1 mm of recurrence. The results of the study indicate that the combined approach in correcting the facial profile is an effective procedure to achieve a more harmonic and consistent clinical outcome. The recurrence rate of less than 1 mm on the chin bone measurements is relevant to support this statement. An aesthetically proportionate face is strongly determined by the nasal-cervical relationship when observing the patient's profile. Even after a successful rhinoplasty, the patient's face can lack aesthetic attractiveness. Combined rhinoplasty-genioplasty is usually the best solution, particularly for patients with microgenia. It provides optimum patient satisfaction with a low incidence of recurrence. 4.


Neonatal microstructural development of the internal capsule on diffusion tensor imaging correlates with severity of gait and motor deficits.
Neonatal microstructural development in the posterior limbs of the internal capsule (PLIC) was assessed using diffusion tensor imaging (DTI) fractional anisotropy (FA) in 24 very-low-birthweight preterm infants at 37 weeks' gestational age and compared with the children's gait and motor deficits at 4 years of age. There were 14 participants with normal neonatal FA values (seven females, seven males; born at 27.6 weeks [SD 2.3] gestational age; birthweight 1027g [SD 229]) and 10 participants with low FA values in the PLIC (four females, six males; born at 28.4 weeks [SD 2.0] gestational age; birthweight 1041g [SD 322]). Seven of the 10 children with low FA and none of the children with normal FA had been diagnosed with CP by the time of gait testing. Among children with low neonatal FA, there was a strong negative correlation between FA of the combined left and right side PLIC and log NI (r=-0.89, p=0.001) and between FA and GMFCS (r=-0.65, p=0.04) at 4 years of age. There was no correlation between FA and gait NI or GMFCS at 4 years of age among children with normal neonatal FA. This preliminary study suggests neonatal DTI may be an important predictor of the severity of future gait and motor deficits.


Solution NMR characterization of chemokine CXCL8/IL-8 monomer and dimer binding to glycosaminoglycans: structural plasticity mediates differential binding interactions.
Chemokine CXCL8/interleukin-8 (IL-8) plays a crucial role in directing neutrophils and oligodendrocytes to combat infection/injury and tumour cells in metastasis development. CXCL8 exists as monomers and dimers and interaction of both forms with glycosaminoglycans (GAGs) mediate these diverse cellular processes. However, very little is known regarding the structural basis underlying CXCL8-GAG interactions. There are conflicting reports on the affinities, geometry and whether the monomer or dimer is the high-affinity GAG ligand. To resolve these issues, we characterized the binding of a series of heparin-derived oligosaccharides [heparin disaccharide (dp2), heparin tetrasaccharide (dp4), heparin octasaccharide (dp8) and heparin 14-mer (dp14)] to the wild-type (WT) dimer and a designed monomer using solution NMR spectroscopy. The pattern and extent of binding-induced chemical shift perturbation (CSP) varied between dimer and monomer and between longer and shorter oligosaccharides. NMR-based structural models show that different interaction modes coexist and that the nature of interactions varied between monomer and dimer and oligosaccharide length. MD simulations indicate that the binding interface is structurally plastic and provided residue-specific details of the dynamic nature of the binding interface. Binding studies carried out under conditions at which WT CXCL8 exists as monomers and dimers provide unambiguous evidence that the dimer is the high-affinity GAG ligand. Together, our data indicate that a set of core residues function as the major recognition/binding site, a set of peripheral residues define the various binding geometries and that the structural plasticity of the binding interface allows multiplicity of binding interactions. We conclude that structural plasticity most probably regulates in vivo CXCL8 monomer/dimer-GAG interactions and function.


