Habitat and Vegetation Variables Are Not Enough When Predicting Tick Populations in the Southeastern United States.
Two tick-borne diseases with expanding case and vector distributions are ehrlichiosis (transmitted by Amblyomma americanum) and rickettiosis (transmitted by A. maculatum and Dermacentor variabilis). There is a critical need to identify the specific habitats where each of these species is likely to be encountered to classify and pinpoint risk areas. Consequently, an in-depth tick prevalence study was conducted on the dominant ticks in the southeast. Vegetation, soil, and remote sensing data were used to test the hypothesis that habitat and vegetation variables can predict tick abundances. No variables were significant predictors of A. americanum adult and nymph tick abundance, and no clustering was evident because this species was found throughout the study area. For A. maculatum adult tick abundance was predicted by NDVI and by the interaction between habitat type and plant diversity; two significant population clusters were identified in a heterogeneous area suitable for quail habitat. For D. variabilis no environmental variables were significant predictors of adult abundance; however, D. variabilis collections clustered in three significant areas best described as agriculture areas with defined edges. This study identified few landscape and vegetation variables associated with tick presence. While some variables were significantly associated with tick populations, the amount of explained variation was not useful for predicting reliably where ticks occur; consequently, additional research that includes multiple sampling seasons and locations throughout the southeast are warranted. This low amount of explained variation may also be due to the use of hosts for dispersal, and potentially to other abiotic and biotic variables. Host species play a large role in the establishment, maintenance, and dispersal of a tick species, as well as the maintenance of disease cycles, dispersal to new areas, and identification of risk areas.


Niche conservatism as an emerging principle in ecology and conservation biology.
The diversity of life is ultimately generated by evolution, and much attention has focused on the rapid evolution of ecological traits. Yet, the tendency for many ecological traits to instead remain similar over time [niche conservatism (NC)] has many consequences for the fundamental patterns and processes studied in ecology and conservation biology. Here, we describe the mounting evidence for the importance of NC to major topics in ecology (e.g. species richness, ecosystem function) and conservation (e.g. climate change, invasive species). We also review other areas where it may be important but has generally been overlooked, in both ecology (e.g. food webs, disease ecology, mutualistic interactions) and conservation (e.g. habitat modification). We summarize methods for testing for NC, and suggest that a commonly used and advocated method (involving a test for phylogenetic signal) is potentially problematic, and describe alternative approaches. We suggest that considering NC: (1) focuses attention on the within-species processes that cause traits to be conserved over time, (2) emphasizes connections between questions and research areas that are not obviously related (e.g. invasives, global warming, tropical richness), and (3) suggests new areas for research (e.g. why are some clades largely nocturnal? why do related species share diseases?).


Where to search top-K biomedical ontologies?
Searching for precise terms and terminological definitions in the biomedical data space is problematic, as researchers find overlapping, closely related and even equivalent concepts in a single or multiple ontologies. Search engines that retrieve ontological resources often suggest an extensive list of search results for a given input term, which leads to the tedious task of selecting the best-fit ontological resource (class or property) for the input term and reduces user confidence in the retrieval engines. A systematic evaluation of these search engines is necessary to understand their strengths and weaknesses in different search requirements. We have implemented seven comparable Information Retrieval ranking algorithms to search through ontologies and compared them against four search engines for ontologies. Free-text queries have been performed, the outcomes have been judged by experts and the ranking algorithms and search engines have been evaluated against the expert-based ground truth (GT). In addition, we propose a probabilistic GT that is developed automatically to provide deeper insights and confidence to the expert-based GT as well as evaluating a broader range of search queries. The main outcome of this work is the identification of key search factors for biomedical ontologies together with search requirements and a set of recommendations that will help biomedical experts and ontology engineers to select the best-suited retrieval mechanism in their search scenarios. We expect that this evaluation will allow researchers and practitioners to apply the current search techniques more reliably and that it will help them to select the right solution for their daily work. The source code (of seven ranking algorithms), ground truths and experimental results are available at https://github.com/danielapoliveira/bioont-search-benchmark.


Invasive carnivores alter ecological function and enhance complementarity in scavenger assemblages on ocean beaches.
Species composition is expected to alter ecological function in assemblages if species traits differ strongly. Such effects are often large and persistent for nonnative carnivores invading islands. Alternatively, high similarity in traits within assemblages creates a degree of functional redundancy in ecosystems. Here we tested whether species turnover results in functional ecological equivalence or complementarity, and whether invasive carnivores on islands significantly alter such ecological function. The model system consisted of vertebrate scavengers (dominated by raptors) foraging on animal carcasses on ocean beaches on two Australian islands, one with and one without invasive red foxes (Vulpes vulpes). Partitioning of scavenging events among species, carcass removal rates, and detection speeds were quantified using camera traps baited with fish carcasses at the dune-beach interface. Complete segregation of temporal foraging niches between mammals (nocturnal) and birds (diurnal) reflects complementarity in carrion utilization. Conversely, functional redundancy exists within the bird guild where several species of raptors dominate carrion removal in a broadly similar way. As predicted, effects of red foxes were large. They substantially changed the nature and rate of the scavenging process in the system: (1) foxes consumed over half (55%) of all carrion available at night, compared with negligible mammalian foraging at night on the fox-free island, and (2) significant shifts in the composition of the scavenger assemblages consuming beach-cast carrion are the consequence of fox invasion at one island. Arguably, in the absence of other mammalian apex predators, the addition of red foxes creates a new dimension of functional complementarity in beach food webs. However, this functional complementarity added by foxes is neither benign nor neutral, as marine carrion subsidies to coastal red fox populations are likely to facilitate their persistence as exotic carnivores.


Ovarian response prediction in GnRH antagonist treatment for IVF using anti-Müllerian hormone.
What is the clinical value of anti-Müllerian hormone (AMH) for the prediction of high or low ovarian response in controlled ovarian stimulation for IVF using GnRH antagonist treatment? AMH as a single test has substantial accuracy for ovarian response prediction in GnRH antagonist treatment for IVF, with a higher accuracy for predicting a high response than for low response. The role of AMH and other patient characteristics in ovarian response prediction has been studied extensively in long GnRH agonist protocols; however, little information is available regarding the clinical value in GnRH antagonists. This is an observational (retrospective) substudy as part of an ongoing cohort study. A total of 487 patients scheduled for IVF/ICSI between 2006 and 2011 were included in the study. Patients with a regular cycle who underwent their first IVF/ICSI cycle with GnRH antagonist treatment while receiving a starting dose of 150 or 225 IU recombinant FSH were included in the study. Patients were divided into three subgroups according to the following ovarian response categories: high (>15 oocytes or cycle cancellation), normal (4-15 oocytes) and low (<4 oocytes or cycle cancellation). Serum samples collected prior to IVF treatment were used to determine serum AMH levels. According to the predefined ovarian response categories, 58 patients were classified as high, 326 as normal and 101 as low responders, and the ongoing pregnancy rates did not differ among groups (19.0, 22.1 and 16.8%, respectively, P = 0.9). For the prediction of high response, AMH had an area under the receiver-operating characteristic curve (AUC) of 0.87. Both female age and BMI had lower accuracy (AUC 0.66 and 0.58, respectively). For low response prediction, again AMH had a better accuracy (AUC 0.79) than female age and BMI (AUC 0.59 and 0.56, respectively). In a multivariate model, including the factors age, AMH, BMI, smoking, type and duration of subfertility, only BMI added some predictive value to AMH for both high and low response prediction. Clinical test characteristics demonstrated that using a specificity of ∼90%, the detection rate of AMH for high and low response, corresponding with a test cut-off of 4.5 and 0.8 µg/l, was ∼60 and ∼45%, respectively. The impact of the antral follicle count (AFC) on ovarian response prediction in GnRH antagonists was not assessed; however, previously studies demonstrated that for GnRH antagonists, AMH has a better accuracy than AFC. The current study demonstrates that AMH is an adequate predictor for both high and low response in GnRH antagonist cycles, showing a similar accuracy to GnRH agonists, as reported previously. The optimization and individualization of GnRH antagonist protocols may be improved by using an AMH-tailored approach. This study was funded by the Academic Institutional Resources of the Department of Reproductive Medicine of the UMC Utrecht. O.H., M.J.C.E, E.W.G.L and H.L.T. have nothing to declare. N.S.M. has received fees and/or grant support from the following companies (in alphabetic order): Anecova, Ferring, Informa, Merck Serono and MSD. B.C.J.M.F. has received fees and/or grant support from the following companies (in alphabetic order); Childhealth, CVON, Ferring, Ova-Science, PregLem, Roche and Watson laboratories. F.J.B. has received fees and/or grant support from the following companies (in alphabetic order); Merck Serono and MSD. www.clinicaltrials.gov, Protocol ID 13-109.


Mild Traumatic Brain Injury Leads to Decreased Inhibition and a Differential Response of Calretinin Positive Interneurons in the Injured Cortex.
It is clear that even mild forms of traumatic brain injury (TBI) can have lasting cognitive effects; however, the specific cellular changes responsible for the functional deficits remain poorly understood. Previous studies suggest that not all neurons respond in the same way and that changes to neuronal architecture may be subtype specific. The current study aimed to characterize the response of interneurons to TBI. To model TBI in vitro, the neurites of primary cortical neurons were transected at 15 days in vitro. In response, calretinin+ interneurons underwent significant neurite remodeling around the injury site. By examining the response of pyramidal neurons, GAD67-GFP+ interneurons, and calretinin+ interneurons to the injury, we found that this response was specific to the calretinin+ cells. To determine whether calretinin+ interneurons respond in this way to a clinically relevant in vivo model of mild diffuse and focal injury, we subjected mice to the lateral fluid percussion injury model. We found that calretinin+ interneuron density was unaltered by this mild injury, but consistent with our in vitro data, these neurons underwent morphological alterations in their dendrites. These alterations evolved over a 28-day period, and calretinin+ interneurons in the injured mice had a reduction in mean dendrite length and reduced number of secondary dendrites than those in the sham-injured controls by 7 days post-injury. Further, these structural alterations were accompanied by a reduction in the frequency of miniature inhibitory post-synaptic currents in layer V pyramidal neurons. These data suggest that even a mild TBI can lead to an overall change in the excitatory/inhibitory balance of the cortex that may play an important role in the longer-term behavioral pathology associated with mild TBI.


