Multimedia manuscript. Heller myotomy and intraluminal fundoplication: a NOTES technique.
It is generally accepted that the most effective treatment of achalasia is a surgical myotomy. Nevertheless, if a myotomy alone is performed, reflux may occur in up to 30% of patients. The aim of this study was to explore a transoral incisionless stepwise approach to both esophageal Heller myotomy and fundoplication. The first step consisted of creating the esophageal myotomy. Under general anesthesia, with the pig supine, endoscopy was performed to assess the location of the esophagogastric junction (EGJ). The mucosa on the right posterolateral esophageal wall was cut with the needle-knife 15 cm above the lower esophageal sphincter (LES) and then dilated with blunt dissection to introduce the scope. A submucosal tunnel was created distally with CO(2) and blunt dissection. Once the gastroesophageal junction (GEJ) and the clasp fibers were identified, the muscular layer was cut. The scope was withdrawn into the lumen and the mucosal flap was sealed with endoscopic clips. The adequacy of the myotomy was evaluated using pre- and postoperative manometry and by comparing the EGJ distensibility before, during, and after the division of the esophageal muscular fibers using the functional lumen imaging probe, EndoFLIP®. The second step, consisted of building a transoral incisionless fundoplication 4 weeks postoperatively using the EsophyX™. Both Heller myotomy and endoscopic fundoplication were accomplished successfully with no injury to the esophageal mucosa. Postoperative manometry demonstrated a 50% loss in mean LES pressure (mean preoperative LES pressure = 22.2 mmHg; mean postoperative LES pressure = 10 mmHg, P < 0.005). The EndoFLIP® showed a preoperative minimal diameter of 6 mm with a cross-sectional area of 28 mm(2). Postoperatively, the junction was more compliant (minimal diameter = 15 mm; cross-sectional area = 177 mm(2)), with the main improvement in distensibility occurring when the clasps fibers were removed. A stepwise transoral incisionless approach to esophageal Heller myotomy and partial fundoplication is feasible and effective in the porcine model. A distensibility test such as the EndoFLIP® may provide better information on the opening and closing dynamics of the EGJ, rather than just relying on the sphincter tonic state as measured by manometry.


Global Level of Plasma DNA Methylation is Associated with Overall Survival in Patients with Hepatocellular Carcinoma.
The impact of folate deficiency on global DNA methylation is uncertain. It also is unclear whether global DNA methylation is associated with outcome in HCC. LINE-1 methylation levels, as a surrogate marker of global methylation, may be influenced by folate deficiency. However, the interaction between LINE-1 methylation and folate level on overall survival (OS) in hepatocellular carcinoma (HCC) patients is unknown. We evaluated whether LINE-1 hypomethylation and folate deficiency are associated with HCC prognosis. We prospectively recruited 172 HCC patients between 2008 and 2012. LINE-1 methylation levels in plasma and white blood cells (WBC) were measured by pyrosequencing, and plasma folate levels by a radioprotein-binding assay. Patients with plasma LINE-1 methylation <70.0% (hypomethylation) had significantly worse OS compared with those with ≥70.0% methylation (hypermethylation) [hazard ratio (HR) = 1.77; 95% confidence interval (CI) 1.12-2.79; P = 0.015]. HCC patients with lower plasma folate levels also had worse survival (<27.7 vs. ≥27.7 nmol/L; HR = 1.96; 95% CI, 1.24-3.09; P = 0.004). Furthermore, survival was poor in patients in whom both plasma LINE-1 methylation and folate levels were low compared with those patients in whom both levels were high (HR = 3.36; 95%CI, 1.77-6.40; P < 0.001). This interaction neared statistical significance (P = 0.057). No significant association was found between WBC LINE-1 methylation levels and survival. These findings suggest that both lower plasma levels of LINE-1 methylation and folate are associated with worse survival in HCC patients.