Double bag or Y-set versus standard transfer systems for continuous ambulatory peritoneal dialysis in end-stage kidney disease.
Peritonitis is the most frequent serious complication of continuous ambulatory peritoneal dialysis (CAPD). It has a major influence on the number of patients switching from CAPD to haemodialysis and has probably restricted the wider acceptance and uptake of CAPD as an alternative mode of dialysis.This is an update of a review first published in 2000. This systematic review sought to determine if modifications of the transfer set (Y-set or double bag systems) used in CAPD exchanges are associated with a reduction in peritonitis and an improvement in other relevant outcomes. We searched the Cochrane Renal Group's Specialised Register through contact with the Trials Search Co-ordinator. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE and EMBASE. Date of last search: 22 October 2013. Randomised controlled trials (RCTs) or quasi-RCTs comparing double bag, Y-set and standard peritoneal dialysis (PD) exchange systems in patients with end-stage kidney disease. Data were abstracted by a single investigator onto a standard form and analysed by Review Manager. Analysis was by a random effects model and results were expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). Twelve eligible trials with a total of 991 randomised patients were identified. Despite the large total number of patients, few trials covered the same interventions, small numbers of patients were enrolled in each trial and the methodological quality was suboptimal. Y-set and twin-bag systems were superior to conventional spike systems (7 trials, 485 patients, RR 0.64, 95% CI 0.53 to 0.77) in preventing peritonitis in PD. Disconnect systems should be the preferred exchange systems in CAPD.


Quality measures for the care of adult patients with obstructive sleep apnea.
Obstructive sleep apnea (OSA) is a prevalent disorder associated with a multitude of adverse outcomes when left untreated. There is significant heterogeneity in the evaluation and management of OSA resulting in variation in cost and outcomes. Thus, the goal for developing these measures was to have a way to evaluate the outcomes and reliability of the processes involved with the standard care approaches used in the diagnosis and management of OSA. The OSA quality care measures presented here focus on both outcomes and processes. The AASM commissioned the Adult OSA Quality Measures Workgroup to develop quality care measures aimed at optimizing care for adult patients with OSA. These quality care measures developed by the Adult OSA Quality Measures Workgroup are an extension of the original Centers for Medicare & Medicaid Services (CMS) approved Physician Quality Reporting System (PQRS) measures group for OSA. The measures are based on the available scientific evidence, focus on public safety, and strive to improve quality of life and cardiovascular outcomes for individual OSA patients. The three outcomes that were selected were as follows: (1) improve disease detection and categorization; (2) improve quality of life; and (3) reduce cardiovascular risk. After selecting these relevant outcomes, a total of ten process measures were chosen that could be applied and assessed for the purpose of accomplishing these outcomes. In the future, the measures described in this document may be reported through the PQRS in addition to, or as a replacement for, the current OSA measures group. The overall objective for the development of these measures is that implementation of these quality measures will result in improved patient outcomes, reduce the public health burden of OSA, and provide a measurable standard for evaluating and managing OSA.


Evaluating a novel approach to stimulate open science collaborations: a case series of "study-a-thon" events within the OHDSI and European IMI communities.
We introduce and review the concept of a study-a-thon as a catalyst for open science in medicine, utilizing harmonized real world, observation health data, tools, skills, and methods to conduct network studies, generating insights for those wishing to use study-a-thons for future research. A series of historical study-a-thons since 2017 to present were reviewed for thematic insights as to the opportunity to accelerate the research method to conduct studies across therapeutic areas. Review of publications and experience of the authors generated insights to illustrate the conduct of study-a-thons, key learning, and direction for those wishing to conduct future such study-a-thons. A review of six study-a-thons have provided insights into their scientific impact, and 13 areas of insights for those wishing to conduct future study-a-thons. Defining aspects of the study-a-thon method for rapid, collaborative research through network studies reinforce the need to clear scientific rationale, tools, skills, and methods being collaboratively to conduct a focused study. Well-characterized preparatory, execution and postevent phases, coalescing skills, experience, data, clinical input (ensuring representative clinical context to the research query), and well-defined, logical steps in conducting research via the study-a-thon method are critical. A study-a-thon is a focused multiday research event generating reliable evidence on a specific medical topic across different countries and health systems. In a study-a-thon, a multidisciplinary team collaborate to create an accelerated contribution to scientific evidence and clinical practice. It critically accelerates the research process, without inhibiting the quality of the research output and evidence generation, through a reproducible process.