Test-Retest Reliability of the Digijump Machine.
Repetitive jumping has been identified as a possible exercise modality able to provide sufficient stimulus to improve bone health. However, it is necessary to establish whether repetitive jumping can elicit a consistent physiological response with the ablity to monitor work rate. The purpose of this investigation was to determine the stability reliability of the Digijump device for the commonly used laboratory measures of oxygen uptake (VO2), heart rate (HR), and rate of perceived exertion (RPE). College-aged individuals (N = 17) completed two 3-min repetitive jumping bouts on the Digijump machine (120 jumps per minute, jump height = 1.27 cm) at least seven days apart. Stability reliability was calculated using the intraclass correlation coefficient derived from 1-way ANOVA. Absolute VO2 displayed the highest test-retest reliability (0.95), while the coefficient for relative VO2 was also acceptable (0.71). The test-retest reliability coefficients for HR (0.89), and RPE (0.75) were determined to be within acceptable limits. Coefficients for all variables compared well with the stability reliability reported for other ergometers such as the Stairmaster, treadmill, and cycle. This data represent an important step in determining the validity of the Digijump machine for physiological testing.


Microplate-based platform for combined chromatin and DNA methylation immunoprecipitation assays.
The processes that compose expression of a given gene are far more complex than previously thought presenting unprecedented conceptual and mechanistic challenges that require development of new tools. Chromatin structure, which is regulated by DNA methylation and histone modification, is at the center of gene regulation. Immunoprecipitations of chromatin (ChIP) and methylated DNA (MeDIP) represent a major achievement in this area that allow researchers to probe chromatin modifications as well as specific protein-DNA interactions in vivo and to estimate the density of proteins at specific sites genome-wide. Although a critical component of chromatin structure, DNA methylation has often been studied independently of other chromatin events and transcription. To allow simultaneous measurements of DNA methylation with other genomic processes, we developed and validated a simple and easy-to-use high throughput microplate-based platform for analysis of DNA methylation. Compared to the traditional beads-based MeDIP the microplate MeDIP was more sensitive and had lower non-specific binding. We integrated the MeDIP method with a microplate ChIP assay which allows measurements of both DNA methylation and histone marks at the same time, Matrix ChIP-MeDIP platform. We illustrated several applications of this platform to relate DNA methylation, with chromatin and transcription events at selected genes in cultured cells, human cancer and in a model of diabetic kidney disease. The high throughput capacity of Matrix ChIP-MeDIP to profile tens and potentially hundreds of different genomic events at the same time as DNA methylation represents a powerful platform to explore complex genomic mechanism at selected genes in cultured cells and in whole tissues. In this regard, Matrix ChIP-MeDIP should be useful to complement genome-wide studies where the rich chromatin and transcription database resources provide fruitful foundation to pursue mechanistic, functional and diagnostic information at genes of interest in health and disease.


Tunable continuous-wave deep-ultraviolet laser based on Ce:LiCAF.
We demonstrate chopped-cw lasing in a Ce:LiCAF oscillator directly generating deep-UV light around 290 nm. The cw output was achieved by asynchronous pumping of a Ce:LiCAF oscillator by a mode-locked frequency quadrupled Nd:YVO4 laser that generates 23 ps pulses of 266 nm light at a repetition rate of 80 MHz. The pump laser was chopped with 8.3% duty cycle to minimize thermal effects in the frequency quadrupling stage. The maximum output power achieved was 384 mW when pumped with 3.3 W of pulsed 266 nm light, with a slope efficiency of 33%. The laser output was tunable from 286 to 295 nm with the potential to be broadened over the full gain bandwidth of Ce:LiCAF from 280 to 315 nm.


Microarray expression analysis and identification of serum biomarkers for Niemann-Pick disease, type C1.
Niemann-Pick disease type C (NPC) is a lysosomal storage disorder characterized by liver disease and progressive neurodegeneration. Deficiency of either NPC1 or NPC2 leads to the accumulation of cholesterol and glycosphingolipids in late endosomes and early lysosomes. In order to identify pathological mechanisms underlying NPC and uncover potential biomarkers, we characterized liver gene expression changes in an Npc1 mouse model at six ages spanning the pathological progression of the disease. We identified altered gene expression at all ages, including changes in asymptomatic, 1-week-old mice. Biological pathways showing early altered gene expression included: lipid metabolism, cytochrome P450 enzymes involved in arachidonic acid and drug metabolism, inflammation and immune responses, mitogen-activated protein kinase and G-protein signaling, cell cycle regulation, cell adhesion and cytoskeleton remodeling. In contrast, apoptosis and oxidative stress appeared to be late pathological processes. To identify potential biomarkers that could facilitate monitoring of disease progression, we focused on a subset of 103 differentially expressed genes that encode secreted proteins. Further analysis identified two secreted proteins with increased serum levels in NPC1 patients: galectin-3 (LGALS3), a pro-inflammatory molecule, and cathepsin D (CTSD), a lysosomal aspartic protease. Elevated serum levels of both proteins correlated with neurological disease severity and appeared to be specific for NPC1. Expression of Lgals3 and Ctsd was normalized following treatment with 2-hydroxypropyl-β-cyclodextrin, a therapy that reduces pathological findings and significantly increases Npc1(-/-) survival. Both LGALS3 and CTSD have the potential to aid in diagnosis and serve as biomarkers to monitor efficacy in therapeutic trials.


Molecular targets of nickel and chromium in human and experimental systems.
Water-insoluble nickel compounds tend to be carcinogenic because they enter cells through phagocytosis. Highly water-soluble nickel salts, such as nickel chloride, do not enter cells well and thus are not carcinogenic in vivo. Carcinogenic nickel compounds produce selective damage to heterochromatic regions in Chinese hamster chromosomes, probably because of the high concentration of proteins and amino acids in this highly condensed genetically inactive chromatin region. Bivalent nickel ions are highly affinitive to amino acids as compared with deoxyribonucleic acid (DNA). The interaction with proteins is believed to cause this effect. In addition, when nickel binds to proteins, it can be oxidized, and DNA protein damage ensues. A new method detects DNA-protein cross-links induced by various agents, such as nickel, chromium and cis-platinum. It has demonstrated an increase in DNA-protein cross-links in cultured cells from animals treated with chromate and welders exposed to welding fumes.


Capture and culture: organizational identity in New York Blue Cross.
This article explores the changing corporate culture of New York's Blue Cross and Blue Shield plan in its first fifty years. As the plan grew, corporate culture evolved over four sequential phases: the plan first had the character of an experiment, then that of a movement, a business, and, most recently, a corporate agglomerate. Accompanying this evolution has been an identity crisis, as the need to adapt to a turbulent environment has challenged the plan's settled understanding of its core values, namely, voluntarism, community, and cooperation.


[Drug sensitivity and expression of beta-lactamase in enterococci isolated at Okayama University Hospital].
The following results were obtained from a study of Enterococci isolated at the Okayama University Hospital from 1990 to 1994. 1) The isolation frequency of Enterococci was about 6% for each year. 2) The percentage of Enterococcus faecalis (E. faecalis) among Enterococci decreased each year, but the percentage of Enterococcus faecium (E. faecium), and Enterococcus avium (E. avium) increased each year. 3) Results of drug sensitivity tests revealed that the incidence of ofloxacin (OFLX) resistant E. faecalis and E. avium increased each year. Also, the resistance of E. faecalis to ampicillin (ABPC), the primary medication choice for treating E. faecalis, increased each year. 4) A few vancomycin (VCM) non-sensitive Enterococci were isolated. These bacteria showed low-sensitivity toward ABPC, imipenem (IPM), gentamicin (GM), and OFLX, and the extent of multiple drug resistance increased each year. 5) One hundred strains of Enterococci were selected to examine the expression of beta-lactamase using the broth method and the iodine-starch method. However, beta-lactamase producing strains were not detected.


Gemcitabine chemotherapy and single-fraction stereotactic body radiotherapy for locally advanced pancreatic cancer.
Fractionated radiotherapy and chemotherapy for locally advanced pancreatic cancer achieves only modest local control. This prospective trial evaluated the efficacy of a single fraction of 25 Gy stereotactic body radiotherapy (SBRT) delivered between Cycle 1 and 2 of gemcitabine chemotherapy. A total of 16 patients with locally advanced, nonmetastatic, pancreatic adenocarcinoma received gemcitabine with SBRT delivered 2 weeks after completion of the first cycle. Gemcitabine was resumed 2 weeks after SBRT and was continued until progression or dose-limiting toxicity. The gross tumor volume, with a 2-3-mm margin, was treated in a single 25-Gy fraction by Cyberknife. Patients were evaluated at 4-6 weeks, 10-12 weeks, and every 3 months after SBRT. All 16 patients completed SBRT. A median of four cycles (range one to nine) of chemotherapy was delivered. Three patients (19%) developed local disease progression at 14, 16, and 21 months after SBRT. The median survival was 11.4 months, with 50% of patients alive at 1 year. Patients with normal carbohydrate antigen (CA)19-9 levels either at diagnosis or after Cyberknife SBRT had longer survival (p <0.01). Acute gastrointestinal toxicity was mild, with 2 cases of Grade 2 (13%) and 1 of Grade 3 (6%) toxicity. Late gastrointestinal toxicity was more common, with five ulcers (Grade 2), one duodenal stenosis (Grade 3), and one duodenal perforation (Grade 4). A trend toward increased duodenal volumes radiated was observed in those experiencing late effects (p = 0.13). SBRT with gemcitabine resulted in comparable survival to conventional chemoradiotherapy and good local control. However, the rate of duodenal ulcer development was significant.