On the relationship between cloud water composition and cloud droplet number concentration.
Aerosol-cloud interactions are the largest source of uncertainty in quantifying anthropogenic radiative forcing. The large uncertainty is, in part, due to the difficulty of predicting cloud microphysical parameters, such as the cloud droplet number concentration (N d). Even though rigorous first-principle approaches exist to calculate N d, the cloud and aerosol research community also relies on empirical approaches such as relating N d to aerosol mass concentration. Here we analyze relationships between N d and cloud water chemical composition, in addition to the effect of environmental factors on the degree of the relationships. Warm, marine, stratocumulus clouds off the California coast were sampled throughout four summer campaigns between 2011 and 2016. A total of 385 cloud water samples were collected and analyzed for 80 chemical species. Single- and multispecies log-log linear regressions were performed to predict N d using chemical composition. Single-species regressions reveal that the species that best predicts N d is total sulfate ( R adj 2 = 0.40 ). Multispecies regressions reveal that adding more species does not necessarily produce a better model, as six or more species yield regressions that are statistically insignificant. A commonality among the multispecies regressions that produce the highest correlation with N d was that most included sulfate (either total or non-sea-salt), an ocean emissions tracer (such as sodium), and an organic tracer (such as oxalate). Binning the data according to turbulence, smoke influence, and in-cloud height allowed for examination of the effect of these environmental factors on the composition-N d correlation. Accounting for turbulence, quantified as the standard deviation of vertical wind speed, showed that the correlation between N d with both total sulfate and sodium increased at higher turbulence conditions, consistent with turbulence promoting the mixing between ocean surface and cloud base. Considering the influence of smoke significantly improved the correlation with N d for two biomass burning tracer species in the study region, specifically oxalate and iron. When binning by in-cloud height, non-sea-salt sulfate and sodium correlated best with N d at cloud top, whereas iron and oxalate correlated best with N d at cloud base.


Low urinary kallikrein excretion and elevated blood pressure normalized by orally kallikrein in essential hypertension.
1. Urinary kallikrein was measured in 67 patients with essential hypertension and 25 normotensive subjects variously on unrestricted and low sodium diet. Also, the effect of orally applied hog pancreatic kallikrein on elevated blood pressure and kallikrein excretion was evaluated. 2. Urinary kallikrein was reduced in a large subgroup of patients with sustained essential hypertension. 3. With salt restriction, urinary kallikrein rose markedly in normotensive subjects and patients with borderline hypertension but not in those with sustained hypertension. 4. Oral kallikrein normalized reduced kallikrein excretion and lowered elevated blood pressure. 5. The rise in urinary kallikrein with oral kallikrein was due to an increased formation of endogenous enzyme. 6. A defective kallikrein-kinin system may be involved in both the low urinary kallikrein excretion and the hypertension.


NpR3784 is the prototype for a distinctive group of red/green cyanobacteriochromes using alternative Phe residues for photoproduct tuning.
Cyanobacteriochromes (CBCRs) are photosensory proteins found in cyanobacteria and are distantly related to the widespread phytochromes. Whereas plant phytochromes exhibit responses to red and far-red light, CBCRs use the same photoisomerization of a linear tetrapyrrole (bilin) chromophore to respond to a wide range of colors. NpR6012g4 from Nostoc punctiforme and AnPixJ from Anabaena sp. PCC 7120 belong to a large subfamily of red/green CBCRs that exhibit a red-absorbing dark state similar to that of phytochrome but a green-absorbing photoproduct rather than a far-red-absorbing one. In these canonical red/green CBCRs, the photoproduct is blue-shifted relative to the orange absorption observed in the absence of native protein structure. This spectral tuning of the photoproduct requires a conserved Phe residue on the second β strand of the CBCR GAF domain, consistent with a trapped-twist mechanism in which the bilin is sterically constrained in the photoproduct. N. punctiforme also produces NpR3784, a CBCR with a similar red/green photocycle to that of NpR6012g4. NpR3784 lacks both the β2 Phe and other residues characteristic of the canonical red/green CBCRs. In the current work, we identify NpR3784 homologs with red/green photocycles in other cyanobacteria. Spectral tuning in this NpR3784 group is accomplished by a different set of conserved Phe residues, including a characteristic Phe residue on β1. This set of Phe residues cannot be interchanged with the Phe residues found in canonical red/green CBCRs such as NpR6012g4. Our results provide new insights into the flexible protein-chromophore interactions used by CBCRs to generate their remarkable spectral diversity.


