Synthetic Cannabinoid Use in a Psychiatric Patient Population: A Pilot Study.
Consumption of natural cannabis (NC) and synthetic cannabinoids (SCs) has been associated with psychotic disorders. We compared the prevalence of use, consumer profiles, and psychosis-inducing potential of NC and SCs in a specific high-risk population. This prospective pilot study included 332 patients (18-64 years, mean 36.83, SD 13.33). Patients' sociodemographics and medical histories as well as illicit substance use and psychiatric symptom histories were collected using a drug consumption survey that assessed the use of new psychoactive substances and the Psychotic Symptoms Interview. In total, 7.2% of all patients, 10.6% of psychotic patients, and 4.5% of nonpsychotic patients reported SC consumption. Compared with SCs, NC was consumed much more frequently by its users (mean 222.73, SD 498.27). NC and SC use induced persistent psychosis. Psychotic symptoms were first experienced by patients with a history of NC or SC use during intoxication and persisted after cessation (>1 year) of drug use. Positive and negative symptoms tended to be more severe in SC and NC users, respectively. NC and SCs may cause different symptom clusters. These relationships should be further evaluated.


Expression of N-cadherin by human squamous carcinoma cells induces a scattered fibroblastic phenotype with disrupted cell-cell adhesion.
E-cadherin is a transmembrane glycoprotein that mediates calcium-dependent, homotypic cell-cell adhesion and plays an important role in maintaining the normal phenotype of epithelial cells. Disruption of E-cadherin activity in epithelial cells correlates with formation of metastatic tumors. Decreased adhesive function may be implemented in a number of ways including: (a) decreased expression of E-cadherin; (b) mutations in the gene encoding E-cadherin; or (c) mutations in the genes that encode the catenins, proteins that link the cadherins to the cytoskeleton and are essential for cadherin mediated cell-cell adhesion. In this study, we explored the possibility that inappropriate expression of a nonepithelial cadherin by an epithelial cell might also result in disruption of cell-cell adhesion. We showed that a squamous cell carcinoma-derived cell line expressed N-cadherin and displayed a scattered fibroblastic phenotype along with decreased expression of E- and P-cadherin. Transfection of this cell line with antisense N-cadherin resulted in reversion to a normal-appearing squamous epithelial cell with increased E- and P-cadherin expression. In addition, transfection of a normal-appearing squamous epithelial cell line with N-cadherin resulted in downregulation of both E- and P-cadherin and a scattered fibroblastic phenotype. In all cases, the levels of expression of N-cadherin and E-cadherin were inversely related to one another. In addition, we showed that some squamous cell carcinomas expressed N-cadherin in situ and those tumors expressing N-cadherin were invasive. These studies led us to propose a novel mechanism for tumorigenesis in squamous epithelial cells; i.e., inadvertent expression of a nonepithelial cadherin.


Five year cost savings of a multimodal treatment program for child sexual abuse (CSA): a social return on investment study.
Specialized mental health services for the treatment of Child Sexual Abuse (CSA) are generally expensive and labour intensive. They require a trauma-informed approach that may involve multiple services and therapeutic modalities, provided over the course of several months. That said, given the broad-ranging, long term negative sequelae of CSA, an evaluation of the cost-benefit analysis of treatment is clearly justified. We performed a Social Return on Investment (SROI) analysis of data gathered as part of the treatment program at the Be Brave Ranch in Edmonton, Canada to determine the value-for-money of the services provided. We endeavoured to take a conservative, medium-term (5 year) perspective; this is in contrast to short term (1-2 year) effects, which may rapidly dissipate, or long term (15-20 year) effects, which are likely diffuse and difficult to measure. As such, our analysis was based on an average annual intake of 100 children/adolescents (60:40 split) and their families, followed over a five-year timeframe. Financial proxies were assigned to benefits not easily monetized, and six potential domains of cost savings were identified. Our analyses suggest that each dollar spent in treatment results in an average cost savings of $11.60 (sensitivity analysis suggests range of 9.20-12.80). The largest value-for-money was identified as the domain of crisis prevention, via the avoidance of rare but costly events associated with the long term impacts of CSA. Somewhat surprisingly, savings related to the area of criminal justice were minimal, compared to other social domains analysed. Implications are discussed. Our results support the cost effectiveness of the investment associated with specialized, evidence-based early interventions for CSA. These approaches alleviate severe, negative outcomes associated with CSA, resulting in both economic savings and social benefits. These findings rest upon a number of assumptions, and generalizability of these results is therefore limited to similar programs located in comparable areas. However, the SROI ratio achieved in this analysis, in excess of $11:1, supports the idea that, while costly, these services more than pay for themselves over time.


Virtual ellipsometry on layered micro-facet surfaces.
Microfacet-based BRDF models are a common tool to describe light scattering from glossy surfaces. Apart from their wide-ranging applications in optics, such models also play a significant role in computer graphics for photorealistic rendering purposes. In this paper, we mainly investigate the computer graphics aspect of this technology, and present a polarisation-aware brute force simulation of light interaction with both single and multiple layered micro-facet surfaces. Such surface models are commonly used in computer graphics, but the resulting BRDF is ultimately often only approximated. Recently, there has been work to try to make these approximations more accurate, and to better understand the behaviour of existing analytical models. However, these brute force verification attempts still emitted the polarisation state of light and, as we found out, this renders them prone to mis-estimating the shape of the resulting BRDF lobe for some particular material types, such as smooth layered dielectric surfaces. For these materials, non-polarising computations can mis-estimate some areas of the resulting BRDF shape by up to 23%. But we also identified some other material types, such as dielectric layers over rough conductors, for which the difference turned out to be almost negligible. The main contribution of our work is to clearly demonstrate that the effect of polarisation is important for accurate simulation of certain material types, and that there are also other common materials for which it can apparently be ignored. As this required a BRDF simulator that we could rely on, a secondary contribution is that we went to considerable lengths to validate our software. We compare it against a state-of-art model from graphics, a library from optics, and also against ellipsometric measurements of real surface samples.


Clustered burst firing in FMR1 premutation hippocampal neurons: amelioration with allopregnanolone.
Premutation CGG repeat expansions (55-200 CGG repeats; preCGG) within the fragile X mental retardation 1 (FMR1) gene cause fragile X-associated tremor/ataxia syndrome (FXTAS). Defects in neuronal morphology and migration have been described in a preCGG mouse model. Mouse preCGG hippocampal neurons (170 CGG repeats) grown in vitro develop abnormal networks of clustered burst (CB) firing, as assessed by multielectrode array recordings and clustered patterns of spontaneous Ca(2+) oscillations, neither typical of wild-type (WT) neurons. PreCGG neurons have reduced expression of vesicular GABA and glutamate (Glu) transporters (VGAT and VGLUT1, respectively), and preCGG hippocampal astrocytes display a rightward shift on Glu uptake kinetics, compared with WT. These alterations in preCGG astrocytes and neurons are associated with 4- to 8-fold elevated Fmr1 mRNA and occur despite consistent expression of fragile X mental retardation protein levels at ∼50% of WT levels. Abnormal patterns of activity observed in preCGG neurons are pharmacologically mimicked in WT neurons by addition of Glu or the mGluR1/5 agonist, dihydroxyphenylglycine, to the medium, or by inhibition of astrocytic Glu uptake with dl-threo-β-benzyloxyaspartic acid, but not by the ionotropic Glu receptor agonists, α-2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid or N-methyl-d-aspartic acid. The mGluR1 (7-(hydroxyimino)cyclopropa [b]chromen-1a-carboxylate ethyl ester) or mGluR5 (2-methyl-6-(phenylethynyl)pyridine hydrochloride) antagonists reversed CB firing. Importantly, the acute addition of the neurosteroid allopregnanolone mitigated functional impairments observed in preCGG neurons in a reversible manner. These results demonstrate abnormal mGluR1/5 signaling in preCGG neurons, which is ameliorated by mGluR1/5 antagonists or augmentation of GABA(A) receptor signaling, and identify allopregnanolone as a candidate therapeutic lead.


Food group intake of children and adolescents (6-18 years) on a vegetarian, vegan or omnivore diet: results of the VeChi Youth Study.
Plant-based, i.e. vegetarian (without meat and fish) or vegan (exclusively plant-based foods) diets are in trend also among children and adolescents, but data on food intake in this group are lacking. Here, we compare the consumption of food groups of vegetarian (n 145), vegan (n 110) and omnivore (n 135) children and adolescents (6-18 years) in Germany using data of the VeChi Youth Study. Each food item reported in 3 d weighed dietary records was assigned to one of eighteen food groups and individual mean intake per day (g/MJ) was calculated. Group differences were assessed using covariance analyses adjusted for age, sex and other covariates. For food groups with a high number of non-consumers, non-parametric Kruskal-Wallis tests were run. Pairwise comparison of vegetarian and vegan groups indicated significantly higher intakes of legumes, nuts, milk alternatives (all P = 0·0003) and meat alternatives (P = 0·0065) among vegan subjects. Intake of these food groups of omnivore participants was low (Q3:0·0 g/MJ for legumes, milk alternatives and meat alternatives, 0·5 g/MJ for nuts). Dairy intake of vegetarians (11·6 g/MJ) was significantly lower than of omnivore subjects (24·7 g/MJ) (P = 0·0003). Intake of fats/oils and sweet foods was lowest in vegan compared with vegetarian and omnivore participants (P< 0·05). Whole grain intake was higher in vegan participants (14·5 g/MJ) than of vegetarian (9·1 g/MJ) and omnivore (6·5 g/MJ) participants (P = 0·0003). Longitudinal studies are necessary to evaluate the long-term health consequences of vegetarian, vegan and omnivore food patterns, especially in childhood and adolescence.