Effect of IV alteplase on the ischemic brain lesion at 24-48 hours after ischemic stroke.
To determine whether alteplase alters the development of ischemic lesions on brain imaging after stroke. The Third International Stroke Trial (IST-3) was a randomized controlled trial of IV alteplase for ischemic stroke. We assessed CT or brain MRI at baseline (pretreatment) and 24 to 48 hours posttreatment for acute lesion visibility, extent, and swelling, masked to all other data. We analyzed associations between treatment allocation, change in brain tissue appearances between baseline and follow-up imaging, and 6-month functional outcome in IST-3. We performed a meta-analysis of randomized trials of alteplase vs control with pre- and postrandomization imaging. Of 3,035 patients recruited in IST-3, 2,916 had baseline and follow-up brain imaging. Progression in either lesion extent or swelling independently predicted poorer 6-month outcome (adjusted odds ratio [OR] = 0.92, 95% confidence interval [CI] 0.88-0.96, p < 0.001; OR = 0.73, 95% CI 0.66-0.79, p < 0.001, respectively). Patients allocated alteplase were less likely than controls to develop increased lesion visibility at follow-up (OR = 0.77, 95% CI 0.67-0.89, p < 0.001), but there was no evidence that alteplase reduced progression of lesion extent or swelling. In meta-analysis of 6 trials including IST-3 (n = 4,757), allocation to alteplase was associated with a reduction in ischemic lesion extent on follow-up imaging (OR = 0.85, 95% CI 0.76-0.95, p = 0.004). Alteplase was associated with reduced short-term progression in lesion visibility. In meta-analysis, alteplase reduced lesion extent. These findings may indicate that alteplase improves functional outcome by reducing tissue damage. This study provides Class II evidence that IV alteplase impedes the progression of ischemic brain lesions on imaging after stroke.


A critical link between heart failure self-care and intrathoracic impedance.
Effective self-care is regarded as essential to the management of heart failure (HF). The influence of self-care on HF decompensation, however, is not well understood. Accordingly, we examined the relationship between self-care and fluid accumulation accompanying worsening HF as indexed by decreasing intrathoracic impedance (Z). Z data were collected from 58 HF patients with OptiVol enabled devices (Medtronic Inc, Minneapolis, Minnesota). Heart failure self-care was measured with the European Heart Failure Self-care Behaviour Scale. Regression modeling was used to describe the influence of HF self-care on the likelihood of a fluid index (FI) threshold crossing, the number of threshold crossings, and number of days spent above threshold. Patients were elderly (74.98 [SD, 8.12] years), with a mean left ventricular ejection fraction of 26.21% (SD, 9.77%), and 63.7% had class New York Heart Association III HF. Patients were followed up for 317 (SD, 96) days; 65.5% had FI threshold crossings (mean 1.45 [SD, 1.56] crossings), spending an average of 33.8 (SD, 42.4) days above FI threshold. Controlling for age, sex, left ventricular ejection fraction, functional class, and duration of follow-up, each additional point on the European Heart Failure Self-care Behaviour Scale was associated with an increase in the odds of having had an FI threshold crossing (adjusted odds ratio, 1.201; 95% confidence interval, 1.013-1.424; P<.05) and more days spent above FI threshold (incidence rate ratio, 1.051; 95% confidence interval, 1.002-1.102; P<.05). Intrathoracic impedance measurements obtained from implantable devices provide important information regarding the influence of self-care on fluid accumulation in patients with HF.


SUMOylation of the MAGUK protein CASK regulates dendritic spinogenesis.
Membrane-associated guanylate kinase (MAGUK) proteins interact with several synaptogenesis-triggering adhesion molecules. However, direct evidence for the involvement of MAGUK proteins in synapse formation is lacking. In this study, we investigate the function of calcium/calmodulin-dependent serine protein kinase (CASK), a MAGUK protein, in dendritic spine formation by RNA interference. Knockdown of CASK in cultured hippocampal neurons reduces spine density and shrinks dendritic spines. Our analysis of the time course of RNA interference and CASK overexpression experiments further suggests that CASK stabilizes or maintains spine morphology. Experiments using only the CASK PDZ domain or a mutant lacking the protein 4.1-binding site indicate an involvement of CASK in linking transmembrane adhesion molecules and the actin cytoskeleton. We also find that CASK is SUMOylated. Conjugation of small ubiquitin-like modifier 1 (SUMO1) to CASK reduces the interaction between CASK and protein 4.1. Overexpression of a CASK-SUMO1 fusion construct, which mimicks CASK SUMOylation, impairs spine formation. Our study suggests that CASK contributes to spinogenesis and that this is controlled by SUMOylation.


Double blinded, vehicle controlled, crossover study on the efficacy of a topical endocannabinoid membrane transporter inhibitor in atopic Beagles.
The endocannabinoid system is important for skin homeostasis and alterations are linked to inflammatory diseases like atopic dermatitis (AD). Importantly, activation of cannabinoid receptor CB2 decreases pruritus and inflammation in mouse models. Reduction of inactivation of endogenous cannabinoids could, therefore, be a therapeutic option for AD. Dogs spontaneously develop AD, which closely mimics the human disease making them suitable to test new therapies. Our study aimed to test the effects of a topical endocannabinoid membrane transporter inhibitor (WOL067-531, 1% gel) on pruritus and dermatitis in a canine model of AD. Nineteen Beagles allergic to dust mites (DM) were randomized to receive either active ingredient or vehicle on inguinal area while challenged epicutaneously with DM twice weekly for 28 days. Treatment was administered twice daily and started after three challenges (day 8). Dermatitis and pruritus were scored weekly by personnel blinded to treatment allocation. Dermatitis was scored using a validated scoring system and pruritus was scored using camera recordings. After a 4-week washout, dogs were crossed over and the study was repeated. On days 15 and 22, dermatitis scores were significantly increased after DM challenge in the vehicle group (16.34, p = 0.0089 and 7.42, p = 0.04845, respectively) but not in the active ingredient group (p = 0.3177 and p = 0.3190, respectively). Significant decrease on pruritus both on inguinal area and overall (p = 0.048 and p = 0.032, respectively) occurred in the active ingredient group. No adverse effects were noted. In conclusion, the newly developed topical endocannabinoid membrane transporter inhibitor (WOL067-531) minimized allergic flares and pruritus in a canine model of AD.


Nut consumption has favorable effects on lipid profiles of Korean women with metabolic syndrome.
Nut consumption has been studied for its cardioprotective effects. However, the findings of clinical intervention studies are inconsistent; and no intervention studies have been conducted in the Korean population. We hypothesized that nut supplementation may have favorable influence on metabolic markers. Therefore, this study aimed to investigate the effects of nut consumption on metabolic parameters and biomarkers related to inflammation, oxidative stress, and endothelial function in Korean adults with metabolic syndrome. To this end, we designed a randomized, parallel, controlled dietary intervention study (ClinicalTrials.gov NCT02023749). Subjects with metabolic syndrome and a body mass index of at least 23 kg/m(2) were randomized to the Control group and the Nut group, which received supplementation with 30 g/d of mixed nuts (walnuts, peanuts, and pine nuts) for 6 weeks. Sixty volunteers were included in the final analysis. Metabolic markers were evaluated at baseline and at the end of the study. Total cholesterol and non-high-density lipoprotein cholesterol levels significantly improved in the Nut group compared to those in the Control group (P = .023 and P = .016, respectively) in women. Biomarkers related to inflammation, oxidative stress, and endothelial function did not significantly change from baseline in either group. Thus, supplementing a usual diet with mixed nuts for 6 weeks had favorable effects on several lipid parameters in Korean women with metabolic syndrome. These findings present a possible mechanism for the cardioprotective effects of nut consumption.


Real-time classification of experience-related ensemble spiking patterns for closed-loop applications.
Communication in neural circuits across the cortex is thought to be mediated by spontaneous temporally organized patterns of population activity lasting ~50 -200 ms. Closed-loop manipulations have the unique power to reveal direct and causal links between such patterns and their contribution to cognition. Current brain-computer interfaces, however, are not designed to interpret multi-neuronal spiking patterns at the millisecond timescale. To bridge this gap, we developed a system for classifying ensemble patterns in a closed-loop setting and demonstrated its application in the online identification of hippocampal neuronal replay sequences in the rat. Our system decodes multi-neuronal patterns at 10 ms resolution, identifies within 50 ms experience-related patterns with over 70% sensitivity and specificity, and classifies their content with 95% accuracy. This technology scales to high-count electrode arrays and will help to shed new light on the contribution of internally generated neural activity to coordinated neural assembly interactions and cognition.


The role of the cerebellum in subsecond time perception: evidence from repetitive transcranial magnetic stimulation.
In three experiments, we investigated the role of the cerebellum in sub- and suprasecond time perception by using repetitive transcranial magnetic stimulation (rTMS). In Experiment 1, subjects underwent four 8-min 1-Hz rTMS sessions in a within-subject design. rTMS sites were the medial cerebellum (real and sham rTMS), left lateral cerebellum, and right lateral cerebellum. Following each rTMS session, subjects completed a subsecond temporal bisection task (stimuli in the range 400-800 msec). Compared with sham rTMS, rTMS applied over the right lateral or medial cerebellum induced a leftward shift of the psychophysical function (perceived lengthening of time). In Experiment 2, a separate sample of subjects underwent the identical rTMS procedure and completed a suprasecond bisection task (stimuli in the 1000-2000 msec range). In this experiment, rTMS to the cerebellar sites did not produce any significant changes compared with sham rTMS. Experiment 3 employed a within-subject design to replicate findings from Experiments 1 and 2. Subjects underwent four rTMS conditions (sub- and suprabisection tasks following medial cerebellar and sham rTMS). rTMS induced a significant leftward shift of psychophysical function in the subsecond bisection, but not in the suprasecond bisection. In this study, we have demonstrated that transient cerebellar stimulation can differently affect the ability to estimate time intervals below and above a duration of 1 sec. The results of this study provide direct evidence for the role of the cerebellum in processing subsecond time intervals. This study further suggests that the perception of sub- and suprasecond intervals is likely to depend upon distinct neural systems.