Fatigue severity remains stable over time and independently associated with orthostatic symptoms in chronic fatigue syndrome: a longitudinal study.
to examine fatigue variability over time in chronic fatigue syndrome (CFS) and the effect of other symptoms on its predictability. longitudinal cohort study of patients with CFS (Fukuda criteria). specialist CFS clinical service. phase 1: 100 patients who participated in a study of CFS symptoms in 2005 were revisited in 2009. Phase 2: 25 patients completed fatigue diaries to address intra- and inter-day variability in perceived fatigue. phase 1: subjects completed fatigue impact scale (FIS), Epworth sleepiness scale (ESS), orthostatic grading scale (OGS) and hospital anxiety and depression scale (HADS). Changes in variables represented the differences between 2005 and 2009. Phase 2: subjects rated fatigue on a scale of 0 (no fatigue) to 10 (severe fatigue) four times a day for 5 weeks. symptom assessment tools were available in both 2005 and 2009 for 74% of patients. FIS and HADS depression (HAD-D) and anxiety (HAD-A) scores significantly improved during follow-up whereas ESS and OGS remained stable. FIS improved in 29/74 (39%) subjects, and by ≥ 10 points in 19 (26%). FIS worsened by ≥ 10 points in 33/74 (45%) subjects. On multivariate analysis, independent predictors of current fatigue (FIS in 2009) were FIS in 2005, HAD-D in 2009, OGS in 2009 and change in HAD-A. Reported fatigue was stable from week to week and from day to day. Patients reported higher fatigue in the morning (mean ± SD; 6.4 ± 2), becoming significantly lower at lunchtime (6.2 ± 2; P < 0.05) and increasing again to 7 ± 2 at bedtime. current fatigue is independently associated with current autonomic symptom burden, current depression and change in anxiety during follow-up. These findings have implications for targeted symptom management in CFS.


Polymer-fullerene composite solar cells.
Fossil fuel alternatives, such as solar energy, are moving to the forefront in a variety of research fields. Polymer-based organic photovoltaic systems hold the promise for a cost-effective, lightweight solar energy conversion platform, which could benefit from simple solution processing of the active layer. The function of such excitonic solar cells is based on photoinduced electron transfer from a donor to an acceptor. Fullerenes have become the ubiquitous acceptors because of their high electron affinity and ability to transport charge effectively. The most effective solar cells have been made from bicontinuous polymer-fullerene composites, or so-called bulk heterojunctions. The best solar cells currently achieve an efficiency of about 5%, thus significant advances in the fundamental understanding of the complex interplay between the active layer morphology and electronic properties are required if this technology is to find viable application.


Systematic two-hybrid and comparative proteomic analyses reveal novel yeast pre-mRNA splicing factors connected to Prp19.
Prp19 is the founding member of the NineTeen Complex, or NTC, which is a spliceosomal subcomplex essential for spliceosome activation. To define Prp19 connectivity and dynamic protein interactions within the spliceosome, we systematically queried the Saccharomyces cerevisiae proteome for Prp19 WD40 domain interaction partners by two-hybrid analysis. We report that in addition to S. cerevisiae Cwc2, the splicing factor Prp17 binds directly to the Prp19 WD40 domain in a 1:1 ratio. Prp17 binds simultaneously with Cwc2 indicating that it is part of the core NTC complex. We also find that the previously uncharacterized protein Urn1 (Dre4 in Schizosaccharomyces pombe) directly interacts with Prp19, and that Dre4 is conditionally required for pre-mRNA splicing in S. pombe. S. pombe Dre4 and S. cerevisiae Urn1 co-purify U2, U5, and U6 snRNAs and multiple splicing factors, and dre4Δ and urn1Δ strains display numerous negative genetic interactions with known splicing mutants. The S. pombe Prp19-containing Dre4 complex co-purifies three previously uncharacterized proteins that participate in pre-mRNA splicing, likely before spliceosome activation. Our multi-faceted approach has revealed new low abundance splicing factors connected to NTC function, provides evidence for distinct Prp19 containing complexes, and underscores the role of the Prp19 WD40 domain as a splicing scaffold.


Use of Shigella flexneri to study autophagy-cytoskeleton interactions.
Shigella flexneri is an intracellular pathogen that can escape from phagosomes to reach the cytosol, and polymerize the host actin cytoskeleton to promote its motility and dissemination. New work has shown that proteins involved in actin-based motility are also linked to autophagy, an intracellular degradation process crucial for cell autonomous immunity. Strikingly, host cells may prevent actin-based motility of S. flexneri by compartmentalizing bacteria inside 'septin cages' and targeting them to autophagy. These observations indicate that a more complete understanding of septins, a family of filamentous GTP-binding proteins, will provide new insights into the process of autophagy. This report describes protocols to monitor autophagy-cytoskeleton interactions caused by S. flexneri in vitro using tissue culture cells and in vivo using zebrafish larvae. These protocols enable investigation of intracellular mechanisms that control bacterial dissemination at the molecular, cellular, and whole organism level.