The scoring of movements in sleep.
The International Classification of Sleep Disorders (ICSD-2) has separated sleep-related movement disorders into simple, repetitive movement disorders (such as periodic limb movements in sleep [PLMS], sleep bruxism, and rhythmic movement disorder) and parasomnias (such as REM sleep behavior disorder and disorders of partial arousal, e.g., sleep walking, confusional arousals, night terrors). Many of the parasomnias are characterized by complex behaviors in sleep that appear purposeful, goal directed and voluntary but are outside the conscious awareness of the individual and therefore inappropriate. All of the sleep-related movement disorders described here have specific polysomnographic findings. For the purposes of developing and/or revising specifications and polysomnographic scoring rules, the AASM Scoring Manual Task Force on Movements in Sleep reviewed background literature and executed evidence grading of 81 relevant articles obtained by a literature search of published articles between 1966 and 2004. Subsequent evidence grading identified limited evidence for reliability and/or validity for polysomnographic scoring criteria for periodic limb movements in sleep, REM sleep behavior disorder, and sleep bruxism. Published scoring criteria for rhythmic movement disorder, excessive fragmentary myoclonus, and hypnagogic foot tremor/alternating leg muscle activation were empirical and based on descriptive studies. The literature review disclosed no published evidence defining clinical consequences of excessive fragmentary myoclonus or hypnagogic foot tremor/alternating leg muscle activation. Because of limited or absent evidence for reliability and/or validity, a standardized RAND/UCLA consensus process was employed for recommendation of specific rules for the scoring of sleep-associated movements.


Microwave-assisted synthesis of hydroxyl-containing isoquinolines by metal-free radical cyclization of vinyl isocyanides with alcohols.
A convenient microwave-assisted protocol for the synthesis of hydroxyl-containing isoquinolines from a metal-free radical cyclization reaction of vinyl isonitriles with alcohols was developed with moderate-to-excellent yields. Vinyl isonitriles are coupled with alkyl radicals through direct catalytic functionalization of the α sp3 C-H bond of alcohols. The methodology demonstrates a broad substrate scope, shows excellent functional group tolerance, is highly atom-economical and highly efficient, thus enabling the preparation of diverse potentially valuable hydroxyl-containing isoquinolines.


Developmental changes in the transcriptome of human cerebral cortex tissue: long noncoding RNA transcripts.
The human neocortex is characterized by protracted developmental intervals of synaptogenesis and myelination, which allow for an extended period of learning. The molecular basis of these and other postnatal developmental changes in the human cerebral cortex remain incompletely understood. Recently, a new large class of mammalian genes, encoding nonmessenger, long nonprotein-coding ribonucleic acid (lncRNA) molecules has been discovered. Although their function remains uncertain, numerous lncRNAs have primate-specific sequences and/or show evidence of rapid, lineage-specific evolution, making them potentially relevant to the evolution of unique human neural properties. To examine the hypothesis that lncRNA expression varies with age, potentially paralleling known developmental trends in synaptogenesis, myelination, and energetics, we quantified levels of nearly 6000 lncRNAs in 36 surgically resected human neocortical samples (primarily derived from temporal cortex) spanning infancy to adulthood. Our analysis identified 8 lncRNA genes with distinct developmental expression patterns. These lncRNA genes contained anthropoid-specific exons, as well as splice sites and polyadenylation signals that resided in primate-specific sequences. To our knowledge, our study is the first to describe developmental expression profiles of lncRNA in surgically resected in vivo human brain tissue. Future analysis of the functional relevance of these transcripts to neural development and energy metabolism is warranted.


Dominant TEL1-hy mutations compensate for Mec1 lack of functions in the DNA damage response.
Eukaryotic genome integrity is safeguarded by two highly conserved protein kinases that are called ATR and ATM for humans and Mec1 and Tel1 for Saccharomyces cerevisiae. Although they share sequence similarities and substrates, these protein kinases perform different specialized functions. In particular, Mec1 plays a key role in the DNA damage checkpoint response, whereas Tel1 primarily is involved in telomere homeostasis, and its checkpoint function is masked by the prevailing activity of Mec1. In order to understand how this specificity is achieved, we searched for TEL1 mutations able to compensate for the lack of Mec1 functions. Here, we describe seven independent dominant TEL1-hy alleles that are able to suppress, to different extents, both the hypersensitivity to genotoxic agents and the checkpoint defects of Mec1-deficient cells. Most of these alleles also cause telomere overelongation. In vitro kinase activity was increased compared to that of wild-type Tel1 in the Tel1-hy385, Tel1-hy394, Tel1-hy680, and Tel1-hy909 variants, but its activity was not affected by the TEL1-hy184 and TEL1-hy628 mutations and was slightly reduced by the TEL1-hy544 mutation. Thus, the phenotypes caused by at least some Tel1-hy variants are not simply the consequence of improved catalytic activity. Further characterization shows that Tel1-hy909 not only can sense and signal a single double-stranded DNA break, unlike wild-type Tel1, but also contributes more efficiently than Tel1 to single-stranded DNA accumulation at double-strand ends, thus enhancing Mec1 signaling activity. Moreover, it causes unscheduled checkpoint activation in unperturbed conditions and upregulates the checkpoint response to small amounts of DNA lesions. Finally, Tel1-hy544 can activate the checkpoint more efficiently than wild-type Tel1, while it causes telomere shortening, indicating that the checkpoint and telomeric functions of Tel1 can be separable.


Examination of the source and extended virulence genotypes of Escherichia coli contaminating retail poultry meat.
Extraintestinal pathogenic Escherichia coli (ExPEC) are major players in human urinary tract infections, neonatal bacterial meningitis, and sepsis. Recently, it has been suggested that there might be a zoonotic component to these infections. To determine whether the E. coli contaminating retail poultry are possible extraintestinal pathogens, and to ascertain the source of these contaminants, they were assessed for their genetic similarities to E. coli incriminated in colibacillosis (avian pathogenic E. coli [APEC]), E. coli isolated from multiple locations of apparently healthy birds at slaughter, and human ExPEC. It was anticipated that the retail poultry isolates would most closely resemble avian fecal E. coli since only apparently healthy birds are slaughtered, and fecal contamination of carcasses is the presumed source of meat contamination. Surprisingly, this supposition proved incorrect, as the retail poultry isolates exhibited gene profiles more similar to APEC than to fecal isolates. These isolates contained a number of ExPEC-associated genes, including those associated with ColV virulence plasmids, and many belonged to the B2 phylogenetic group, known to be virulent in human hosts. Additionally, E. coli isolated from the crops and gizzards of apparently healthy birds at slaughter also contained a higher proportion of ExPEC-associated genes than did the avian fecal isolates examined. Such similarities suggest that the widely held beliefs about the sources of poultry contamination may need to be reassessed. Also, the presence of ExPEC-like clones on retail poultry meat means that we cannot yet rule out poultry as a source of ExPEC human disease.


Motion Segmentation & Multiple Object Tracking by Correlation Co-Clustering.
Models for computer vision are commonly defined either w.r.t. low-level concepts such as pixels that are to be grouped, or w.r.t. high-level concepts such as semantic objects that are to be detected and tracked. Combining bottom-up grouping with top-down detection and tracking, although highly desirable, is a challenging problem. We state this joint problem as a co-clustering problem that is principled and tractable by existing algorithms. We demonstrate the effectiveness of this approach by combining bottom-up motion segmentation by grouping of point trajectories with high-level multiple object tracking by clustering of bounding boxes. We show that solving the joint problem is beneficial at the low-level, in terms of the FBMS59 motion segmentation benchmark, and at the high-level, in terms of the Multiple Object Tracking benchmarks MOT15, MOT16 and the MOT17 challenge, and is state-of-the-art in some metrics.


Ribozyme-mediated down-regulation of ErbB-4 in estrogen receptor-positive breast cancer cells inhibits proliferation both in vitro and in vivo.
ErbB-4 is a recently discovered member of the class I receptor tyrosine kinase family (ErbB). Little is known about its expression and its importance in human malignancy. To delineate the biological function of ErbB-4 receptors in breast cancer, we used a hammerhead ribozyme strategy to achieve down-regulation of ErbB-4 receptors in various breast cancer cell lines. We observed that down-regulation of ErbB-4 in estrogen receptor-positive (ER+) human breast cancer cell lines (MCF-7 and T47D), which express relatively high levels of ErbB-4, significantly inhibited colony formation. No effects were observed in estrogen receptor-negative (ER-) MDA-MB-453 cells, which express low levels of endogenous ErbB4 and high levels of ErbB-2 and ErbB-3. This occurred despite the fact that fluorescence-activated cell sorter analysis of these latter cells revealed that the expression of the ErbB-4 receptor was completely abrogated by ribozyme treatment. Furthermore, down-regulation of ErbB-4 in T47D and MCF-7 cells significantly inhibited tumor formation in athymic nude mice (P < 0.03 and P < 0.001, respectively). In addition, NRG-stimulated phosphorylation of ErbB-4- and NRG-induced colony formation was significantly reduced in ribozyme-transfected T47D cells. These data provide the first evidence that elevation of ErbB-4 expression plays a role in the proliferation of some ER+ human breast cancer cell lines (T47D and MCF-7) that express high levels of ErbB-4. We have also investigated the expression of ErbB-4 in human primary breast carcinoma specimens, using immunohistochemical staining with an anti-ErbB-4 monoclonal antibody. ErbB-4 expression was found in 60% of the 50 primary breast tumors examined, and high intense immunoreactivity of ErbB-4 was detected in 18% of these primary breast tumors. ErbB-4 receptor expression appeared to correlate with ER+ primary breast tumors. A similar correlation was also observed in the human breast cancer cell lines. These results provide a better understanding of the biological significance of ErbB-4 receptor in breast cancer. Our data suggest that elevation of the ErbB-4 receptor plays a role in ER+ breast cancer cell proliferation. Moreover, ribozyme technology provides a useful tool to delineate the role of a particular gene product.


"People sometimes react funny if they're not told enough": women's views about the risks of diagnostic laparoscopy.
To explore women's views about the risks and benefits of diagnostic laparoscopy in the investigation of chronic pelvic pain, including how much information it is thought appropriate to give about three specific risks: death, major complications and the chance that the procedure would have an inconclusive result. A qualitative analysis of semi-structured, audio-taped interviews with 20 women about their experiences of undergoing a diagnostic laparoscopy in a day surgery unit. Interviews were conducted 3-6 months after the procedure. All the women who were interviewed were aware that diagnostic laparoscopy carried risks, including the small risk of death associated with general anaesthesia. One-third of respondents said that they had initially been reluctant to discuss the risks of the procedure in general terms. However, when specific examples of complications and risks were introduced all but one of the respondents reported that they would have liked to discuss these at the time that the decision to have the operation was made. Women maintained that the information was needed to make an informed decision about whether to have the operation, to help them understand and cope should things go wrong and in order to make appropriate plans to cover contingencies. Most were surprised to hear that the procedure is frequently inconclusive and thought that this information should be made clear to women contemplating a laparoscopy. Women undergoing diagnostic laparoscopy for the investigation of chronic pelvic pain wish to be given full and accurate information about complication rates such as bowel perforation, what to expect during their recovery, and the chances of finding a cause for their pain. Although they may not want to dwell on the risk of death, they do need to be informed about the specific risks associated with the procedure in order to make a balanced decision.