Sonic hedgehog controls enteric nervous system development by patterning the extracellular matrix.
The enteric nervous system (ENS) develops from neural crest cells that migrate along the intestine, differentiate into neurons and glia, and pattern into two plexuses within the gut wall. Inductive interactions between epithelium and mesenchyme regulate gut development, but the influence of these interactions on ENS development is unknown. Epithelial-mesenchymal recombinations were constructed using avian hindgut mesenchyme and non-intestinal epithelium from the bursa of Fabricius. These recombinations led to abnormally large and ectopically positioned ganglia. We hypothesized that sonic hedgehog (Shh), a secreted intestinal epithelial protein not expressed in the bursa, mediates this effect. Inhibition of Shh signaling, by addition of cyclopamine or a function-blocking antibody, resulted in large, ectopic ganglia adjacent to the epithelium. Shh overexpression, achieved in ovo using Shh-encoding retrovirus and in organ culture using recombinant protein, led to intestinal aganglionosis. Shh strongly induced the expression of versican and collagen type IX, whereas cyclopamine reduced expression of these chondroitin sulfate proteoglycans that are known to be inhibitory to neural crest cell migration. Shh also inhibited enteric neural crest-derived cell (ENCC) proliferation, promoted neuronal differentiation, and reduced expression of Gdnf, a key regulator of ENS formation. Ptc1 and Ptc2 were not expressed by ENCCs, and migration of isolated ENCCs was not inhibited by Shh protein. These results suggest that epithelial-derived Shh acts indirectly on the developing ENS by regulating the composition of the intestinal microenvironment.


Coordinate regulation of ribosomal component synthesis in Acanthamoeba castellanii: 5S RNA transcription is down regulated during encystment by alteration of TFIIIA activity.
Transcription of large rRNA precursor and 5S RNA were examined during encystment of Acanthamoeba castellanii. Both transcription units are down regulated almost coordinately during this process, though 5S RNA transcription is not as completely shut down as rRNA transcription. The protein components necessary for transcription of 5S RNA and tRNA were determined, and fractions containing transcription factors comparable to TFIIIA, TFIIIB, and TFIIIC, as well as RNA polymerase III and a 3'-end processing activity, were identified. Regulation of 5S RNA transcription could be recapitulated in vitro, and the activities of the required components were compared. In contrast to regulation of precursor rRNA, there is no apparent change during encystment in the activity of the polymerase dedicated to 5S RNA expression. Similarly, the transcriptional and promoter-binding activities of TFIIIC are not altered in parallel with 5S RNA regulation. TFIIIB transcriptional activity is unaltered in encysting cells. In contrast, both the transcriptional and DNA-binding activities of TFIIIA are strongly reduced in nuclear extracts from transcriptionally inactive cells. These results were analyzed in terms of mechanisms for coordinate regulation of rRNA and 5S RNA expression.


Individual differences in migratory behavior shape population genetic structure and microhabitat choice in sympatric blackcaps (Sylvia atricapilla).
In migratory birds, traits such as orientation and distance are known to have a strong genetic background, and they often exhibit considerable within-population variation. How this variation relates to evolutionary responses to ongoing selection is unknown because the underlying mechanisms that translate environmental changes into population genetic changes are unclear. We show that within-population genetic structure in southern German blackcaps (Sylvia atricapilla) is related to individual differences in migratory behavior. Our 3-year study revealed a positive correlation between individual migratory origins, denoted via isotope (δ (2)H) values, and genetic distances. Genetic diversity and admixture differed not only across a recently established migratory polymorphism with NW- and SW-migrating birds but also across δ (2)H clusters within the same migratory route. Our results suggest assortment based on individual migratory origins which would facilitate evolutionary responses. We scrutinized arrival times and microhabitat choice as potential mechanisms mediating between individual variation in migratory behavior and assortment. We found significant support that microhabitat choice, rather than timing of arrival, is associated with individual variation in migratory origins. Moreover, examining genetic diversity across the migratory divide, we found migrants following the NW route to be genetically more distinct from each other compared with migrants following the traditional SW route. Our study suggests that migratory behavior shapes population genetic structure in blackcaps not only across the migratory divide but also on an individual level independent of the divide. Thus, within-population variation in migratory behavior might play an important role in translating environmental change into genetic change.


Microglia along sex lines: From brain colonization, maturation and function, to implication in neurodevelopmental disorders.
In addition to their traditional role as immune sentinels, recent discoveries over the last decade have shown that microglial functions now include regulation of neuronal/glial cell migration, differentiation and maturation, as well as neuronal network formation. It was thus proposed that disruption of these microglial roles, during critical periods of brain development, could lead to the pathological onset of several neurodevelopmental disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, epilepsy, schizophrenia, and major depressive disorder. The prevalence of these disorders exhibits a clear distinction along sex lines with very little known about the mechanisms underlying this difference. One of the fundamental discoveries that arose from recent research into the physiological roles of microglia in neurodevelopment is their sexual dimorphism, raising the intriguing possibility that sex differences in microglial colonization, maturation and/or function in the developing brain could underlie the emergence of various neurodevelopmental disorders. This review discusses the physiological roles of microglia across neurodevelopment, these roles in the two sexes, and the recent evidence that microglial sexually dimorphic nature may contribute, at least partially, to neurodevelopmental disorders.


A roadmap for global synthesis of the plant tree of life.
Providing science and society with an integrated, up-to-date, high quality, open, reproducible and sustainable plant tree of life would be a huge service that is now coming within reach. However, synthesizing the growing body of DNA sequence data in the public domain and disseminating the trees to a diverse audience are often not straightforward due to numerous informatics barriers. While big synthetic plant phylogenies are being built, they remain static and become quickly outdated as new data are published and tree-building methods improve. Moreover, the body of existing phylogenetic evidence is hard to navigate and access for non-experts. We propose that our community of botanists, tree builders, and informaticians should converge on a modular framework for data integration and phylogenetic analysis, allowing easy collaboration, updating, data sourcing and flexible analyses. With support from major institutions, this pipeline should be re-run at regular intervals, storing trees and their metadata long-term. Providing the trees to a diverse global audience through user-friendly front ends and application development interfaces should also be a priority. Interactive interfaces could be used to solicit user feedback and thus improve data quality and to coordinate the generation of new data. We conclude by outlining a number of steps that we suggest the scientific community should take to achieve global phylogenetic synthesis.


[Evaluation of risk factors for retinopathy of prematurity].
To evaluate the incidence and risk factors of ROP (retinopathy of prematurity) through a prospective multicenter study. Eleven children's or maternal & child hospitals participated in a collective network. All infants of birth weight < 2000 g, born in or transferred to one of the participating centers from January 1st 2005 to February 28th 2006 were recruited. Timely ophthalmologic examinations were performed. The relevant data at baseline and endpoints were collected at each unit. A total of 882 preterm infants fulfilled the screening criteria and 752 finished a followup. And 123 infants (16.4%) had some degree of ROP. Infants with ROP had a lower gestational age, birth weight and a longer duration of oxygen versus those without ROP [(30.82 +/- 0.20) weeks vs (32.56 +/- 0.09) weeks, (1430 +/- 25) g vs (1636 +/-10) g, (11.6 +/- 1.4) d vs (4.4 +/- 0.3) d]. Through a univariate analysis, birth weight, gestational age, asphyxia, oxygen duration > 5 days, apnea, surfactant usage, pneumonia, anemia, blood transfusion, acidosis and neonatal respiratory distress syndrome (NRDS) were associated with ROP (P < 0.05). Logistic regression analysis showed that birth weight (OR = 0.998), apnea (OR = 1.653) and blood transfusion (OR = 1.763) were independent risk factors for ROP. Asphyxia, oxygen duration > 5 days, surfactant usage, anemia, acidosis and NRDS, lower birth weight, apnea and blood transfusion may improve the risks of ROP.


Systematic reviews and knowledge translation.
Proven effective interventions exist that would enable all countries to meet the Millennium Development Goals. However, uptake and use of these interventions in the poorest populations is at least 50% less than in the richest populations within each country. Also, we have recently shown that community effectiveness of interventions is lower for the poorest populations due to a "staircase" effect of lower coverage/access, worse diagnostic accuracy, less provider compliance and less consumer adherence. We propose an evidence-based framework for equity-oriented knowledge translation to enhance community effectiveness and health equity. This framework is represented as a cascade of steps to assess and prioritize barriers and thus choose effective knowledge translation interventions that are tailored for relevant audiences (public, patient, practitioner, policy-maker, press and private sector), as well as the evaluation, monitoring and sharing of these strategies. We have used two examples of effective interventions (insecticide-treated bednets to prevent malaria and childhood immunization) to illustrate how this framework can provide a systematic method for decision-makers to ensure the application of evidence-based knowledge in disadvantaged populations. Future work to empirically validate and evaluate the usefulness of this framework is needed. We invite researchers and implementers to use the cascade for equity-oriented knowledge translation as a guide when planning implementation strategies for proven effective interventions. We also encourage policy-makers and health-care managers to use this framework when deciding how effective interventions can be implemented in their own settings.


Non-linguistic Conditions for Causativization as a Linguistic Attractor.
An attractor, in complex systems theory, is any state that is more easily or more often entered or acquired than departed or lost; attractor states therefore accumulate more members than non-attractors, other things being equal. In the context of language evolution, linguistic attractors include sounds, forms, and grammatical structures that are prone to be selected when sociolinguistics and language contact make it possible for speakers to choose between competing forms. The reasons why an element is an attractor are linguistic (auditory salience, ease of processing, paradigm structure, etc.), but the factors that make selection possible and propagate selected items through the speech community are non-linguistic. This paper uses the consonants in personal pronouns to show what makes for an attractor and how selection and diffusion work, then presents a survey of several language families and areas showing that the derivational morphology of pairs of verbs like fear and frighten, or Turkish korkmak 'fear, be afraid' and korkutmak 'frighten, scare', or Finnish istua 'sit' and istutta 'seat (someone)', or Spanish sentarse 'sit down' and sentar 'seat (someone)' is susceptible to selection. Specifically, the Turkish and Finnish pattern, where 'seat' is derived from 'sit' by addition of a suffix-is an attractor and a favored target of selection. This selection occurs chiefly in sociolinguistic contexts of what is defined here as linguistic symbiosis, where languages mingle in speech, which in turn is favored by certain demographic, sociocultural, and environmental factors here termed frontier conditions. Evidence is surveyed from northern Eurasia, the Caucasus, North and Central America, and the Pacific and from both modern and ancient languages to raise the hypothesis that frontier conditions and symbiosis favor causativization.