Inferring nonneutral evolution from contrasting patterns of polymorphisms and divergences in different protein coding regions of enterovirus 71 circulating in Taiwan during 1998-2003.
Enterovirus (EV) 71 is one of the common causative agents for hand, foot, and, mouth disease (HFMD). In recent years, the virus caused several outbreaks with high numbers of deaths and severe neurological complications. Despite the importance of these epidemics, several aspects of the evolutionary and epidemiological dynamics, including viral nucleotide variations within and between different outbreaks, rates of change in immune-related structural regions vs. non-structural regions, and forces driving the evolution of EV71, are still not clear. We sequenced four genomic segments, i.e., the 5' untranslated region (UTR), VP1, 2A, and 3C, of 395 EV71 viral strains collected from 1998 to 2003 in Taiwan. The phylogenies derived from different genomic segments revealed different relationships, indicating frequent sequence recombinations as previously noted. In addition to simple recombinations, exchanges of the P1 domain between different species/genotypes of human enterovirus species (HEV)-A were repeatedly observed. Contrasting patterns of polymorphisms and divergences were found between structural (VP1) and non-structural segments (2A and 3C), i.e., the former was less polymorphic within an outbreak but more divergent between different HEV-A species than the latter two. Our computer simulation demonstrated a significant excess of amino acid replacements in the VP1 region implying its possible role in adaptive evolution. Between different epidemic seasons, we observed high viral diversity in the epidemic peaks followed by severe reductions in diversity. Viruses sampled in successive epidemic seasons were not sister to each other, indicating that the annual outbreaks of EV71 were due to genetically distinct lineages. Based on observations of accelerated amino acid changes and frequent exchanges of the P1 domain, we propose that positive selection and subsequent frequent domain shuffling are two important mechanisms for generating new genotypes of HEV-A. Our viral dynamics analysis suggested that the importation of EV71 from surrounding areas likely contributes to local EV71 outbreaks.


AddNeuroMed and ADNI: similar patterns of Alzheimer's atrophy and automated MRI classification accuracy in Europe and North America.
The European Union AddNeuroMed program and the US-based Alzheimer Disease Neuroimaging Initiative (ADNI) are two large multi-center initiatives designed to collect and validate biomarker data for Alzheimer's disease (AD). Both initiatives use the same MRI data acquisition scheme. The current study aims to compare and combine magnetic resonance imaging (MRI) data from the two study cohorts using an automated image analysis pipeline and a multivariate data analysis approach. We hypothesized that the two cohorts would show similar patterns of atrophy, despite demographic differences and could therefore be combined. MRI scans were analyzed from a total of 1074 subjects (AD=295, MCI=444 and controls=335) using Freesurfer, an automated segmentation scheme which generates regional volume and regional cortical thickness measures which were subsequently used for multivariate analysis (orthogonal partial least squares to latent structures (OPLS)). OPLS models were created for the individual cohorts and for the combined cohort to discriminate between AD patients and controls. The ADNI cohort was used as a replication dataset to validate the model created for the AddNeuroMed cohort and vice versa. The combined cohort model was used to predict conversion to AD at baseline of MCI subjects at 1 year follow-up. The AddNeuroMed, the ADNI and the combined cohort showed similar patterns of atrophy and the predictive power was similar (between 80 and 90%). The combined model also showed potential in predicting conversion from MCI to AD, resulting in 71% of the MCI converters (MCI-c) from both cohorts classified as AD-like and 60% of the stable MCI subjects (MCI-s) classified as control-like. This demonstrates that the methods used are robust and that large data sets can be combined if MRI imaging protocols are carefully aligned.


Shuttle case records: link between general practice and the specialist unit.
General practitioners have participated in the long term follow up of 367 patients who have undergone treatment with potent antirheumatic drugs at this hospital. Over the past two and a half years we have used the "shuttle case record" system, whereby patients' records are mailed back and forth between our department and general practitioners. This seems to work well. It is safe for the patients, and they save time and money in travel. The general practitioners like it, it improves communication between them and the specialist unit, and it enables the specialist unit to use its resources and manpower more effectively. The system may also be used to monitor patients with other chronic disorders, and it may be a valuable tool for doing research in general practice.