Short message service reminder intervention doubles sexually transmitted infection/HIV re-testing rates among men who have sex with men.
To evaluate the impact of a short message service (SMS) reminder system on HIV/sexually transmitted infection (STI) re-testing rates among men who have sex with men (MSM). The SMS reminder programme started in late 2008 at a large Australian sexual health clinic. SMS reminders were recommended 3-6 monthly for MSM considered high-risk based on self-reported sexual behaviour. The evaluation compared HIV negative MSM who had a HIV/STI test between 1 January and 31 August 2010 and received a SMS reminder (SMS group) with those tested in the same time period (comparison group) and pre-SMS period (pre-SMS group, 1 January 2008 and 31 August 2008) who did not receive the SMS. HIV/STI re-testing rates were measured within 9 months for each group. Baseline characteristics were compared between study groups and multivariate logistic regression used to assess the association between SMS and re-testing and control for any imbalances in the study groups. There were 714 HIV negative MSM in the SMS group, 1084 in the comparison group and 1753 in the pre-SMS group. In the SMS group, 64% were re-tested within 9 months compared to 30% in the comparison group (p<0.001) and 31% in the pre-SMS group (p<0.001). After adjusting for baseline differences, re-testing was 4.4 times more likely (95% CI 3.5 to 5.5) in the SMS group than the comparison group and 3.1 times more likely (95% CI 2.5 to 3.8) than the pre-SMS group. SMS reminders increased HIV/STI re-testing among HIV negative MSM. SMS offers a cheap, efficient system to increase HIV/STI re-testing in a busy clinical setting.


Mechanisms of endothelial to mesenchymal transition in the retina in diabetes.
Hyperglycemia-induced endothelial damage is a key pathogenetic factor in diabetic retinopathy. Endothelial damage may lead to phenotypic changes in the cells manifested by reduced expression of endothelial markers and increased expression of mesenchymal markers, termed endothelial to mesenchymal transition (EndMT). We investigated mechanisms of such changes in the retinal endothelial cells and in the retina of diabetic animals. Human retinal microvascular endothelial cells were grown in medium containing 5 mM glucose or 25 mM glucose with or without TGFβ1 peptide or TGFβ1 inhibitor or miR-200b mimic transfection. Messenger RNA levels of endothelial markers, mesenchymal markers, and specific signaling molecules of TGFβ pathway were quantified. Expression of miR-200b and histone acetylator p300 was quantified. Retinal tissues from mice with endothelial-specific overexpression of miR-200b, with or without streptozotocin-induced diabetes, were similarly examined. Glucose caused decreased expression of mRNA and protein levels of endothelial markers and increased expression of mesenchymal markers with reduced miR-200b. A glucose-like effect was seen using TGFβ1 peptide. Such changes were mediated by miR-200b and p300. In the retinas of wild-type diabetic mice, EndMT was observed, which was prevented in miR-200b transgenic mice with diabetes. These data indicate glucose-induced EndMT in vitro and in vivo is possibly mediated through TGFβ and regulated by miR-200b and p300.


Role of a heterotrimeric G protein in regulation of Arabidopsis seed germination.
Seed germination is regulated by many signals. We investigated the possible involvement of a heterotrimeric G protein complex in this signal regulation. Seeds that carry a protein null mutation in the gene encoding the alpha subunit of the G protein in Arabidopsis (GPA1) are 100-fold less responsive to gibberellic acid (GA), have increased sensitivity to high levels of Glc, and have a near-wild-type germination response to abscisic acid and ethylene, indicating that GPA1 does not directly couple these signals in germination control. Seeds ectopically expressing GPA1 are at least a million-fold more responsive to GA, yet still require GA for germination. We conclude that the GPA1 indirectly operates on the GA pathway to control germination by potentiation. We propose that this potentiation is directly mediated by brassinosteroids (BR) because the BR response and synthesis mutants, bri1-5 and det2-1, respectively, share the same GA sensitivity as gpa1 seeds. Furthermore, gpa1 seeds are completely insensitive to brassinolide rescue of germination when the level of GA in seeds is reduced. A lack of BR responsiveness is also apparent in gpa1 roots and hypocotyls suggesting that BR signal transduction is likely coupled by a heterotrimeric G protein at various points in plant development.


Successful intrauterine treatment of cystic hygroma colli using OK-432. A case report.
A 36-year-old multiparous woman was referred at 25 weeks of gestation with suspected cystic hygroma. Ultrasonographic examination demonstrated large multiple cysts around the fetal neck. We treated them by injection of OK-432 at 29 and 32 weeks of gestation. The cysts decreased in size after the intrauterine treatment. A female baby was delivered at 38 weeks of gestation. She was healthy, and there was only a small swelling of the skin in the nuchal area at birth. One month later, the slight swelling of the skin had completely disappeared. Intrauterine injection of OK-432 was a safe and effective therapy for fetal cystic hygroma.