Temporal Integration of Motion Streaks in Migraine.
Migraine is associated with differences in visual perception, specifically, deficits in the perception of motion. Migraine groups commonly show poorer performance (higher thresholds) on global motion tasks compared to control groups. Successful performance on a global motion task depends on several factors, including integrating signals over time. A "motion streak" task was used to investigate specifically integration over time in migraine and control groups. The motion streak effect depends on the integration of a moving point over time to create the illusion of a line, or "streak". There was evidence of a slower optimum speed for eliciting the motion streak effect in migraine compared to control groups, suggesting temporal integration is different in migraine. In addition, performance on the motion streak task showed a relationship with headache frequency.


Ticks on dogs and cats: a pet owner-based survey in a rural town in northeastern Switzerland.
Changes in the endemic foci of tick populations and invasions of tick species to new areas have become evident in Europe, leading to changes in the epidemiology of tick-transmitted diseases. However, data about tick infestations of pet animals are limited. Following the recent identification of a new focus of canine babesiosis in northeastern Switzerland, we investigated the occurrence of tick vectors in this region by using a pet owner-based sampling strategy. All dog owners in a rural town were sent postal requests to send ticks from their dogs and cats over two consecutive years, beginning in April 2012. In total 3003 ticks were submitted for identification from 249 dogs (approximately 20% of the resident dog population) and from 117 cats. Ixodes ricinus was the most abundant species identified in 96.8% (n=2124) and 74.3% (n=601) of the individual samples submitted from dogs and cats, respectively. Two other tick species, I. hexagonus and Dermacentor reticulatus, were recorded on both host species, with host infestation prevalences below 2%. On cats (but not on dogs), as many as 24.0% (n=194) of the specimens were identified as a fourth tick species, I. trianguliceps. Overall, 93.5% of the ticks were adults (93.8% and 93.0% in dogs and cats), 4.4% nymphs (5.7% in dogs and 1% in cats) and 2% larvae (0.5% and 6.0% in dogs and cats), respectively. The highest infestation intensity was 49 I. ricinus ticks from an individual dog. However, 55.6% of the submissions from dogs and 24.8% from cats contained only one tick. This survey demonstrated that pet owners can contribute to a cost-effective tick surveillance and identified a new tick focus of D. reticulatus. The finding of I. trianguliceps exclusively on cats might be related to behavioural traits of the cats or to a more readily detection of these very small ticks during petting by their owners.


Comprehensive multilevel in vivo and in vitro analysis of heart rate fluctuations in mice by ECG telemetry and electrophysiology.
The normal heartbeat slightly fluctuates around a mean value; this phenomenon is called physiological heart rate variability (HRV). It is well known that altered HRV is a risk factor for sudden cardiac death. The availability of genetic mouse models makes it possible to experimentally dissect the mechanism of pathological changes in HRV and its relation to sudden cardiac death. Here we provide a protocol that allows for a comprehensive multilevel analysis of heart rate (HR) fluctuations. The protocol comprises a set of techniques that include in vivo telemetry and in vitro electrophysiology of intact sinoatrial network preparations or isolated single sinoatrial node (SAN) cells. In vitro preparations can be completed within a few hours, with data acquisition within 1 d. In vivo telemetric ECG requires 1 h for surgery and several weeks for data acquisition and analysis. This protocol is of interest to researchers investigating cardiovascular physiology and the pathophysiology of sudden cardiac death.


Intraductal biliopancreatic imaging: European Society of Gastrointestinal Endoscopy (ESGE) technology review.
This technology review expresses the current view of the European Society of Gastrointestinal Endoscopy (ESGE) on the available techniques for intraductal biliopancreatic imaging. The three cholangioscopy techniques are described: the "dual-operator" and " single-operator" mother-baby approaches using dedicated instruments, and the "direct" technique using currently available ultrathin gastroscopes. The mother-baby method is standardized and reproducible, while direct cholangioscopy is technically demanding and its safety requires further evaluation. As well as direct visualization of the bile ducts, cholangioscopy has the further advantage of allowing targeted biopsy. Image quality is still suboptimal for single-operator cholangioscopy, while the other techniques have achieved adequately detailed imaging. The costs of mother-baby cholangioscopy are high and its application in clinical practice should be restricted to selected cases (i.e. indeterminate biliary strictures/intraluminal lesions, difficult biliary stones) and to the setting of tertiary care centers. Peroral pancreatoscopy may find an indication in situations where other imaging modalities (mainly EUS) are inconclusive (i.e. delineation of main duct intraductal papillary mucinous neoplasia extension, sampling of indeterminate main pancreatic duct strictures). Intraductal ultrasonography (IDUS) has a poorer performance than EUS in the staging of pancreatic malignancies and can increase the risk of pancreatitis. A promising indication for IDUS could be the evaluation of indeterminate biliary strictures and ampullary tumors. Probe-based confocal laser endomicroscopy (pCLE) of the bile ducts is a difficult and expensive technique. Appropriate training needs to be established, since interpretation of images is challenging. pCLE can be an important diagnostic tool in the setting of indeterminate biliary strictures.


The Validity and Reliability of Commercially Available Resistance Training Monitoring Devices: A Systematic Review.
Monitoring resistance training has a range of unique difficulties due to differences in physical characteristics and capacity between athletes, and the indoor environment in which it often occurs. Traditionally, methods such as volume load have been used, but these have inherent flaws. In recent times, numerous portable and affordable devices have been made available that purport to accurately and reliably measure kinetic and kinematic outputs, potentially offering practitioners a means of measuring resistance training loads with confidence. However, a thorough and systematic review of the literature describing the reliability and validity of these devices has yet to be undertaken, which may lead to uncertainty from practitioners on the utility of these devices. A systematic review of studies that investigate the validity and/or reliability of commercially available devices that quantify kinetic and kinematic outputs during resistance training. Following PRISMA guidelines, a systematic search of SPORTDiscus, Web of Science, and Medline was performed; studies included were (1) original research investigations; (2) full-text articles written in English; (3) published in a peer-reviewed academic journal; and (4) assessed the validity and/or reliability of commercially available portable devices that quantify resistance training exercises. A total of 129 studies were retrieved, of which 47 were duplicates. The titles and abstracts of 82 studies were screened and the full text of 40 manuscripts were assessed. A total of 31 studies met the inclusion criteria. Additional 13 studies, identified via reference list assessment, were included. Therefore, a total of 44 studies were included in this review. Most of the studies within this review did not utilise a gold-standard criterion measure when assessing validity. This has likely led to under or overreporting of error for certain devices. Furthermore, studies that have quantified intra-device reliability have often failed to distinguish between technological and biological variability which has likely altered the true precision of each device. However, it appears linear transducers which have greater accuracy and reliability compared to other forms of device. Future research should endeavour to utilise gold-standard criterion measures across a broader range of exercises (including weightlifting movements) and relative loads.


Elastic Properties of Nucleic Acids by Single-Molecule Force Spectroscopy.
We review the current knowledge on the use of single-molecule force spectroscopy techniques to extrapolate the elastic properties of nucleic acids. We emphasize the lesser-known elastic properties of single-stranded DNA. We discuss the importance of accurately determining the elastic response in pulling experiments, and we review the simplest models used to rationalize the experimental data as well as the experimental approaches used to pull single-stranded DNA. Applications used to investigate DNA conformational transitions and secondary structure formation are also highlighted. Finally, we provide an overview of the effects of salt and temperature and briefly discuss the effects of contour length and sequence dependence.


An 11-year-old girl with a left-ankle injury.
The following case is presented to illustrate the roentgenographic and clinical findings of a condition of interest to the orthopaedic surgeon. The initial history, physical findings, and roentgenographic examinations are found on this page. The final clinical and roentgenographic differential diagnoses are presented on the following pages.


Patient-reported experience of clinical care of osteogenesis imperfecta (OI) during the COVID-19 pandemic.
Research on the effects of the COVID-19 pandemic on people with rare diseases is limited. Few studies compare healthcare throughout the progression of the ongoing pandemic. To assess the impact of the pandemic on individuals with osteogenesis imperfecta across two consecutive years, understand what challenges were encountered, and analyse the experience of remote consultation. An initial survey was distributed following the first lockdown in August 2020, and a second survey in April 2021. The surveys explored four themes- effects on therapy, alternatives to consultation, effect on mental health, and perceived risks of COVID-19. In the 2020 survey, of the 110 respondents, 69 (63%) had at least one appointment delayed due to the lockdown, compared with 89 of the 124 respondents (72%) in 2021. Of the 110 respondents in 2020, 57 (52%) had a remote consultation, increasing to 92 of 124 (74%) in the follow-up survey. In the 2020 survey 63 of 91 respondents (69%) expressed anxiety due to lockdown, compared with 76 of 124 (61%) in 2021. The percentage of total respondents expressing a preference for remote consultation was 48% in 2020, increasing to 71% in 2021. The pandemic has had widespread effects on the mental and physical health of those with OI. These effects, alongside appointment delays, have increased as the pandemic progresses. Encouragingly, the increasing preference for remote consultation may indicate that this could be a viable long-lasting alternative to face-to-face appointments, especially for patients who previously traveled vast distances for specialist care.