Living kidney donor informed consent practices vary between US and non-US centers.
Living kidney donation rates are increasing in the United States and internationally. Major consensus statements on the care of living kidney donors recommend communicating all potential health and psychosocial risks to donors. We evaluated the degree of international variation in the process of informed consent of potential donors during their evaluation. Transplant professionals attending the 2006 World Transplant Congress responded to a survey assessing their process of informed consent, evaluation and communication of living donor risk. US-based respondents were compared to non-US respondents. There were 221 respondents from 177 transplant centers and 40 countries (48% US respondents). Across US and non-US transplant centers, potential donors were most likely to receive written material about living donor risk by mail prior to evaluation, receive risk information in person during evaluation, have a psychosocial evaluation, which usually lasted longer than 30 min and sign an official donation consent form presented to them by a surgeon or nephrologist. Although over 75% of respondents stated that donors received information about medical risks such as hypertension, chronic kidney disease and potential need for dialysis, there was less consistency regarding whether or not respondents conveyed an increased risk of these medical complications to donors. Additionally, the financial and psychosocial costs associated with being a living donor were inconsistently communicated to donors during the informed consent process. Compared to non-US respondents, US respondents were more likely to use written material and visual aids to convey risks to donors, have mandatory psychosocial evaluations and provide access to donor support groups. US transplant centers were also more likely to discuss the possibility of the donors needing dialysis or a transplant if their remaining kidney fails in the future, possible travel expenses and loss of work income due to donation recovery. Conversely, the US respondents were less likely to offer long-term follow-up and to utilize nephrologists to obtain written donor consent for donation. As dependence on living organ donation increases best practices for informed consent, donor evaluation and uniform risk conveyance need to be established. This may be accomplished by using a model informed consent template to ensure that informed consent from donors is consistently obtained.


Chronic pain, opioid prescriptions, and mortality in Denmark: A population-based cohort study.
This study aimed to investigate the risk of death, development of cancer, and hospital inpatient admissions resulting from injuries and toxicity/poisoning among opioid users with chronic noncancer pain. A population-based cohort of 13,127 adults, who have participated in the Danish Health Interview Surveys in 2000 or 2005 and have been followed up prospectively by registers until the end of 2011, were classified according to the absence or presence of chronic pain (ie, pain lasting ⩾ 6 months) and long-term or short-term opioid use (individuals using at least 1 prescription per month for 6 months in the previous year and at least 1 prescription in the previous year, respectively). The risk of all-cause mortality was 1.72 (95% confidence interval [CI]=1.23-2.41) times higher among long-term opioid users than among individuals without chronic pain. The risk of death was lower, but still significantly higher in short-term (1.36, 95% CI=1.07-1.72) and non-opioid users with chronic pain (1.39, 95% CI=1.22-1.59) than in the background population. There was no statistically significant association between long-term opioid use and cardiovascular and cancer mortality. No deaths among opioid users were caused by accidents or suicides, although opioid users had higher risks of injuries and toxicity/poisoning resulting in hospital inpatient admissions than individuals without chronic pain. The risk of all-cause mortality was significantly higher among long-term opioid users, but no obvious associations between long-term opioid use and cause-specific mortality were observed. However, opioid use increased the risk of injuries and toxicity/poisoning resulting in hospital inpatient admissions.


Prevalence of hepatitis C virus infection in hemodialysis patients in Sudan.
To estimate the prevalence of positivity of hepatitis C virus (HCV) antibodies in the hemodialysis population in Sudan and the risk factors of this infection in them we studied 46 hemodialysis patients (34 males, 12 females) in the Khartoum Kidney Dialysis Center (KKDC) in December 1994. Also we studied 37 healthy staff members in that unit. The blood of both groups was screened for HCV antibodies using a second generation ELISA test and confirmed by two bead supplemental assays. In the patients group, 16 cases (34.9%) were confirmed seropositive for HCV. There was a history of jaundice in four them. The mean duration on dialysis was 3.28 years in the HCV seropositive group compared with 2.2 years in the HCV seronegative group (P < 0.05). The mean frequency of blood transfusion was 2.68 units of blood in the HCV seropositive group, while it was 3.16 units in the HCV seronegative group which was not significantly different. Only two patients had high liver enzymes in the HCV seropositive groups, while there were seven patients with high liver enzymes in the HCV seronegative group. There were two staff members (5.41%) with positive HCV antibodies, but none had a history of jaundice or elevated liver enzymes. Both staff members were not involved in the direct patients care. We conclude that the prevalence of HCV antibody positivity was high in the hemodialysis population in Sudan. Nosocomial transmission may be the factor of transmission since we found no correlation with the blood transfusions.