Speciation in ancient cryptic species complexes: evidence from the molecular phylogeny of Brachionus plicatilis (Rotifera).
Continental lake-dwelling zooplanktonic organisms have long been considered cosmopolitan species with little geographic variation in spite of the isolation of their habitats. Evidence of morphological cohesiveness and high dispersal capabilities support this interpretation. However, this view has been challenged recently as many such species have been shown either to comprise cryptic species complexes or to exhibit marked population genetic differentiation and strong phylogeographic structuring at a regional scale. Here we investigate the molecular phylogeny of the cosmopolitan passively dispersing rotifer Brachionus plicatilis (Rotifera: Monogononta) species complex using nucleotide sequence variation from both nuclear (ribosomal internal transcribed spacer 1, ITS1) and mitochondrial (cytochrome c oxidase subunit I, COI) genes. Analysis of rotifer resting eggs from 27 salt lakes in the Iberian Peninsula plus lakes from four continents revealed nine genetically divergent lineages. The high level of sequence divergence, absence of hybridization, and extensive sympatry observed support the specific status of these lineages. Sequence divergence estimates indicate that the B. plicatilis complex began diversifying many millions of years ago, yet has showed relatively high levels of morphological stasis. We discuss these results in relation to the ecology and genetics of aquatic invertebrates possessing dispersive resting propagules and address the apparent contradiction between zooplanktonic population structure and their morphological stasis.


Non-steroidal anti-inflammatory drugs and risk of first hospital admission for heart failure in the general population.
To estimate the risk of a first hospital admission for heart failure (HF) associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs). Cohort study with a nested case-control analysis based on the UK General Practice Research Database. Overall, 1396 cases of first hospital admission for non-fatal HF were identified (January 1997 to December 2000) and compared with a random sample of 5000 controls. The incidence rate was 2.7/1000 person years. Prior clinical diagnosis of HF was the main independent risk factor triggering a first HF hospitalisation (relative risk 7.3, 95% confidence interval (CI) 6.1 to 8.8). The risk of a first hospital admission for HF associated with current use of NSAIDs was 1.3 (95% CI 1.1 to 1.6) after controlling for major confounding factors. No effects of dose and duration were found. The relative risk in current users of NSAIDs with prior HF was 8.6 (95% CI 5.3 to 13.8) compared with patients who did not use NSAIDs and without prior clinical diagnosis of HF. Use of NSAIDs was associated with a small increase in risk of a first hospitalisation for HF. In patients with prior clinical diagnosis of HF, the use of NSAIDs may lead to worsening of pre-existing HF that triggers their hospital admission. This increased risk, although small, may result in considerable public health impact, particularly among the elderly.


Genital manifestations of tropical diseases.
Genital symptoms in tropical countries and among returned travellers can arise from a variety of bacterial, protozoal, and helminthic infections which are not usually sexually transmitted. The symptoms may mimic classic sexually transmitted infections (STIs) by producing ulceration (for example, amoebiasis, leishmaniasis), wart-like lesions (schistosomiasis), or lesions of the upper genital tract (epididymo-orchitis caused by tuberculosis, leprosy, and brucellosis; salpingitis as a result of tuberculosis, amoebiasis, and schistosomiasis). A variety of other genital symptoms less suggestive of STI are also seen in tropical countries. These include hydrocele (seen with filariasis), which can be no less stigmatising than STI, haemospermia (seen with schistosomiasis), and hypogonadism (which may occur in lepromatous leprosy). This article deals in turn with genital manifestations of filariasis, schistosomiasis, amoebiasis, leishmaniasis, tuberculosis and leprosy and gives clinical presentation, diagnosis, and treatment.


Machine learning models identify molecules active against the Ebola virus in vitro.
The search for small molecule inhibitors of Ebola virus (EBOV) has led to several high throughput screens over the past 3 years. These have identified a range of FDA-approved active pharmaceutical ingredients (APIs) with anti-EBOV activity in vitro and several of which are also active in a mouse infection model. There are millions of additional commercially-available molecules that could be screened for potential activities as anti-EBOV compounds. One way to prioritize compounds for testing is to generate computational models based on the high throughput screening data and then virtually screen compound libraries. In the current study, we have generated Bayesian machine learning models with viral pseudotype entry assay and the EBOV replication assay data. We have validated the models internally and externally. We have also used these models to computationally score the MicroSource library of drugs to select those likely to be potential inhibitors. Three of the highest scoring molecules that were not in the model training sets, quinacrine, pyronaridine and tilorone, were tested in vitro and had EC 50 values of 350, 420 and 230 nM, respectively. Pyronaridine is a component of a combination therapy for malaria that was recently approved by the European Medicines Agency, which may make it more readily accessible for clinical testing. Like other known antimalarial drugs active against EBOV, it shares the 4-aminoquinoline scaffold. Tilorone, is an investigational antiviral agent that has shown a broad array of biological activities including cell growth inhibition in cancer cells, antifibrotic properties, α7 nicotinic receptor agonist activity, radioprotective activity and activation of hypoxia inducible factor-1. Quinacrine is an antimalarial but also has use as an anthelmintic. Our results suggest data sets with less than 1,000 molecules can produce validated machine learning models that can in turn be utilized to identify novel EBOV inhibitors in vitro.


Percutaneous balloon catheter closure of a patent foramen ovale in a patient with pulmonary disease, profound hypoxemia, and normal right heart pressures.
Right-to-left intracardiac shunting across a patent foramen ovale (PFO) has been reported in patients with pulmonary embolism, right ventricular (RV) infarction, positive pressure ventilation with positive end-expiratory pressure, heart failure with left ventricular assist devices, cardiac tamponade, and unilateral diaphragmatic paralysis. The primary driving force for these shunts is a reduction in the compliance of the pulmonary bed or right ventricle; right atrial pressure is usually elevated and pulmonary hypertension is frequently present. Significant shunting and hypoxemia are unusual in the absence of these diseases. We encountered a patient with normal pulmonary pressures, severe hypoxemia, pulmonary disease, and intracardiac shunting across a PFO in whom it was difficult to determine how great a role intracardiac shunting was playing in his hypoxemia. To assess this, we performed percutaneous balloon catheter occlusion of the PFO, using transthoracic echocardiography with contrast to confirm closure of the PFO. Therapeutic balloon occlusion has been reported in severe hypoxemia due to shunting across a PFO in a patient with RV infarction. Our case is unique, however, in two respects. First, this patient had normal right-sided cardiac pressures and normal RV function and, thus, no obvious driving force for a significant right-to-left shunt. Second, transthoracic echocardiography with contrast was used before and after balloon inflation to confirm closure of the PFO. This technique helped to answer the important clinical question of whether surgical closure of the PFO in this patient with both lung disease and intracardiac shunting would significantly improve his oxygenation.


Modification of anisotropic plasma diffusion via auxiliary electrons emitted by a carbon nanotubes-based electron gun in an electron cyclotron resonance ion source.
The diffusion mechanism in magnetized plasmas is a largely debated issue. A short circuit model was proposed by Simon, assuming fluxes of lost particles along the axial (electrons) and radial (ions) directions which can be compensated, to preserve the quasi-neutrality, by currents flowing throughout the conducting plasma chamber walls. We hereby propose a new method to modify Simon's currents via electrons injected by a carbon nanotubes-based electron gun. We found this improves the source performances, increasing the output current for several charge states. The method is especially sensitive to the pumping frequency. Output currents for given charge states, at different auxiliary electron currents, will be reported in the paper and the influence of the frequency tuning on the compensation mechanism will be discussed.


Biliopancreatic diversion with transitory gastroplasty preserving duodenal bulb: 3 years experience.
The authors have performed 521 bariatric surgery operations (319 restrictive procedures and 202 malabsorptive procedures). During the last few years we have introduced an evolution of biliopancreatic diversion (BPD): BPD with transitory gastroplasty, preserving the duodenal bulb (53 cases). From a technical point of view, the operation consists of a BPD, coupled with a gastroplasty which is transitory due to the use of a polydioxanone (PDS) band. In the last few cases, instead of a VBG (with PDS band) in order to make the operation completely reversible without any suture on the stomach, we made a gastric pouch by banding with PDS calibrated with the same tube as for the Lap-band (20 cc). We maintained completely the duodenal bulb (5 cm from the pylorus), making an end-to-side duodeno-ileal isoperistaltic anastomosis. With this anastomosis, only 2% of patients developed an anastomotic ulcer. With this new procedure, results have been good in terms of weight loss (similar to that of BPD-AHS) and in nutritional complications. No patient has had hypoalbuminemia, diarrhea or halitosis. BPD with temporary gastric restriction has provided satisfactory results.


Neuropsychiatric predictors of progression from amnestic-mild cognitive impairment to Alzheimer's disease: the role of depression and apathy.
The aim of the study is to evaluate whether depression or apathy in patients with amnestic-mild cognitive impairment (MCI) increases the risk of progressing to Alzheimer's disease (AD). We investigated 131 consecutive memory-clinic outpatients with newly-diagnosed amnestic-MCI (mean age 70.8, SD=6.5). Psychiatric disorders were diagnosed at baseline according to the criteria for depression and apathy in AD. Neuropsychiatric symptoms were assessed with the Neuropsychiatric Inventory (NPI). Follow-up examinations were conducted after six months and annually for four years. Neurologists diagnosed AD at follow-up using NINCDS-ADRDA criteria. Cox proportional hazard models with 95% confidence intervals were used to test the hypothesis that apathy or depression increases the risk of developing AD. At baseline, 36.6% amnestic-MCI patients had a diagnosis of depression and 10.7% had apathy. Patients with both amnestic-MCI and an apathy diagnosis had an almost sevenfold risk of AD progression compared to amnestic-MCI patients without apathy (HR=6.9; 2.3-20.6), after adjustment for age, gender, education, baseline global cognitive and functional status, and depression. Furthermore, the risk of developing AD increased 30% per point on the NPI apathy item (HR=1.3; 1.1-1.4). There was no increased risk of developing AD in amnestic-MCI patients with either a diagnosis or symptoms of depression. In conclusion, apathy, but not depression, predicts which patients with amnestic-MCI will progress to AD. Thus, apathy has an important impact on amnestic-MCI and should be considered a mixed cognitive/psychiatric disturbance related to ongoing AD neurodegeneration.