Comparative ribosome profiling reveals extensive translational complexity in different Trypanosoma brucei life cycle stages.
While gene expression is a fundamental and tightly controlled cellular process that is regulated at multiple steps, the exact contribution of each step remains unknown in any organism. The absence of transcription initiation regulation for RNA polymerase II in the protozoan parasite Trypanosoma brucei greatly simplifies the task of elucidating the contribution of translation to global gene expression. Therefore, we have sequenced ribosome-protected mRNA fragments in T. brucei, permitting the genome-wide analysis of RNA translation and translational efficiency. We find that the latter varies greatly between life cycle stages of the parasite and ∼100-fold between genes, thus contributing to gene expression to a similar extent as RNA stability. The ability to map ribosome positions at sub-codon resolution revealed extensive translation from upstream open reading frames located within 5' UTRs and enabled the identification of hundreds of previously un-annotated putative coding sequences (CDSs). Evaluation of existing proteomics and genome-wide RNAi data confirmed the translation of previously un-annotated CDSs and suggested an important role for >200 of those CDSs in parasite survival, especially in the form that is infective to mammals. Overall our data show that translational control plays a prevalent and important role in different parasite life cycle stages of T. brucei.


Liquid biopsy in gastrointestinal stromal tumors: a novel approach.
The role of molecular analysis in the management of gastrointestinal stromal tumors (GIST) remains indisputable. To date, tumor tissue extracted from specimens obtained by surgical or biopsy procedures has been the only source of the tumor DNA required for the molecular and genomic assessment of cancer. However, tumor tissue sampling has several clinical limitations: for example, the invasiveness of these procedures precludes repeated sampling. Thus, it is possible to obtain only a static molecular picture of the disease, a picture that lacks the inter- and intra-metastatic molecular heterogeneity that characterizes most GIST. In contrast, circulating tumor DNA obtained from a patient's bloodstream, known as liquid biopsy, can theoretically overcome the limitations of tissue biopsies and provide the same molecular and genomic information. GIST are recognized as a paradigm of molecular biology among solid tumors. Although few but promising data on liquid biopsy in GIST have been accumulated to date, these tumors may provide the optimal field for application of this challenging approach.


Chemistry must respond to the crisis of transgression of planetary boundaries.
Recent assessments alarmingly indicate that many of the world's leading chemicals are transgressing one or more of the nine planetary boundaries, which define safe operating spaces within which humanity can continue to develop and thrive for generations to come. The unfolding crisis cannot be ignored and there is a once-in-a-century opportunity for chemistry - the science of transformation of matter - to make a critical difference to the future of people and planet. How can chemists contribute to meeting these challenges and restore stability and strengthen resilience to the planetary system that humanity needs for its survival? To respond to the wake-up call, three crucial steps are outlined: (1) urgently working to understand the nature of the looming threats, from a chemistry perspective; (2) harnessing the ingenuity and innovation that are central to the practice of chemistry to develop sustainable solutions; and (3) transforming chemistry itself, in education, research and industry, to re-position it as 'chemistry for sustainability' and lead the stewardship of the world's chemical resources. This will require conservation of material stocks in forms that remain available for use, through attention to circularity, as well as strengthening engagement in systems-based approaches to designing chemistry research and processes informed by convergent working with many other disciplines.


Ultrasound guidance for upper and lower limb blocks.
Peripheral nerve blocks can be performed using ultrasound guidance. It is not yet clear whether this method of nerve location has benefits over other existing methods. This review was originally published in 2009 and was updated in 2014. The objective of this review was to assess whether the use of ultrasound to guide peripheral nerve blockade has any advantages over other methods of peripheral nerve location. Specifically, we have asked whether the use of ultrasound guidance:1. improves success rates and effectiveness of regional anaesthetic blocks, by increasing the number of blocks that are assessed as adequate2. reduces the complications, such as cardiorespiratory arrest, pneumothorax or vascular puncture, associated with the performance of regional anaesthetic blocks In the 2014 update we searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 8); MEDLINE (July 2008 to August 2014); EMBASE (July 2008 to August 2014); ISI Web of Science (2008 to April 2013); CINAHL (July 2014); and LILACS (July 2008 to August 2014). We completed forward and backward citation and clinical trials register searches.The original search was to July 2008. We reran the search in May 2015. We have added 11 potential new studies of interest to the list of 'Studies awaiting classification' and will incorporate them into the formal review findings during future review updates. We included randomized controlled trials (RCTs) comparing ultrasound-guided peripheral nerve block of the upper and lower limbs, alone or combined, with at least one other method of nerve location. In the 2014 update, we excluded studies that had given general anaesthetic, spinal, epidural or other nerve blocks to all participants, as well as those measuring the minimum effective dose of anaesthetic drug. This resulted in the exclusion of five studies from the original review. Two authors independently assessed trial quality and extracted data. We used standard Cochrane methodological procedures, including an assessment of risk of bias and degree of practitioner experience for all studies. We included 32 RCTs with 2844 adult participants. Twenty-six assessed upper-limb and six assessed lower-limb blocks. Seventeen compared ultrasound with peripheral nerve stimulation (PNS), and nine compared ultrasound combined with nerve stimulation (US + NS) against PNS alone. Two studies compared ultrasound with anatomical landmark technique, one with a transarterial approach, and three were three-arm designs that included US, US + PNS and PNS.There were variations in the quality of evidence, with a lack of detail in many of the studies to judge whether randomization, allocation concealment and blinding of outcome assessors was sufficient. It was not possible to blind practitioners and there was therefore a high risk of performance bias across all studies, leading us to downgrade the evidence for study limitations using GRADE. There was insufficient detail on the experience and expertise of practitioners and whether experience was equivalent between intervention and control.We performed meta-analysis for our main outcomes. We found that ultrasound guidance produces superior peripheral nerve block success rates, with more blocks being assessed as sufficient for surgery following sensory or motor testing (Mantel-Haenszel (M-H) odds ratio (OR), fixed-effect 2.94 (95% confidence interval (CI) 2.14 to 4.04); 1346 participants), and fewer blocks requiring supplementation or conversion to general anaesthetic (M-H OR, fixed-effect 0.28 (95% CI 0.20 to 0.39); 1807 participants) compared with the use of PNS, anatomical landmark techniques or a transarterial approach. We were not concerned by risks of indirectness, imprecision or inconsistency for these outcomes and used GRADE to assess these outcomes as being of moderate quality. Results were similarly advantageous for studies comparing US + PNS with NS alone for the above outcomes (M-H OR, fixed-effect 3.33 (95% CI 2.13 to 5.20); 719 participants, and M-H OR, fixed-effect 0.34 (95% CI 0.21 to 0.56); 712 participants respectively). There were lower incidences of paraesthesia in both the ultrasound comparison groups (M-H OR, fixed-effect 0.42 (95% CI 0.23 to 0.76); 471 participants, and M-H OR, fixed-effect 0.97 (95% CI 0.30 to 3.12); 178 participants respectively) and lower incidences of vascular puncture in both groups (M-H OR, fixed-effect 0.19 (95% CI 0.07 to 0.57); 387 participants, and M-H OR, fixed-effect 0.22 (95% CI 0.05 to 0.90); 143 participants). There were fewer studies for these outcomes and we therefore downgraded both for imprecision and paraesthesia for potential publication bias. This gave an overall GRADE assessment of very low and low for these two outcomes respectively. Our analysis showed that it took less time to perform nerve blocks in the ultrasound group (mean difference (MD), IV, fixed-effect -1.06 (95% CI -1.41 to -0.72); 690 participants) but more time to perform the block when ultrasound was combined with a PNS technique (MD, IV, fixed-effect 0.76 (95% CI 0.55 to 0.98); 587 participants). With high levels of unexplained statistical heterogeneity, we graded this outcome as very low quality. We did not combine data for other outcomes as study results had been reported using differing scales or with a combination of mean and median data, but our interpretation of individual study data favoured ultrasound for a reduction in other minor complications and reduction in onset time of block and number of attempts to perform block. There is evidence that peripheral nerve blocks performed by ultrasound guidance alone, or in combination with PNS, are superior in terms of improved sensory and motor block, reduced need for supplementation and fewer minor complications reported. Using ultrasound alone shortens performance time when compared with nerve stimulation, but when used in combination with PNS it increases performance time.We were unable to determine whether these findings reflect the use of ultrasound in experienced hands and it was beyond the scope of this review to consider the learning curve associated with peripheral nerve blocks by ultrasound technique compared with other methods.


Determinants of judgment and decision making quality: the interplay between information processing style and situational factors.
A framework is presented to better characterize the role of individual differences in information processing style and their interplay with contextual factors in determining decision making quality. In Experiment 1, we show that individual differences in information processing style are flexible and can be modified by situational factors. Specifically, a situational manipulation that induced an analytical mode of thought improved decision quality. In Experiment 2, we show that this improvement in decision quality is highly contingent on the compatibility between the dominant thinking mode and the nature of the task. That is, encouraging an intuitive mode of thought led to better performance on an intuitive task but hampered performance on an analytical task. The reverse pattern was obtained when an analytical mode of thought was encouraged. We discuss the implications of these results for the assessment of decision making competence, and suggest practical directions to help individuals better adjust their information processing style to the situation at hand and make optimal decisions.


Tracheal allotransplantation after withdrawal of immunosuppressive therapy.
Reconstruction of long-segment tracheal defects requires a vascularized allograft. We report successful tracheal allotransplantation after indirect revascularization of the graft in a heterotopic position. Immunosuppressive therapy was administered before the operation, and the tracheal allograft was wrapped in the recipient's forearm fascia. Once revascularization was achieved, the mucosal lining was replaced progressively with buccal mucosa from the recipient. At 4 months, the tracheal chimera was fully lined with mucosa, which consisted of respiratory epithelium from the donor and buccal mucosa from the recipient. After withdrawal of immunosuppressive therapy, the tracheal allograft was moved to its correct anatomical position with an intact blood supply. No treatment-limiting adverse effects occurred.