Regulatory B cells (B10 cells) have a suppressive role in murine lupus: CD19 and B10 cell deficiency exacerbates systemic autoimmunity.
B cells play critical roles in the pathogenesis of lupus. To examine the influence of B cells on disease pathogenesis in a murine lupus model, New Zealand Black and New Zealand White F(1) hybrid (NZB/W) mice were generated that were deficient for CD19 (CD19(-/-) NZB/W mice), a B cell-specific cell surface molecule that is essential for optimal B cell signal transduction. The emergence of anti-nuclear Abs was significantly delayed in CD19(-/-) NZB/W mice compared with wild type NZB/W mice. However, the pathologic manifestations of nephritis appeared significantly earlier, and survival was significantly reduced in CD19(-/-) NZB/W mice compared with wild type mice. These results demonstrate both disease-promoting and protective roles for B cells in lupus pathogenesis. Recent studies have identified a potent regulatory B cell subset (B10 cells) within the rare CD1d(hi)CD5(+) B cell subset of the spleen that regulates acute inflammation and autoimmunity through the production of IL-10. In wild type NZB/W mice, the CD1d(hi)CD5(+)B220(+) B cell subset that includes B10 cells was increased by 2.5-fold during the disease course, whereas CD19(-/-) NZB/W mice lacked this CD1d(hi)CD5(+) regulatory B cell subset. However, the transfer of splenic CD1d(hi)CD5(+) B cells from wild type NZB/W mice into CD19(-/-) NZB/W recipients significantly prolonged their survival. Furthermore, regulatory T cells were significantly decreased in CD19(-/-) NZB/W mice, but the transfer of wild type CD1d(hi)CD5(+) B cells induced T regulatory cell expansion in CD19(-/-) NZB/W mice. These results demonstrate an important protective role for regulatory B10 cells in this systemic autoimmune disease.


Automation of Detection of Cervical Cancer Using Convolutional Neural Networks.
Classification of digital cervical images acquired during visual inspection with acetic acid (VIA) is an important step in automated image-based cervical cancer detection. Many algorithms have been developed for classification of cervical images based on extracting mathematical features and classifying these images. Deciding the suitability of a feature and learning the algorithm is a complex task. On the other hand, convolutional neural networks (CNNs) self-learn most suitable hierarchical features from the raw input image. In this paper, we demonstrate the feasibility of using a shallow layer CNN for classification of image patches of cervical images as cancerous or not cancerous. We used cervix images acquired after the application of 3%-5% acetic acid using an Android device in 102 women. Of these, 42 cervix images belonged in the VIA-positive category (pathologic) and 60 in the VIA-negative category (healthy controls). A total of 275 image patches of 15 × 15 pixels were manually extracted from VIA-positive areas, and we considered these patches as positive examples. Similarly, 409 image patches were extracted from VIA-negative areas and were labeled as VIA negative. These image patches were classified using a shallow layer CNN composed of a layer each of convolutional, rectified linear unit, pooling, and two fully connected layers. A classification accuracy of 100% is achieved using shallow CNN.


Light sleep versus slow wave sleep in memory consolidation: a question of global versus local processes?
Sleep is strongly involved in memory consolidation, but its role remains unclear. 'Sleep replay', the active potentiation of relevant synaptic connections via reactivation of patterns of network activity that occurred during previous experience, has received considerable attention. Alternatively, sleep has been suggested to regulate synaptic weights homeostatically and nonspecifically, thereby improving the signal:noise ratio of memory traces. Here, we reconcile these theories by highlighting the distinction between light and deep nonrapid eye movement (NREM) sleep. Specifically, we draw on recent studies to suggest a link between light NREM and active potentiation, and between deep NREM and homeostatic regulation. This framework could serve as a key for interpreting the physiology of sleep stages and reconciling inconsistencies in terminology in this field.