Angiorganoid: vitalizing the organoid with blood vessels.
The emergence of the organoid simulates the native organs and this mini organ offers an excellent platform for probing multicellular interaction, disease modeling and drug discovery. Blood vessels constitute the instructive vascular niche which is indispensable for organ development, function and regeneration. Therefore, it is expected that the introduction of infiltrated blood vessels into the organoid might further pump vitality and credibility into the system. While the field is emerging and growing with new concepts and methodologies, this review aims at presenting various sources of vascular ingredients for constructing vascularized organoids and the paired methodology including de- and recellularization, bioprinting and microfluidics. Representative vascular organoids corresponding to specific tissues are also summarized and discussed to elaborate on the next generation of organoid development.


Cigarette smoking among adults and trends in smoking cessation - United States, 2008.
Cigarette smoking continues to be the leading cause of preventable morbidity and mortality in the United States. Full implementation of population-based strategies and clinical interventions can educate adult smokers about the dangers of tobacco use and assist them in quitting. To assess progress toward the Healthy People 2010 objective of reducing the prevalence of cigarette smoking among adults to <12% (objective 27-1a), CDC analyzed data from the 2008 National Health Interview Survey (NHIS). This report summarizes the results of that analysis, which indicated that during 1998-2008, the proportion of U.S. adults who were current cigarette smokers declined 3.5% (from 24.1% to 20.6%). However, the proportion did not change significantly from 2007 (19.8%) to 2008 (20.6%). In 2008, adults aged >or=25 years with low educational attainment had the highest prevalence of smoking (41.3% among persons with a General Educational Development certificate [GED] and 27.5% among persons with less than a high school diploma, compared with 5.7% among those with a graduate degree). Adults with education levels at or below the equivalent of a high school diploma, who comprise approximately half of current smokers, had the lowest quit ratios (2008 range: 39.9% to 48.8%). Evidence-based programs known to be effective at reducing smoking should be intensified among groups with lower education, and health-care providers should take education level into account when communicating about smoking hazards and cessation to these patients.


Optimizing Operating Parameters of High-Temperature Steam for Disinfecting Total Nematodes and Bacteria in Soil: Application of the Box-Behnken Design.
Concerns about the widespread use of pesticides have been growing due to the adverse effects of chemicals on the environment and human health. It has prompted worldwide research into the development of a replacement to chemical disinfection of soil. The efficiency of steam sterilization, an alternative to chemical methods, has improved as technology has advanced, and the Agricultural Research and Extension Service in Korea recommends the use of steam sterilization. However, few studies have been conducted on the effects and operating conditions of high-temperature steam disinfection. In this study, we present the optimum operating conditions of a high-steam disinfector, to maximize the cost-effectiveness and removal efficiency of total nematodes and total bacteria in soil using the Box-Behnken design. The experimental data were fitted to a second-order polynomial equation using multiple regression analysis, with coefficients of determination (R2) for each model of 0.9279, 0.9678, and 0.9979. The optimum conditions were found to be a steam temperature of 150.56 °C, running speed of 1.69 m/min, and spray depth of 15.0 cm, with a corresponding desirability value of 0.8367. In the model, these conditions cause the prediction of the following responses: nematode removal efficiency of 93.99%, bacteria removal efficiency of 97.49%, and oil consumption of 70.49 mL/m2. At the optimum conditions for the steam disinfector, the removal efficiencies of nematodes and bacteria were maximized, and the oil consumption was minimized. The results of our study can be used as basic data for efficient soil disinfection using high-temperature steam.


Total knee replacement with and without patellar resurfacing: a prospective, randomised trial using the profix total knee system.
We have examined the differences in clinical outcome of total knee replacement (TKR) with and without patellar resurfacing in a prospective, randomised study of 181 osteoarthritic knees in 142 patients using the Profix total knee system which has a femoral component with features considered to be anatomical and a domed patellar implant. The procedures were carried out between February 1998 and November 2002. A total of 159 TKRs in 142 patients were available for review at a mean of four years (3 to 7). The patients and the clinical evaluator were blinded in this prospective study. Evaluation was undertaken annually by an independent observer using the knee pain scale and the Knee Society clinical rating system. Specific evaluation of anterior knee pain, stair-climbing and rising from a seated to a standing position was also undertaken. No benefit was shown of TKR with patellar resurfacing over that without resurfacing with respect to any of the measured outcomes. In 22 of 73 knees (30.1%) with and 18 of 86 knees (20.9%) without patellar resurfacing there was some degree of anterior knee pain (p = 0.183). No revisions related to the patellofemoral joint were performed in either group. Only one TKR in each group underwent a re-operation related to the patellofemoral joint. A significant association between knee flexion contracture and anterior knee pain was observed in those knees with patellar resurfacing (p = 0.006).


Neural substrates of implicit and explicit emotional processes: a unifying framework for psychosomatic medicine.
There are two broad themes in psychosomatic medicine research that relate emotions to physical disease outcomes. Theme 1 holds that self-reported negative affect has deleterious effects and self-reported positive affect has salubrious effects on health. Theme 2 holds that interference with the experience or expression of negative affect has adverse health consequences. From the perspective of self-report these two traditions appear contradictory. A key thesis of this paper is that the foundational distinction in cognitive neuroscience between explicit (conscious) and implicit (unconscious) processes, corresponding to Themes 1 and 2, respectively, provides a unifying framework that makes empirical research on unconscious emotional processes more tractable. A psychological model called "levels of emotional awareness" is presented first that places implicit and explicit emotional processes on a cognitive-developmental continuum. This model holds that the ability to become consciously aware of one's own feelings is a cognitive skill that goes through a developmental process similar to that which Piaget described for other cognitive functions. Empirical findings using the Levels of Emotional Awareness Scale are presented. A parallel hierarchical model of the neural substrates of emotional awareness is presented next supported by recent neuroimaging and lesion work. The evidence presented in this review suggests that the neural substrates of implicit and explicit emotional processes are distinct, that the latter have a modulatory effect on the former, and that at the neural level Theme 1 and Theme 2 phenomena share critical similarities. The implications of this psychobiological model for research in psychosomatic medicine are discussed.


Lowering of plasma glucose concentrations with bezafibrate in patients with moderately controlled NIDDM.
The goal of this study was to investigate whether treatment with bezafibrate improves glucose tolerance in non-insulin-dependent diabetes mellitus (NIDDM). The study included 37 NIDDM patients with HbA1 concentrations greater than 8.5% and normal kidney and liver function who were being treated with diet alone or diet together with a sulfonylurea drug. One patient withdrew because of constipation. At randomization and after 3 mo of treatment, patients were given a standard mixed-test-meal tolerance test (MTT; 500 cal) after an overnight fast, and plasma glucose, insulin, C-peptide, metabolite, nonesterified fatty acid (NEFA), and triglyceride concentrations were measured at 15- to 30-min intervals. Serum lipid, HbA1, and fructosamine concentrations were measured at monthly intervals. Glucose, NEFA, and triglyceride concentrations were significantly lower throughout the second MTT in bezafibrate patients (P less than 0.01-0.001) but not in the placebo group. Fasting serum insulin and C-peptide levels, but not postprandial concentrations, were reduced only in bezafibrate patients (P less than 0.05). After 3 mo, mean fasting serum triglyceride concentrations fell from 2.2 to 1.4 mM (P less than 0.001), total serum cholesterol concentrations from 6.3 to 5.5 mM (P less than 0.001), and low-density lipoprotein cholesterol concentrations from 4.2 to 3.5 mM (P less than 0.001) in bezafibrate patients. There were no changes in serum lipid concentrations in the placebo group. Treatment of patients with moderately controlled NIDDM with bezafibrate improves glucose tolerance and the serum lipid profile. Bezafibrate treatment may be a useful adjunct to hypoglycemic therapy in patients with NIDDM.


Extracorporeal shock wave therapy for the treatment of chronic plantar fasciitis: indications, protocol, intermediate results, and a comparison of results to fasciotomy.
A review of the history, mechanism of action, and application of extracorporeal shock wave therapy for chronic plantar fasciitis is presented. The results of 40 feet treated with this modality are reviewed after a mean follow-up time of 8.4 months. All procedures were performed under intravenous sedation and local infiltrative anesthesia. An electrohydraulic shock wave with a mean of 20.6 kV combined with a mean of 2,506 pulses was used. The results of a similar demographic class of patients having undergone a percutaneous plantar fasciotomy at our institution were compared to the results of this cohort of shock wave patients. Eighty-two percent of the patients treated with extracorporeal shock wave therapy were successfully treated as compared to 83% with a percutaneous plantar fasciotomy. The mean score on the 11-point visual analog scale for satisfied patients was 7.9 preoperatively and 2.95 within 7 days postoperatively. After 3 months, the mean visual analog score was 4.2 or 50% of the preoperative value after a mean of 8.4 months following treatment. Eighty-three percent of the patients treated stated that shock wave therapy improved their symptoms. There were no complications encountered in any patient in this study. Extracorporeal shock wave therapy is an effective treatment, which significantly reduces the symptoms associated with chronic plantar fasciitis and compares favorably to the results achieved with surgical intervention in the form of a percutaneous plantar fasciotomy.


Total synthesis and mass spectrometric analysis of a Mycobacterium tuberculosis phosphatidylglycerol featuring a two-step synthesis of (R)-tuberculostearic acid.
We report the total synthesis of (R)-tuberculostearic acid-containing Mycobacterium tuberculosis phosphatidylglycerol (PG). The approach features a two-step synthesis of (R)-tuberculostearic acid, involving an (S)-citronellyl bromide linchpin, and the phosphoramidite-assisted assembly of the full PG structure. Collision-induced dissociation mass spectrometry of two chemically-synthesized PG acyl regioisomers revealed diagnostic product ions formed by preferential loss of carboxylate at the secondary (sn-2) position.