Metastability in an open quantum Ising model.
We apply a recently developed theory for metastability in open quantum systems to a one-dimensional dissipative quantum Ising model. Earlier results suggest this model features either a nonequilibrium phase transition or a smooth but sharp crossover, where the stationary state changes from paramagnetic to ferromagnetic, accompanied by strongly intermittent emission dynamics characteristic of first-order coexistence between dynamical phases. We show that for a range of parameters close to this transition or crossover point the dynamics of the finite system displays pronounced metastability, i.e., the system relaxes first to long-lived metastable states before eventual relaxation to the true stationary state. From the spectral properties of the quantum master operator we characterize the low-dimensional manifold of metastable states, which are shown to be probability mixtures of two, paramagnetic and ferromagnetic, metastable phases. We also show that for long times the dynamics can be approximated by a classical stochastic dynamics between the metastable phases that is directly related to the intermittent dynamics observed in quantum trajectories and thus the dynamical phases.


Racial/Ethnic disparities in ART adherence in the United States: findings from the MACH14 study.
Minority race/ethnicity is generally associated with antiretroviral therapy nonadherence in US-based studies. Limitations of the existing literature include small samples, subjective adherence measures, and inadequate control for potential confounders such as mental health and substance use, which have been consistently associated with poorer adherence. Individual-level data were pooled from 13 US-based studies employing electronic drug monitoring to assess adherence. Adherence was operationalized as percent of prescribed doses taken from the first 12 (monthly) waves of data in each study. Depression symptoms were aggregated from several widely used assessments, and substance use was operationalized as any use of cocaine/stimulants, heroin/opiates, ecstasy, hallucinogens, or sedatives in the 30-365 days preceding baseline. The final analytic sample of 1809 participants ranged in age from 18 to 72 years and was 67% male. Participants were 53% African American, 14% Latino, and 34% White. In a logistic regression adjusting for age, gender, income, education, and site, race/ethnicity was significantly associated with adherence (P < 0.001) and persisted in a model that also controlled for depression and substance use (P < 0.001), with African Americans having significantly lower adherence than Latinos [odds ratio (OR) = 0.72, P = 0.04] and whites (OR = 0.60, P < 0.001). Adherence did not differ between whites and Latinos (OR = 0.84, P = 0.27). Racial/ethnic differences in demographics, depression, and substance abuse do not explain the lower level of antiretroviral therapy adherence in African Americans observed in our sample. Further research is needed to explain the persistent disparity and might examine factors such as mistrust of providers, health literacy, and inequities in the health care system.


Cell Death-Associated Ribosomal RNA Cleavage in Postmortem Tissues and Its Forensic Applications.
Estimation of postmortem interval (PMI) is a key issue in the field of forensic pathology. With the availability of quantitative analysis of RNA levels in postmortem tissues, several studies have assessed the postmortem degradation of constitutively expressed RNA species to estimate PMI. However, conventional RNA quantification as well as biochemical and physiological changes employed thus far have limitations related to standardization or normalization. The present study focuses on an interesting feature of the subdomains of certain RNA species, in which they are site-specifically cleaved during apoptotic cell death. We found that the D8 divergent domain of ribosomal RNA (rRNA) bearing cell death-related cleavage sites was rapidly removed during postmortem RNA degradation. In contrast to the fragile domain, the 5' terminal region of 28S rRNA was remarkably stable during the postmortem period. Importantly, the differences in the degradation rates between the two domains in mammalian 28S rRNA were highly proportional to increasing PMI with a significant linear correlation observed in mice as well as human autopsy tissues. In conclusion, we demonstrate that comparison of the degradation rates between domains of a single RNA species provides quantitative information on postmortem degradation states, which can be applied for the estimation of PMI.


Emergence of the Zoonotic Biliary Trematode Pseudamphistomum truncatum in Grey Seals (Halichoerus grypus) in the Baltic Sea.
The biliary trematode Pseudamphistomum truncatum parasitizes a wide range of fish-eating mammals, including humans. Here we report the emergence of this parasite in grey seals (Halichoerus grypus) in the Baltic Sea. One hundred eighty-three of 1 554 grey seals (11.9%) examined from 2002-2013 had detectable hepatobiliary trematode infection. Parasite identification was confirmed as P. truncatum by sequencing the ITS2 region of a pool of five to 10 trematodes from each of ten seals collected off the coast of seven different Swedish counties. The proportion of seals parasitized by P. truncatum increased significantly over time and with increasing age of seals. Males were 3.1 times more likely to be parasitized than females and animals killed in fishery interactions were less likely to be parasitized than animals found dead or hunted. There was no significant difference in parasitism of seals examined from the Gulf of Bothnia versus those examined from the Baltic Proper. Although the majority of infections were mild, P. truncatum can cause severe hepatobiliary disease and resulted in liver failure in at least one seal. Because cyprinid fish are the second intermediate host for opisthorchiid trematodes, diets of grey seals from the Baltic Sea were analysed regarding presence of cyprinids. The proportion of gastrointestinal tracts containing cyprinid remains was ten times higher in seals examined from 2008 to 2013 (12.2%) than those examined from 2002 to 2007 (1.2%) and coincided with a general increase of trematode parasitism in the host population. The emergence and relatively common occurrence of P. truncatum in grey seals signals the presence of this parasite in the Baltic Sea ecosystem and demonstrates how aquatic mammals can serve as excellent sentinels of marine ecosystem change. Investigation of drivers behind P. truncatum emergence and infection risk for other mammals, including humans, is highly warranted.


Historical influence on the practice of chiropractic radiology: part II - thematic analysis on the opinions of diplomates of the American Chiropractic College of Radiology about the future.
Over the past 20 years, various authors have addressed the question of the future of chiropractic. Most were positive about the future, with some advocating evidence-based practice and integration with mainstream healthcare, some advocating continued separation with an emphasis on subluxation-based care or the traditional/historical paradigm of chiropractic, and some calling for tolerance and unity. No papers were found specifically inquiring about the future of chiropractic radiology. The study population consisted of all current members of the American Chiropractic College of Radiology (ACCR), estimated at 190 people, known as chiropractic radiologists or Diplomates of the American Chiropractic Board of Radiology (DACBRs). An internet-based, anonymous survey using SurveyMonkey was implemented, supplemented by hard copies distributed at a conference. The main point of interest for this paper is the final item of the overall questionnaire. This item inquired about the future of chiropractic radiology. Thematic analysis was used on the responses, coded in both constructionist and inductive ways to extract both a general outlook and more specific themes. The inductive themes were also assigned secondarily to a SWOT (strengths, weaknesses, opportunities, and threats) analysis. The overall response rate to the survey was 38% (73/190); within the group of respondents, 71 of 73 (98%) answered the item that is the subject of this paper. Opinions on the outlook for chiropractic radiology in the future were more negative than positive, with 14 respondents giving a positive outlook, 26 negative, and 14 non-committal. 28 respondents advocated integration with the wider healthcare community, 11 recommended emphasising separateness or a focus on working within chiropractic, and 15 did not express an opinion on this issue. Ten strengths were noted, 11 weaknesses, 57 opportunities, and 30 threats. The increasing necessity of demonstrating evidence for diagnostic and therapeutic procedures in healthcare makes it likely that chiropractic radiologists and the wider chiropractic profession will need to take a more active position on evidence-based practice. Re-evaluation of guidelines and legislation as well as enforcement policies and practices will be necessary. The consequences of failing to do so may include increased marginalisation and reduced viability as a profession.


Global change pressures on soils from land use and management.
Soils are subject to varying degrees of direct or indirect human disturbance, constituting a major global change driver. Factoring out natural from direct and indirect human influence is not always straightforward, but some human activities have clear impacts. These include land-use change, land management and land degradation (erosion, compaction, sealing and salinization). The intensity of land use also exerts a great impact on soils, and soils are also subject to indirect impacts arising from human activity, such as acid deposition (sulphur and nitrogen) and heavy metal pollution. In this critical review, we report the state-of-the-art understanding of these global change pressures on soils, identify knowledge gaps and research challenges and highlight actions and policies to minimize adverse environmental impacts arising from these global change drivers. Soils are central to considerations of what constitutes sustainable intensification. Therefore, ensuring that vulnerable and high environmental value soils are considered when protecting important habitats and ecosystems, will help to reduce the pressure on land from global change drivers. To ensure that soils are protected as part of wider environmental efforts, a global soil resilience programme should be considered, to monitor, recover or sustain soil fertility and function, and to enhance the ecosystem services provided by soils. Soils cannot, and should not, be considered in isolation of the ecosystems that they underpin and vice versa. The role of soils in supporting ecosystems and natural capital needs greater recognition. The lasting legacy of the International Year of Soils in 2015 should be to put soils at the centre of policy supporting environmental protection and sustainable development.


Prospective study of oral anticoagulants and risk of liver injury in patients with atrial fibrillation.
To assess the risk of liver injury hospitalisation in patients with atrial fibrillation (AF) after initiation of direct oral anticoagulants (DOACs) or warfarin and to determine predictors of liver injury hospitalisation in this population. We studied 113 717 patients (mean age 70, 39% women) with AF included in the MarketScan Commercial and Medicare Supplemental databases with a first prescription for oral anticoagulation after 4 November 2011, followed through 31 December 2014. Of these, 56 879 initiated warfarin, 17 286 initiated dabigatran, 30 347 initiated rivaroxaban and 9205 initiated apixaban. Liver injury hospitalisation and comorbidities were identified from healthcare claims. During a median follow-up of 12 months, 960 hospitalisations with liver injury were identified. Rates of liver injury hospitalisation (per 1000 person-years) by oral anticoagulant were 9.0 (warfarin), 4.0 (dabigatran), 6.6 (rivaroxaban) and 5.6 (apixaban). After multivariable adjustment, liver injury hospitalisation rates were lower in initiators of DOACs compared with warfarin: HR (95% CI) of 0.57 (0.46 to 0.71), 0.88 (0.75 to 1.03) and 0.70 (0.50 to 0.97) for initiators of dabigatran, rivaroxaban, and apixaban, respectively (vs. warfarin). Compared with dabigatran initiators, rivaroxaban initiators had a 56% increased risk of liver injury hospitalisation (HR 1.56, 95% CI 1.22 to 1.99). In addition to type of anticoagulant, prior liver, gallbladder and kidney disease, cancer, anaemia, heart failure and alcoholism significantly predicted liver injury hospitalisation. A predictive model including these variables had adequate discriminative ability (C-statistic 0.67, 95% CI 0.64 to 0.70). Among patients with non-valvular AF, DOACs were associated with lower risk of liver injury hospitalisation compared with warfarin, with dabigatran showing the lowest risk.