Speech pathology for chronic cough: a new approach.
Chronic cough may persist despite systematic evaluation and medical treatment of known associated diseases such as asthma, rhinitis, and gastro-esophageal reflux. These patients have refractory chronic cough and many exhibit laryngeal hypersensitivity that is manifest at both a sensory and motor level. Examples of this are heightened sensitivity of the cough reflex to capsaicin, and laryngeal motor dysfunction with hoarse vocal quality and paradoxical vocal cord movement. Chronic cough that persists despite medical treatment may respond to speech pathology intervention. A multidimensional speech pathology treatment programme was designed based upon methods used to treat hyperfunctional voice disorders and paradoxical vocal fold movement. This included education, vocal hygiene training, cough suppression strategies and psychoeducational counseling. When tested in a single-blind, randomized, placebo-controlled trial involving 87 patients, participants in the treatment group demonstrated a significant reduction in cough, breathing, voice and upper airway symptoms following intervention, as well as improvements in auditory perceptual ratings of voice quality (breathy, rough, strain and glottal fry) and significant improvement in voice acoustic parameters (maximum phonation time, jitter and harmonic-to-noise ratio). Speech pathology intervention can be an effective way to treat refractory chronic cough.


Qualitative insights into Australian consumers' views for and against government action on sugary drinks.
Despite significant evidence of harms associated with high levels of sugar-sweetened beverage (SSB) consumption, and international moves towards regulation to curb overconsumption of such drinks, Australia has been slow to take policy action. This study provides in-depth insights into consumers' reactions to different SSB policy options. Eight focus groups were undertaken with 59 regular SSB consumers and/or household purchasers, stratified by: young adults aged 21-29 years (no children), parents aged 35-50 (with children at home); gender; and socio-economic status. Consumer responses to potential government intervention and policy options were explored using thematic analysis. Three main themes were identified. Theme 1 describes participants' changing views on regulation of SSBs throughout the focus groups, expressed through shifts in understandings of personal responsibility and the role of government. It was noted that the term 'regulation' should be used judiciously, as it was widely misunderstood to infer bans. Theme 2 articulates the participants' preference for child-focused measures and educative measures such as clearer front-of-pack labelling. Taxation on SSBs was viewed more favourably if paired with investment into education. Theme 3 describes the parallels that participants drew between SSBs and other substances. A comprehensive approach that includes education, child-focused interventions and regulatory approaches may increase acceptability of policy measures to curb overconsumption of SSBs.


Expression of hybrid Ia molecules on the cell surface of reticulum cell sarcomas that are undetectable on host SJL/J lymphocytes.
SJL/J (H-2 (8)) lymphocytes, primed in vitro against primary, cultured, and transplantable syngeneic reticulum cell sarcomas (RCS) were found to recognize and bind to the tumor without subsequent cytolysis. Additional data showed that the recognition was also directed against Ia molecules of the H-2(d), but not H-2(k), haplotype. Normal spleen cells of DBA/2, B 10.D2, and B 10.OL mice were bound, whereas those of CBA, B 10.BR, B 10.A, B 10.GD, and D2.GD were not. Furthermore, the Ia molecules were in the form of a hybrid, because spleen cells from F(1) progeny of a B10.A and a B10.GD parent were recognized and bound as effectively as the RCS. Recognition was not restricted solely to the H-2(d) haplotype. Spleen cells from B10.S(9R) mice were also significantly bound. This result suggested that the RCS expresses a hybrid Ia molecule containing a beta-chain of the H-2(8) haplotype. Recognition of this hybrid Ia molecule by the host resulted in a cross- reactive recognition of H-2(d) specificities. Further analysis revealed that the RCS express on their cell surface an alpha-chain of the hybrid Ia molecule which is involved in host anti-tumor recognition. Preincubation of the RCS with monoclonal antibody directed against the Ia.7 specificity on the alpha-chain could block lymphocyte-to-tumor cell binding. The blocking activity could be removed by preabsorption of the antibody on the RCS, as well as normal Ia.7-bearing lymphocytes, but not on lymphocytes that do not express Ia.7, such as SJL/J. The data suggest that the hybrid Ia molecules expressed on the RCS, and recognized by tumor-primed syngeneic lymphocytes, are composed of both a syngeneic and an alien chain. The component alien to the SJL/J host is the Ia.7-bearing alpha-chain. Normal SJL/J cells synthesize but do not express the beta-chain. In the RCS, however, alien alpha-chain synthesis permits expression of the syngeneic beta-chain in the form of a hybrid Ia molecule.


Joint consensus on the use of OCT in coronary bifurcation lesions by the European and Japanese bifurcation clubs.
Coronary artery bifurcation lesions comprise approximately 15-20% of all percutaneous coronary interventions (PCI) and constitute a complex lesion subgroup. Intravascular optical coherence tomography (OCT) is a promising adjunctive tool for guiding coronary bifurcation with its unrivalled high resolution. Compared to angiography, intravascular OCT has a clear advantage in that it depicts ostial lesion(s) in bifurcation without the misleading two-dimensional appearance of conventional angiography such as overlap and foreshortening. In addition, OCT has the ability to reconstruct a bifurcation in three dimensions and to assess the side branch ostium from 3D reconstruction of the main vessel pullback, which can be applied to ensure the optimal recrossing position of the wire after main vessel stenting. Recently, online co-registration of OCT and angiography became widely available, helping the operator to position a stent in precise landing zones, reducing the risk of geographic miss. Despite these technological advances, the currently available clinical data are based mainly on observational studies with a small number of patients; there is little evidence from randomised trials. The joint working group of the European Bifurcation Club and the Japanese Bifurcation Club reviewed all the available literature regarding OCT use in bifurcation lesions and here provides recommendations on OCT guiding of coronary interventions in bifurcation lesions.


Resistant Hypertension and Related Outcomes in a Cohort of Patients with Cardiorenal Multimorbidity Hospitalized in an Internal Medicine Ward.
Resistant hypertension (RH) is characterized by the failure to reach a goal blood pressure despite the administration of three medications at maximally tolerated doses, one of which being a diuretic. RH can be observed in a variety of clinical conditions, such as heart failure and reduced renal function and may confer high cardiovascular risk. To evaluate the prevalence of RH and its association with clinical outcomes; the primary outcome was in-hospital mortality and the composite outcome was all-cause of mortality and morbidity in a cohort of patients with cardiorenal multimorbidity hospitalized in an internal medicine ward. We conducted a retrospective analysis of consecutive hypertensive patients with cardiorenal multimorbidity. The composite outcome incorporated all-cause of in-hospital mortality and occurrence of sepsis, pulmonary embolism, acute coronary syndrome, stroke and renal replacement therapy. We collected data in 141 inpatients with a mean age of 77 years ± 10 (males 65.9 %), estimated glomerular filtration rate of 34 ± 18.6 ml/min with length of stay of 17 ± 12 days. The prevalence of RH was 52.4%. In-hospital mortality was observed in 24 patients (17%) and the composite outcome occurred in 87 patients (61.7%) and among these 74 (85.1%) were patients with RH. Free survival for composite outcome was significantly higher in patients without RH than patients with RH (log rank 7.52, p = 0.006). Resistant hypertension was a risk factor for composite outcome [HR 1.857(C.I. 1.170-2.946, p = 0.009)]. In patients with cardiorenal multimorbidity there is a high proportion of RH that represents a risk factor for composite outcome but not for in-hospital mortality.


Phase 1/2 Dose-Escalation Study of the Use of Intensity Modulated Radiation Therapy to Treat the Prostate and Pelvic Nodes in Patients With Prostate Cancer.
To investigate the feasibility of dose escalation and hypofractionation of pelvic lymph node intensity modulated radiation therapy (PLN-IMRT) in prostate cancer (PCa). In a phase 1/2 study, patients with advanced localized PCa were sequentially treated with 70 to 74 Gy to the prostate and dose-escalating PLN-IMRT at doses of 50 Gy (cohort 1), 55 Gy (cohort 2), and 60 Gy (cohort 3) in 35 to 37 fractions. Two hypofractionated cohorts received 60 Gy to the prostate and 47 Gy to PLN in 20 fractions over 4 weeks (cohort 4) and 5 weeks (cohort 5). All patients received long-course androgen deprivation therapy. Primary outcome was late Radiation Therapy Oncology Group toxicity at 2 years after radiation therapy for all cohorts. Secondary outcomes were acute and late toxicity using other clinician/patient-reported instruments and treatment efficacy. Between August 9, 2000, and June 9, 2010, 447 patients were enrolled. Median follow-up was 90 months. The 2-year rates of grade 2+ bowel/bladder toxicity were as follows: cohort 1, 8.3%/4.2% (95% confidence interval 2.2%-29.4%/0.6%-26.1%); cohort 2, 8.9%/5.9% (4.1%-18.7%/2.3%-15.0%); cohort 3, 13.2%/2.9% (8.6%-20.2%/1.1%-7.7%); cohort 4, 16.4%/4.8% (9.2%-28.4%/1.6%-14.3%); cohort 5, 12.2%/7.3% (7.6%-19.5%/3.9%-13.6%). Prevalence of bowel and bladder toxicity seemed to be stable over time. Other scales mirrored these results. The biochemical/clinical failure-free rate was 71% (66%-75%) at 5 years for the whole group, with pelvic lymph node control in 94% of patients. This study shows the safety and tolerability of PLN-IMRT. Ongoing and planned phase 3 studies will need to demonstrate an increase in efficacy using PLN-IMRT to offset the small increase in bowel side effects compared with prostate-only IMRT.


Functional analysis of a duplication (p.E63_D69dup) in the switch II region of HRAS: new aspects of the molecular pathogenesis underlying Costello syndrome.
Costello syndrome is a congenital disorder comprising a characteristic face, severe feeding difficulties, skeletal, cardiac and skin abnormalities, intellectual disability and predisposition to malignancies. It is caused by heterozygous germline HRAS mutations mostly affecting Gly(12) or Gly(13), which impair HRAS-GTPase activity and result in increased downstream signal flow independent of incoming signals. Functional analyses of rarer HRAS mutations identified in individuals with attenuated Costello syndrome phenotypes revealed altered GDP/GTP nucleotide affinities (p.K117R) and inefficient effector binding (p.E37dup). Thus, both phenotypic and functional variability associated with HRAS mutations are evident. Here, we report on a novel heterozygous HRAS germline mutation (c.187_207dup, p.E63_D69dup) in a girl presenting with a phenotype at the milder end of the Costello syndrome spectrum. The p.E63_D69dup mutation impaired co-precipitation of recombinant HRAS with NF1 GTPase-activating protein (GAP) suggesting constitutive HRAS(E63_D69dup) activation due to GAP insensitivity. Indeed, we identified strongly augmented active HRAS(E63_D69dup) that co-precipitated with effectors RAF1, RAL guanine nucleotide dissociation stimulator and phospholipase C1. However, we could not pull down active HRAS(E63_D69dup) using the target protein PIK3CA, indicating a compromised association between active HRAS(E63_D69dup) and PIK3CA. Accordingly, overexpression of HRAS(E63_D69dup) increased steady-state phosphorylation of MEK1/2 and ERK1/2 downstream of RAF, whereas AKT phosphorylation downstream of phosphoinositide 3-kinase (PI3K) was not enhanced. By analyzing signaling dynamics, we found that HRAS(E63_D69dup) has impaired reagibility to stimuli resulting in reduced and disrupted capacity to transduce incoming signals to the RAF-MAPK and PI3K-AKT cascade, respectively. We suggest that disrupted HRAS reagibility, as we demonstrate for the p.E63_D69dup mutation, is a previously unappreciated molecular pathomechanism underlying Costello syndrome.


Effect of blue light emitting diodes on melanoma cells: involvement of apoptotic signaling.
The present study was undertaken to examine whether blue LED irradiation induces cellular apoptosis in B16-F10 cells and whether it blocks the early growth of melanoma cells in mice. Irradiation with blue LED was observed to reduce cell viability and to induce apoptotic cell death, as accompanied by exposure of phosphatidylserine on the plasma outside membrane and an accumulation of a sub-G1 population. Furthermore, the mitochondrial membrane potential increased, and mitochondria-related apoptotic proteins (cytochrome c, caspase 3, and PARP) were observed. In addition, the level of intracellular superoxide anion (O2(-)) gradually increased. Interestingly the phosphorylation of p53 increased at earlier times under blue LED irradiation, but reduced after exposure for a longer time. Additionally, the thickness of the mice footpad injected with B16-F10 cells decreased significantly until the 9th day of blue LED irradiation, indicating the inhibition of the early growth rate of the melanoma cells. Our data demonstrate that blue LED irradiation induces apoptotic cell death by activating the mitochondria-mediated pathway and reduces the early growth rate of melanoma cells. Further studies are needed to elucidate the precise mechanism of blue LED in melanoma cells.


Transcription Factor TaWRKY51 Is a Positive Regulator in Root Architecture and Grain Yield Contributing Traits.
Wheat is one of the staple food crops. The utilization of elite genetic resources to develop resource-efficient wheat varieties is an effective approach to deal with the challenges of climate change and population growth. WRKY transcription factors (TFs) are multifaceted regulators of plant growth and development and response to environmental stress. The previous studies have shown that TaWRKY51 positively regulates the development of lateral roots, while its roles in agronomic trait development are not clear, and there is no functional marker for molecular breeding. To bridge the gap, we cloned the three members of TaWRKY51 and found they were highly expressed in the roots and flag leaves at the flowering stage and were induced by the multiple abiotic stresses and phytohormones. The highest expression level was observed in TaWRKY51-2D, followed by TaWRKY51-2A and -2B. The two haplotypes/alleles for each member were identified in the natural populations, and functional markers were developed accordingly. The association assays revealed that Hap-2A-I was an elite haplotype for the large spike, Hap-2B-II and allele-G were favorable haplotypes/alleles for long root. However, only Hap-2A-I was selected for wheat breeding in China. The results of transgenic experiments showed that the rice lines overexpressing TaWRKY51 had large panicle, high thousand-grain-weight, and more crown and lateral roots, which further confirmed the results of association analysis. In short, TaWRKY51 is a positive regulator of the root architecture and grain yield (GY) contributing traits. The elite gene resources and functional markers may be utilized in the marker-assisted selection for high-yield breeding in wheat.


Elevated osteoprotegerin is associated with abnormal ankle brachial indices in patients infected with HIV: a cross-sectional study.
Patients infected with HIV have an increased risk for accelerated atherosclerosis. Elevated levels of osteoprotegerin, an inflammatory cytokine receptor, have been associated with a high incidence of cardiovascular disease (including peripheral arterial disease, or PAD), acute coronary syndrome, and cardiovascular mortality. The objective of this study was to determine whether PAD is prevalent in an HIV-infected population, and to identify an association with HIV-specific and traditional cardiovascular risk factors, as well as levels of osteoprotegerin. One hundred and two patients infected with HIV were recruited in a cross-sectional study. To identify the prevalence of PAD, ankle-brachial indices (ABIs) were measured. Four standard ABI categories were utilized: < or = 0.90 (definite PAD); 0.91-0.99 (borderline); 1.00-1.30 (normal); and >1.30 (high). Medical history and laboratory measurements were obtained to determine possible risk factors associated with PAD in HIV-infected patients. The prevalence of PAD (ABI < or = 0.90) in a young HIV-infected population (mean age: 48 years) was 11%. Traditional cardiovascular risk factors, including advanced age and previous cardiovascular history, as well as elevated C-reactive protein levels, were associated with PAD. Compared with patients with normal ABIs, patients with high ABIs had significantly elevated levels of osteoprotegerin [1428.9 (713.1) pg/ml vs. 3088.6 (3565.9) pg/ml, respectively, p = 0.03]. There is a high prevalence of PAD in young HIV-infected patients. A number of traditional cardiovascular risk factors and increased osteoprotegerin concentrations are associated with abnormal ABIs. Thus, early screening and aggressive medical management for PAD may be warranted in HIV-infected patients.


Role of Na+ in the asymmetric paracellular transport of 4-phenylazobenzyloxycarbonyl-L-Pro-L-Leu-Gly-L-Pro-D-Arg across rabbit colonic segments and Caco-2 cell monolayers.
This study was conducted to demonstrate that Na+ played a role in the paracellular transport of 4-phenylazobenzyloxycarbonyl-L-Pro-L-Leu-Gly-L-Pro-D-Arg (Pz-peptide), a hydrophilic proline-containing pentapeptide, across the rabbit colonic mucosa and Caco-2 cell monolayers. Over the 1 to 5 mM concentration range, Pz-peptide transport was 25 to 180 times greater from the mucosal-to-serosal than from the opposite direction. This asymmetry in transport was consistent with the ability of Pz-peptide to lower the transepithelial electrical resistance of Caco-2 cell monolayers only from the mucosal side. Blockade of Na+ access to the apically located amiloride-sensitive Na+ channel in the lower intestinal segments by mucosal 10 microM amiloride, serosal 100 microM ouabain or removal of Na+ ions in the mucosal fluid dramatically reduced Pz-peptide transport to 5% of the control. Moreover, Pz-peptide transport across Caco-2 cell monolayers could be titrated against mucosal Na+ concentration. There was a small mucosal-to-serosal solvent drag effect induced by transepithelial Na+ flux stimulated by Pz-peptide in the colon, contributing in part to enhanced paracellular solute transport. Overall, the above findings are consistent with a scenario whereby Pz-peptide stimulates transepithelial Na+ flux across the colonic segments at the level of the amiloride-sensitive Na+ channel, thereby triggering yet to be identified intracellular biochemical changes that ultimately result in tight junctional opening and enhanced paracellular solute transport.


Auditory cortex represents both pitch judgments and the corresponding acoustic cues.
The neural processing of sensory stimuli involves a transformation of physical stimulus parameters into perceptual features, and elucidating where and how this transformation occurs is one of the ultimate aims of sensory neurophysiology. Recent studies have shown that the firing of neurons in early sensory cortex can be modulated by multisensory interactions [1-5], motor behavior [1, 3, 6, 7], and reward feedback [1, 8, 9], but it remains unclear whether neural activity is more closely tied to perception, as indicated by behavioral choice, or to the physical properties of the stimulus. We investigated which of these properties are predominantly represented in auditory cortex by recording local field potentials (LFPs) and multiunit spiking activity in ferrets while they discriminated the pitch of artificial vowels. We found that auditory cortical activity is informative both about the fundamental frequency (F0) of a target sound and also about the pitch that the animals appear to perceive given their behavioral responses. Surprisingly, although the stimulus F0 was well represented at the onset of the target sound, neural activity throughout auditory cortex frequently predicted the reported pitch better than the target F0.


FDA approved? A critique of the artificial insemination industry in the United States.
Artificial insemination by donor is becoming an increasingly popular means to achieving parenthood. While the majority of couples use artificial insemination to overcome fertility problems, many recipients use artificial insemination to avoid passing a genetic disease to their children. However, case studies reveal the inherent dangers of artificial insemination, namely the lack of proper screening methods to avoid passing genetic diseases to children born by artificial insemination. State-by-state regulation, federal guidelines, and private adjudication have all proven to be inadequate methods of regulating the artificial insemination industry. Ginsberg proposes federal regulation as the only means of achieving a safe artificial insemination industry. The proposed federal regulation would include better genetic screening, a more efficient national sperm donor system, and limited disclosure to recipients of artificial insemination and their children. These measures would help to ensure that couples using artificial insemination get what they expect--healthy sperm, a safe artificial insemination process, and ultimately, a healthy child.


Microvascular obstruction and endothelial activation are independently associated with the clinical manifestations of severe falciparum malaria in adults: an observational study.
Microvascular obstruction and endothelial dysfunction have both been linked to tissue hypoperfusion in falciparum malaria, but their relative contributions to the disease's pathogenesis and outcome are unknown. Microvascular blood flow was quantified in adults with severe falciparum malaria on their admission to hospital; plasma biomarkers of endothelial function were measured simultaneously. The relationship between these indices and the patients' clinical findings and in-hospital course was examined. Microvascular obstruction was observed in 119/142 (84 %) patients; a median (interquartile range (IQR)) of 14.9 % (6.6-34.9 %) of capillaries were obstructed in patients that died versus 8.3 % (1.7-26.6 %) in survivors (P = 0.039). The proportion of obstructed capillaries correlated with the estimated parasite biomass (rs = 0.25, P = 0.004) and with plasma lactate (rs = 0.38, P <0.0001), the strongest predictor of death in the series. Plasma angiopoietin-2 (Ang-2) concentrations were markedly elevated suggesting widespread endothelial activation; the median (IQR) Ang-2 concentration was 21.9 ng/mL (13.4-29.4 ng/mL) in patients that died versus 14.9 ng/mL (9.8-29.3 ng/mL) in survivors (P = 0.035). Ang-2 concentrations correlated with estimated parasite biomass (rs = 0.35, P <0.001) and plasma lactate (rs = 0.37, P <0.0001). Microvascular obstruction and Ang-2 concentrations were not significantly correlated with each other (rs = 0.17, P = 0.06), but were independently associated with plasma lactate (P <0.001 and P = 0.002, respectively). Microvascular obstruction and systemic endothelial activation are independently associated with plasma lactate, the strongest predictor of death in adults with falciparum malaria. This supports the hypothesis that the two processes make an independent contribution to the pathogenesis and clinical manifestations of the disease.