Smaller than a nanoparticle with the design of discrete polynuclear molecular complexes displaying near-infrared to visible upconversion.
This work shows that the operation of near-infrared to visible light-upconversion in a discrete molecule is not limited to non-linear optical processes, but may result from superexcitation processes using linear optics. The design of nine-coordinate metallic sites made up of neutral N-heterocyclic donor atoms in kinetically inert dinuclear [GaEr(L1)(3)](6+) and trinuclear [GaErGa(L2)(3)](9+) helicates leads to [ErN(9)] chromophores displaying unprecedented dual visible nanosecond Er((4)S(3/2)→(4)I15/2) and near-infrared microsecond Er((4)I(13/2)→(4)I1(5/2)) emissive components. Attempts to induce one ion excited-state absorption (ESA) upconversion upon near-infrared excitation of these complexes failed because of the too-faint Er-centred absorption cross sections. The replacement of the trivalent gallium cation with a photophysically-tailored pseudo-octahedral [CrN(6)] chromophore working as a sensitizer for trivalent erbium in [CrEr(L1)(3)](6+) improves the near-infrared excitation efficiency, leading to the observation of a weak energy transfer upconversion (ETU). The connection of a second sensitizer in [CrErCr(L2)(3)](9+) generates a novel mechanism for upconversion, in which the superexcitation process is based on the Cr(III)-sensitizers. Two successive Cr→Er energy transfer processes (concerted-ETU) compete with a standard Er-centred ETU, and a gain in upconverted luminescence by a factor larger than statistical values is predicted and observed.


Evaluating meta-ethnography: a synthesis of qualitative research on lay experiences of diabetes and diabetes care.
Interest in how qualitative health research might be used more widely to inform health policy and medical practice is growing. Synthesising findings from individual qualitative studies may be one method but application of conventional systematic review methodology to qualitative research presents significant philosophical and practical challenges. The aim here was to examine the feasibility of synthesising qualitative research using qualitative methodology including a formative evaluation of criteria for assessing the research to be synthesised. Ten qualitative studies of adult patients' perspectives of diabetes were purposefully selected and questions proposed by the critical appraisal skills programme (CASP) adapted and used to assess papers prior to synthesis. Each study was reviewed independently by two experienced social scientists. The level of agreement between reviewers was determined. Three papers were excluded: one because it turned out not to be qualitative research, one because the quality of the empirical work was poor and one because the qualitative findings reported were also recorded in another paper already included. The synthesis, which had two distinct elements, was conducted using the meta-ethnographic method. Firstly, four papers containing typologies of patient responses to diabetes were synthesised. Secondly, six key concepts were identified from all seven papers as being important in enabling a person with diabetes to achieve a balance in their lives and to attain a sense of well-being and control. These included: time and experience, trust in self, a less subservient approach to care providers, strategic non-compliance with medication, effective support from care providers and an acknowledgement that diabetes is serious. None of the studies included in the synthesis referenced any of the early papers nor did they appear to have taken account of or built upon previous findings. This evaluation confirmed that meta-ethnography can lead to a synthesis and extension of qualitative research in a defined field of study. In addition, from it a practical method of qualitative research assessment evolved. This process is promising but requires further testing and evaluation before it could be recommended for more widespread adoption.


Reduced cancer mortality at high altitude: The role of glucose, lipids, iron and physical activity.
Residency at high altitude (HA) demands adaptation to challenging environmental conditions with hypobaric hypoxia being the most important one. Epidemiological and experimental data suggest that chronic exposure to HA reduces cancer mortality and lowers prevalence of metabolic disorders like diabetes and obesity implying that adaption to HA modifies a broad spectrum of physiological, metabolic and cellular programs with a generally beneficial outcome for humans. However, the complexity of multiple, potentially tumor-suppressive pathways at HA impedes the understanding of mechanisms leading to reduced cancer mortality. Many adaptive processes at HA are tightly interconnected and thus it cannot be ruled out that the entirety or at least some of the HA-related alterations act in concert to reduce cancer mortality. In this review we discuss tumor formation as a concept of competition between healthy and cancer cells with improved fitness - and therefore higher competitiveness - of healthy cells at high altitude. We discuss HA-related changes in glucose, lipid and iron metabolism that may have an impact on tumorigenesis. Additionally, we discuss two parameters with a strong impact on tumorigenesis, namely drug metabolism and physical activity, to underpin their potential contribution to HA-dependent reduced cancer mortality. Future studies are needed to unravel why cancer mortality is reduced at HA and how this knowledge might be used to prevent and to treat cancer patients.


The relationship among strength and mobility measures and self-report outcome scores in persons after rotator cuff repair surgery: impairment measures are not enough.
In the past, measures of active range of motion and strength testing were deemed sufficient to "prove" the efficacy of treatment interventions. In the current outcomes milieu, however, the focus has shifted to patient-centered assessment (ie, patients' ability to perform activities that are personally relevant). We report results from a study with patients in the private practice of a shoulder surgeon. In this study we evaluated the relationship between impairment measures and scores from several shoulder outcome scales. In addition, we examined transcripts of interviews with shoulder patients regarding the impact of shoulder problems on their lives. One hundred eight persons participated in a randomized trial of home exercise instruction after arthroscopic repair of rotator cuff tears. Two impairment measures were used-strength estimates obtained by use of a Nicholas electronic dynamometer and range of motion in the standing position. Self- reported outcomes were measured by use of the Shoulder Pain and Disability Index (SPADI) and the University of Pennsylvania (UPenn) Shoulder Scale. Pearson correlation coefficients were calculated to estimate the associations between scores on impairment measures and self-report measures. R 2 values were calculated to estimate the proportion of variance shared by impairment and self-report scores. We found that the linear relationship between impairment scores and patient-reported outcomes was quite low, explaining as little as 8% of the total variance. Qualitative analysis of patient interviews suggests that patients distinguish between their impairment and their status on personally relevant outcomes. Future research should evaluate the nature of patient judgments of shoulder health outcomes.


Benefits and harms of CT screening for lung cancer: a systematic review.
Lung cancer is the leading cause of cancer death. Most patients are diagnosed with advanced disease, resulting in a very low 5-year survival. Screening may reduce the risk of death from lung cancer. To conduct a systematic review of the evidence regarding the benefits and harms of lung cancer screening using low-dose computed tomography (LDCT). A multisociety collaborative initiative (involving the American Cancer Society, American College of Chest Physicians, American Society of Clinical Oncology, and National Comprehensive Cancer Network) was undertaken to create the foundation for development of an evidence-based clinical guideline. MEDLINE (Ovid: January 1996 to April 2012), EMBASE (Ovid: January 1996 to April 2012), and the Cochrane Library (April 2012). Of 591 citations identified and reviewed, 8 randomized trials and 13 cohort studies of LDCT screening met criteria for inclusion. Primary outcomes were lung cancer mortality and all-cause mortality, and secondary outcomes included nodule detection, invasive procedures, follow-up tests, and smoking cessation. Critical appraisal using predefined criteria was conducted on individual studies and the overall body of evidence. Differences in data extracted by reviewers were adjudicated by consensus. Three randomized studies provided evidence on the effect of LDCT screening on lung cancer mortality, of which the National Lung Screening Trial was the most informative, demonstrating that among 53,454 participants enrolled, screening resulted in significantly fewer lung cancer deaths (356 vs 443 deaths; lung cancer−specific mortality, 274 vs 309 events per 100,000 person-years for LDCT and control groups, respectively; relative risk, 0.80; 95% CI, 0.73-0.93; absolute risk reduction, 0.33%; P = .004). The other 2 smaller studies showed no such benefit. In terms of potential harms of LDCT screening, across all trials and cohorts, approximately 20% of individuals in each round of screening had positive results requiring some degree of follow-up, while approximately 1% had lung cancer. There was marked heterogeneity in this finding and in the frequency of follow-up investigations, biopsies, and percentage of surgical procedures performed in patients with benign lesions. Major complications in those with benign conditions were rare. Low-dose computed tomography screening may benefit individuals at an increased risk for lung cancer, but uncertainty exists about the potential harms of screening and the generalizability of results.


Risk factors for skin, mucosal, and organ bleeding in adults with primary ITP: a nationwide study in Japan.
Bleeding manifestations in primary immune thrombocytopenia (ITP) range from skin petechiae to life-threatening intracranial hemorrhage (ICH). However, the relation between these various bleeding manifestations and the platelet count in ITP remains poorly characterized. Using a nationwide database of patients with ITP during the years 2005 to 2014 (10 years) in Japan, we analyzed 19 415 adult patients newly diagnosed with ITP, including 222 with ICH. The frequency of skin purpura was 64.8%, and this increased linearly with thrombocytopenia without a specific platelet count threshold. In contrast, mucosal bleeding (epistaxis and gingival bleeding) and organ bleeding (melena, hematuria, and ICH) increased exponentially with thrombocytopenia at a platelet count threshold of 10 to 15 × 109/L. Age showed a much weaker correlation than platelet count with skin and mucosal bleeding. However, the incidence of organ bleeding increased exponentially above 60 years of age. Multivariate analysis showed that the presence of mucosal bleeding was a risk factor for occurrence of melena and hematuria but not for ICH. The frequency of ICH was 1.1% and risk factors for ICH were age ≥60 years (odds ratio [OR], 3.09; 95% confidence interval [CI], 2.13-4.47; P < .001), platelet count <10 × 109/L (OR, 2.96; 95% CI, 2.11-4.15; P < .001), and the presence of hematuria (OR, 1.56; 95% CI, 1.04-2.35; P = .033). The relation between ICH and platelet count varied with age. This large-scale analysis of risk factors for bleeding in ITP has revealed distinct characteristics of skin, mucosal, and organ bleeding in adult patients with newly diagnosed ITP, thus indicating those who are at a high risk of severe organ bleeding.