Self-Assembly of Islands on Spherical Substrates by Surface Instability.
Through strain-induced morphological instability, protruding patterns of roughly commensurate nanostructures are self-assembled on the surface of spherical core/shell systems. A three-dimensional (3D) phase field model is established for a closed substrate. We investigate both numerically and analytically the kinetics of the morphological evolution, from grooves to separated islands, which are sensitive to substrate curvature, misfit strain, and modulus ratio between the core and shell. The faster growth rate of surface undulation is associated with the core/shell system of a harder substrate, larger radius, or misfit strain. On the basis of a Ag core/SiO2 shell system, the self-assemblies of SiO2 nanoislands were explored experimentally. The numerical and experimental studies herein could guide the fabrication of ordered quantum structures via surface instability on closed and curved substrates.


Kinematic control of extreme jump angles in the red-legged running frog, Kassina maculata.
The kinematic flexibility of frog hindlimbs enables multiple locomotor modes within a single species. Prior work has extensively explored maximum performance capacity in frogs; however, the mechanisms by which anurans modulate performance within locomotor modes remain unclear. We explored how Kassina maculata, a species known for both running and jumping abilities, modulates take-off angle from horizontal to nearly vertical. Specifically, how do 3D motions of leg segments coordinate to move the centre of mass (COM) upwards and forwards? How do joint rotations modulate jump angle? High-speed video was used to quantify 3D joint angles and their respective rotation axis vectors. Inverse kinematics was used to determine how hip, knee and ankle rotations contribute to components of COM motion. Independent of take-off angle, leg segment retraction (rearward rotation) was twofold greater than adduction (downward rotation). Additionally, the joint rotation axis vectors reoriented through time, suggesting dynamic shifts in relative roles of joints. We found two hypothetical mechanisms for increasing take-off angle. Firstly, greater knee and ankle excursion increased shank adduction, elevating the COM. Secondly, during the steepest jumps, the body rotated rapidly backwards to redirect the COM velocity. This rotation was not caused by pelvic angle extension, but rather by kinematic transmission from leg segments via reorientation of the joint rotation axes. We propose that K. maculata uses proximal leg retraction as the principal kinematic drive while dynamically tuning jump trajectory by knee and ankle joint modulation.


Midwives' attitudes, beliefs and concerns about childhood vaccination: A review of the global literature.
Vaccine hesitancy in industrialised countries is an area of concern. Health professionals play a significant role in parental vaccination decisions, however, to date the role of midwives has not been widely explored. This review sought to describe the attitudes and communication practices of midwives in developed countries towards childhood vaccines. Medline, Cinahl, PsychInfo, Embase and the grey literature were searched. Inclusion criteria were qualitative and quantitative studies reporting midwives' beliefs, attitudes and communication practices toward childhood vaccination. The search returned 366 articles, of which 359 were excluded by abstract. Two additional articles were identified from the grey literature and references, resulting in nine studies from five countries included in the review. Across the studies, the majority of midwives supported vaccination, although a spectrum of beliefs and concerns emerged. A minority expressed reservations about the scientific justification for vaccination, which focussed on what is not yet known rather than mistrust of current evidence. Most midwives felt that vaccines were safe; a minority were unsure, or believed they were unsafe. The majority of midwives agreed that childhood vaccines are necessary. Among those who expressed doubt, a commonly held opinion was that vaccine preventable diseases such as measles are relatively benign and didn't warrant vaccination against them. Finally, the midwifery model of care was shown to focus on providing individualised care, with parental choice being placed at a premium. The midwifery model care appears to differ in approach from others, possibly due to a difference in the underpinning philosophies. Research is needed to understand how midwives see vaccination, and why there appears to be a spectrum of views on the subject. This information will inform the development of resources tailored to the midwifery model of care, supporting midwives in advocating for childhood vaccination.


Role of heme in structural organization of cytochrome c probed by semisynthesis.
The heme prosthetic group of cytochrome c is covalently attached to the protein through thioether bonds to two cysteine side chains. The role of covalent heme attachment to cytochrome c is not understood, and most heme proteins bind the prosthetic group by iron ion ligation and tertiary interactions only. A two-armed attachment seems redundant if the role of covalent connection is to limit heme group orientation or to decouple heme affinity from redox potential. These considerations suggested that one role for covalent attachment of the rigid planar heme might be in organizing the cytochrome c protein structure. Indeed, porphyrin cytochrome c (in which the heme iron ion has been removed) is substantially more ordered than apocytochrome c, having characteristics consistent with a molten globule state. To assess the importance of planar rigidity in ordering this protein, semisynthesis was used to substitute porphyrin by two hydrophobic surrogates, one based on biphenyl and the other on phenanthrene, which have different degrees of planarity and rigidity. The expected two-armed covalent attachment of each surrogate was confirmed in the protein products by a variety of methods including mass spectrometry and NMR. Despite being only about half the size of the porphyrin macrocycle, and lacking any possibility for ligation or polar group interactions with the surrounding protein, the two surrogates confer helix contents that are comparable to that of the molten globule formed by porphyrin cytochrome c under similar solution conditions. The pH titrations of the derivatives monitored by circular dichroism exhibit reversible, bell-shaped folding and unfolding transitions, implying that charge group interactions in the protein are involved in stabilizing the helical structures formed. The thermal transitions of the two derivatives at neutral pH are cooperative, with similar midpoints. The similarity of helical content and structural stability in the two derivatives indicates that the increase in conformational freedom by the biphenyl surrogate does not substantially reduce protein structural stability. The similarity of the two derivatives to porphyrin cytochrome c suggests that the common feature among the three covalently attached groups-their hydrophobicity-is by far the dominant factor in organizing stable structures in the protein.


Orientation of spindle axis and distribution of plasma membrane proteins during cell division in polarized MDCKII cells.
MDCKII cells differentiate into a simple columnar epithelium when grown on a permeable support; the monolayer is polarized for transport and secretion. Individual cells within the monolayer continue to divide at a low rate without disturbing the function of the epithelium as a barrier to solutes. This presents an interesting model for the study of mitosis in a differentiated epithelium which we have investigated by confocal immunofluorescence microscopy. We monitored the distribution of microtubules, centrioles, nucleus, tight junctions, and plasma membrane proteins that are specifically targeted to the apical and basolateral domains. The stable interphase microtubule cytoskeleton was rapidly disassembled at prophase onset and reassembled at cytokinesis. As the interphase microtubules disassembled at prophase, the centrioles moved from their interphase position at the apical membrane to the nucleus and acquired the ability to organize microtubule asters. Orientation of the spindle parallel to the plane of the monolayer occurred between late prophase and metaphase and persisted through cytokinesis. The cleavage furrow formed asymmetrically perpendicular to the plane of the monolayer initiating at the basolateral side and proceeding to the apical domain. The interphase microtubule network reformed after the centrioles migrated from the spindle poles to resume their interphase apical position. Tight junctions (ZO-1), which separate the apical from the basolateral domains, remained assembled throughout all phases of mitosis. E-cadherin and a 58-kD antigen maintained their basolateral plasma membrane distributions, and a 114-kD antigen remained polarized to the apical domain. These proteins were useful for monitoring the changes in shape of the mitotic cells relative to neighboring cells, especially during telophase when the cell shape changes dramatically. We discuss the changes in centriole position during the cell cycle, mechanisms of spindle orientation, and how the maintenance of polarized plasma membrane domains through mitosis may facilitate the rapid reformation of the polarized interphase cytoplasm.


Plasmonic nanojet: an experimental demonstration.
We propose and study a microstructure based on a dielectric cuboid placed on a thin metal film that can act as an efficient plasmonic lens allowing the focusing of surface plasmons at the subwavelength scale. Using numerical simulations of surface plasmon polariton (SPP) field intensity distributions, we observe high-intensity subwavelength spots and formation of the plasmonic nanojet (PJ) at the telecommunication wavelength of 1530 nm. The fabricated microstructure was characterized using amplitude and phase-resolved scattering-type scanning near-field optical microscopy. We show the first experimental observation of the PJ effect for the SPP waves. Such a novel, to the best of our knowledge, and simple platform can provide new pathways for plasmonics, high-resolution imaging, and biophotonics, as well as optical data storage.


Relationship between vitamin B12, folate and homocysteine levels and H. pylori infection in patients with functional dyspepsia: a cross-section study.
H. pylori infection has been associated with many micronutrient deficiencies. There is a dearth of data from communities with nutritional deficiencies and high prevalence of H. pylori infection. The aim of this study was to determine the impact of H. pylori infection on serum levels of vitamin B(12), folate and homocysteine in patients with functional dyspepsia (FD). One hundred and thirty-two patients with FD undergoing gastroscopy were enrolled. The serum was analyzed for B(12), folate and homocysteine levels before gastroscopy. H. pylori infection was diagnosed by histopathological examination of gastric biopsies and urea breath test. An independent sample t-test and the Mann-Whitney test were used to compare mean serum concentrations of biomarkers between H. pylori-positive and H. pylori-negative groups of patients. A Chi-square test was performed to assess the differences among proportions, while Spearman's rho was used for correlation analysis between levels of B(12) and homocysteine. The mean age of the group was 40.3 ± 11.5 (19-72) years. Folate deficiency was seen in 43 (34.6%), B(12) deficiency in 30 (23.1%) and hyperhomocysteinemia in 60 (46.2%) patients. H. pylori was present in 80 (61.5%) patients with FD while it was absent in 50 (38.5%). Mean serum levels of B(12), folate and homocysteine in the H. pylori-positive group of patients were not significantly different from the levels in the H. pylori-negative group (357 ± 170 vs. 313 ± 136 pg/mL; p = 0.13), (4.35 ± 1.89 vs. 4.42 ± 1.93 ng/mL; p = 0.84); (15.88 ± 8.97 vs. 16.62 ± 7.82 μmol/L; p = 0.24); respectively.B(12) deficiency (≤200 pg/mL) was 23.8% in the H. pylori-positive patients versus 22.0% in the H. pylori-negative patients. Folate deficiency (≤3.5 ng/mL) was 33.8% in the H. pylori-positive group versus 36% in the H. pylori-negative group. Hyperhomocysteinemia (>15 μmol/L) was present in 46.2% of H. pylori-positive patients compared to 44% in the H. pylori-negative group. Correlation analysis indicated that serum B(12) levels were inversely associated with serum levels of homocysteine in patients with FD (rho = -0.192; p = 0.028). This study demonstrated an inverse relationship between serum levels of B(12) and homocysteine in patients with FD. Moreover, no impact of the presence of H. pylori was found on B(12), folate and homocysteine levels in such patients.


Physiological and transcriptional responses of Saccharomyces cerevisiae to zinc limitation in chemostat cultures.
Transcriptional responses of the yeast Saccharomyces cerevisiae to Zn availability were investigated at a fixed specific growth rate under limiting and abundant Zn concentrations in chemostat culture. To investigate the context dependency of this transcriptional response and eliminate growth rate-dependent variations in transcription, yeast was grown under several chemostat regimens, resulting in various carbon (glucose), nitrogen (ammonium), zinc, and oxygen supplies. A robust set of genes that responded consistently to Zn limitation was identified, and the set enabled the definition of the Zn-specific Zap1p regulon, comprised of 26 genes and characterized by a broader zinc-responsive element consensus (MHHAACCBYNMRGGT) than so far described. Most surprising was the Zn-dependent regulation of genes involved in storage carbohydrate metabolism. Their concerted down-regulation was physiologically relevant as revealed by a substantial decrease in glycogen and trehalose cellular content under Zn limitation. An unexpectedly large number of genes were synergistically or antagonistically regulated by oxygen and Zn availability. This combinatorial regulation suggested a more prominent involvement of Zn in mitochondrial biogenesis and function than hitherto identified.


Interventions to Reduce the Overuse of Imaging for Pulmonary Embolism: A Systematic Review.
Imaging use in the diagnostic workup of pulmonary embolism (PE) has increased markedly in the last 2 decades. Low PE prevalence and diagnostic yields suggest a significant problem of overuse. The purpose of this systematic review is to summarize the evidence associated with the interventions aimed at reducing the overuse of imaging in the diagnostic workup of PE in the emergency department and hospital wards. PubMed, MEDLINE, Embase, and EBM Reviews from 1998 to March 28, 2017. Experimental and observational studies were included. The types of interventions, their efficacy and safety, the impact on healthcare costs, the facilitators, and barriers to their implementation were assessed. Seventeen studies were included assessing clinical decision support (CDS), educational interventions, performance and feedback reports (PFRs), and institutional policy. CDS impact was most comprehensively documented. It was associated with a reduction in imaging use, ranging from 8.3% to 25.4%, and an increase in diagnostic yield, ranging from 3.4% to 4.4%. The combined implementation of a CDS and PFR resulted in a modest but significant increase in the adherence to guidelines. Few studies appraised the safety of interventions. There was a lack of evidence concerning economic aspects, facilitators, and barriers. A combined implementation of an electronic CDS and PFRs is more effective than purely educational or policy interventions, although evidence is limited. Future studies of high-methodological quality would strengthen the evidence concerning their efficacy, safety, facilitators, and barriers.


N-acetylcysteine as an adjuvant therapy for Helicobacter pylori eradication.
Helicobacter pylori (H pylori) is one of the most common pathogens to establish and cause infection in human beings, affecting about 50% of the world's population. Prevalence may be as high as 83% in Latin American countries and as low as 17% in North America. Approximately 20% of infected people will manifest disease; people at high risk include those who live in low- and middle-income countries with poor sanitary conditions, since the mechanism of transmission seems to be oral-oral or faecal-oral (mostly during infancy). There are several antibiotic regimens to treat the infection, but antibiotic resistance is growing around the world. New adjuvant drugs - such as probiotics, statins, curcumin, and N-acetylcysteine (NAC) - are being tested to enhance eradication rates.N-acetylcysteine can destabilise the biofilm structure; it also has synergic action with antibiotics, and bactericidal effects. In addition, NAC has antioxidant properties, and has a primary mucolytic effect by reducing the thickness of the gastric mucus layer, both of which may exert beneficial adjuvant effects on H pylori eradication. To assess the efficacy and safety of N-acetylcysteine as an adjuvant therapy to antibiotics for Helicobacter pylori eradication. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1966 to April 2018), Embase (1988 to April 2018), CINAHL (1982 to April 2018), LILACS (1982 to April 2018), grey literature databases and trials registries. We handsearched the reference lists of relevant studies. We screened 726 articles and assessed 18 for eligibility. We included randomised controlled trials (RCTs) of any antibiotic regimen plus NAC, in adults infected with H pylori. To be included, trials had to use a control consisting of the same antibiotic regimen with or without placebo. Outcomes of interest were eradication rates, and gastrointestinal, toxic, and allergic adverse events. Reporting of the primary outcomes listed here was not an inclusion criterion for the review. Two review authors independently reviewed and extracted data and completed the 'Risk of bias' assessments. A third review author independently confirmed the 'Risk of bias' assessments. We used Review Manager 5 software for data analysis. We contacted study authors if there was missing information. We included eight RCTs (with a total of 559 participants) in this review. The studies recruited outpatients aged between 17 and 76 years who were referred to endoscopy centres in several different countries. The certainty of evidence was reduced for most outcomes due to the poor methodological quality of included studies; issues mainly related to the generation of allocation sequence, allocation concealment, and blinding (this last domain related specifically to adverse outcomes).We are uncertain whether the addition of NAC to antibiotics improves H pylori eradication rates, compared with the addition of placebo or no NAC (38.8% versus 49.1%, risk ratio (RR) 0.74, 95% confidence interval (CI) 0.51 to 1.08; participants = 559; studies = eight; very low-certainty evidence). A post-hoc sensitivity analysis, in which we removed studies that tested antibiotic regimens no longer recommended in clinical practice, showed that the addition of NAC may improve eradication rates compared to control (27.2% versus 37.6%, RR 0.71, 95% CI 0.53 to 0.94; participants = 397; published studies = five).We are uncertain whether NAC is associated with a higher risk of gastrointestinal adverse events compared to control (23.9% versus 18.9%, RR 1.25, 95% CI 0.85 to 1.85; participants = 336; studies = five; very low-certaintyevidence), or allergic adverse events (2% versus 0%, RR 2.98, 95% CI 0.32 to 27.74; participants = 336; studies = five; very low-certainty evidence). There were no reports of toxic adverse events amongst included studies. We are uncertain whether the addition of NAC to antibiotics improves H pylori eradication rates compared with the addition of placebo or no NAC. Due to the clinical, statistical and methodological heterogeneity found in included studies, and the uncertainty observed when analysing therapy subgroups, any possible beneficial effect of NAC should be regarded cautiously.We are uncertain whether NAC is associated with a higher risk of gastrointestinal or allergic adverse events compared with placebo or no NAC. There were no reports of toxic adverse events amongst the included studies.Further large, well-designed, randomised clinical studies should be conducted, with good reporting standards and appropriate collection of efficacy and safety outcomes, especially for current recommended antibiotic regimens.


Comparison of median frequency between traditional and functional sensor placements during activity monitoring.
Long-term monitoring is of great clinical relevance. Accelerometers are often used to provide information about activities of daily living. The median frequency (fm) of acceleration has recently been suggested as a powerful parameter for activity recognition. However, compliance issues arise when people need to integrate activity recognition sensors into their daily lives. More functional placements should provide higher levels of conformity, but may also affect the quality and generalizability of the signals. How fm changes as a result of a more functional sensor placement remains unclear. This study investigates the agreement in fm for a sensor placed on the back with one in the pocket across a range of daily activities. The translational and gravitational accelerations are also computed to determine if the accelerometer should be fused with additional sensors to improve agreement. Twelve subjects were tested over four tasks and only the "vertical" x-axis showed a moderate agreement (Intraclass Correlation Coefficient of 0.54) after correction for outliers. Generalizability across traditional and functional sensor locations might therefore be limited. Differentiation of the signal into a translational and gravitational component decreased the level of agreement further, suggesting that combined information streams are more robust to changing locations then singular data streams. Integrating multiple sensor modalities to obtain specific components is unlikely to improve agreement across sensor locations. More research is needed to explore measurement signals of more user friendly sensor configurations that will lead to a greater clinical acceptance of body worn sensor systems.


Wavelength-Resolved Photon Fluxes of Indoor Light Sources: Implications for HOx Production.
Photochemistry is a largely unconsidered potential source of reactive species such as hydroxyl and peroxy radicals (OH and HO2, "HOx") indoors. We present measured wavelength-resolved photon fluxes and distance dependences of indoor light sources including halogen, incandescent, and compact fluorescent lights (CFL) commonly used in residential buildings; fluorescent tubes common in industrial and commercial settings; and sunlight entering buildings through windows. We use these measurements to predict indoor HOx production rates from the photolysis of nitrous acid (HONO), hydrogen peroxide (H2O2), ozone (O3), formaldehyde (HCHO), and acetaldehyde (CH3CHO). Our results suggest that while most lamps can photolyze these molecules, only sunlight and fluorescent tubes will be important to room-averaged indoor HOx levels due to the strong distance dependence of the fluxes from compact bulbs. Under ambient conditions, we predict that sunlight and fluorescent lights will photolyze HONO to form OH at rates of 106-107 molecules cm-3 s-1, and that fluorescent lights will photolyze HCHO to form HO2 at rates of ∼106 molecules cm-3 s-1; rates could be 2 orders of magnitude higher under high precursor concentrations. Ozone and H2O2 will not be important photochemical OH sources under most conditions, and CH3CHO will generally increase HO2 production rates only slightly. We also calculated photolysis rate constants for nitrogen dioxide (NO2) and nitrate radicals (NO3) in the presence of the different light sources. Photolysis is not likely an important fate for NO3 indoors, but NO2 photolysis could be an important source of indoor O3.


Smartphone addiction and victimization predicts sleep problems and depression among children.
In this study we examined the phenomena of smartphone addiction, online harassment, and school bullying/victimization to predict the prospective influence these could have on the onset and persistence of sleep problems and depression among children. Responses from 2155 fifth-grade children recruited from 30 primary schools in Taipei were assessed, and a follow-up was performed in the 6th grade. Self-administered questionnaires were collected for each year. Children who reported smartphone addictions, online harassment, and school bullying/victimization coupled with an increase in those factors were more likely to experience the onset and persistence of sleep problems. In addition, children who reported smartphone addiction, online harassment, school bullying/victimization, and poor sleep quality were more likely to experience the onset and persistence of depression. School nurses or pediatric nurses should be able to assess children's Internet use and risks to understand potential influences on sleep quality and mental status and provide recommendations for children, parents and schools.