KEGG for integration and interpretation of large-scale molecular data sets.
Kyoto Encyclopedia of Genes and Genomes (KEGG, http://www.genome.jp/kegg/ or http://www.kegg.jp/) is a database resource that integrates genomic, chemical and systemic functional information. In particular, gene catalogs from completely sequenced genomes are linked to higher-level systemic functions of the cell, the organism and the ecosystem. Major efforts have been undertaken to manually create a knowledge base for such systemic functions by capturing and organizing experimental knowledge in computable forms; namely, in the forms of KEGG pathway maps, BRITE functional hierarchies and KEGG modules. Continuous efforts have also been made to develop and improve the cross-species annotation procedure for linking genomes to the molecular networks through the KEGG Orthology system. Here we report KEGG Mapper, a collection of tools for KEGG PATHWAY, BRITE and MODULE mapping, enabling integration and interpretation of large-scale data sets. We also report a variant of the KEGG mapping procedure to extend the knowledge base, where different types of data and knowledge, such as disease genes and drug targets, are integrated as part of the KEGG molecular networks. Finally, we describe recent enhancements to the KEGG content, especially the incorporation of disease and drug information used in practice and in society, to support translational bioinformatics.


Vital Signs: Estimated Effects of a Coordinated Approach for Action to Reduce Antibiotic-Resistant Infections in Health Care Facilities - United States.
Treatments for health care-associated infections (HAIs) caused by antibiotic-resistant bacteria and Clostridium difficile are limited, and some patients have developed untreatable infections. Evidence-supported interventions are available, but coordinated approaches to interrupt the spread of HAIs could have a greater impact on reversing the increasing incidence of these infections than independent facility-based program efforts. Data from CDC's National Healthcare Safety Network and Emerging Infections Program were analyzed to project the number of health care-associated infections from antibiotic-resistant bacteria or C. difficile both with and without a large scale national intervention that would include interrupting transmission and improved antibiotic stewardship. As an example, the impact of reducing transmission of one antibiotic-resistant infection (carbapenem-resistant Enterobacteriaceae [CRE]) on cumulative prevalence and number of HAI transmission events within interconnected groups of health care facilities was modeled using two distinct approaches, a large scale and a smaller scale health care network. Immediate nationwide infection control and antibiotic stewardship interventions, over 5 years, could avert an estimated 619,000 HAIs resulting from CRE, multidrug-resistant Pseudomonas aeruginosa, invasive methicillin-resistant Staphylococcus aureus (MRSA), or C. difficile. Compared with independent efforts, a coordinated response to prevent CRE spread across a group of inter-connected health care facilities resulted in a cumulative 74% reduction in acquisitions over 5 years in a 10-facility network model, and 55% reduction over 15 years in a 102-facility network model. With effective action now, more than half a million antibiotic-resistant health care-associated infections could be prevented over 5 years. Models representing both large and small groups of interconnected health care facilities illustrate that a coordinated approach to interrupting transmission is more effective than historical independent facilitybased efforts. Public health-led coordinated prevention approaches have the potential to more completely address the emergence and dissemination of these antibiotic-resistant organisms and C. difficile than independent facility-based efforts.


Lower serum magnesium level after exposure to cold in women with primary Raynaud's phenomenon.
Serum levels of magnesium (s-Mg), calcium (s-Ca), potassium (s-K) and sodium (s-Na) were measured in 80 women with primary Raynaud's phenomenon (RP) and in 24 age-matched female controls recruited from a population survey. The blood samples were taken after a 40-min standardized whole body cooling test. The mean s-Mg level in the group with RP was significantly lower than in the controls (0.81 +/- 0.05 vs. 0.86 +/- 0.07 mmol l-1, P less than 0.05). One year later, 66 members of the RP group and 22 members of the control group were investigated further, but without any exposure to cold. No differences in mean s-Mg values were found between the groups. The mean s-Mg level was significantly higher in the blood samples taken later without cold exposure than at the initial examinations after exposure to cold in the RP group, but not in the controls. The s-Mg level was lower after exposure to cold in 82% of the women with RP, compared to 45% of the controls (P less than 0.001). No differences in the other electrolytes were found. It is concluded that exposure to cold under standardized conditions may decrease the s-Mg level in women with primary RP. Further studies of the role of magnesium in patients with RP are required.


Homotypic and heterotypic continuity of symptoms of psychiatric disorders from age 4 to 10 years: a dynamic panel model.
Childhood psychiatric disorders and their symptoms evince both within-disorder (homotypic) and between-disorder (heterotypic) continuities. These continuities may be due to earlier symptoms causing later symptoms or, alternatively, that the same (unknown) causes (e.g., genetics) are operating across time. Applying a novel data analytic approach, we disentangle these two explanations. Participants in a Norwegian community study were assessed biennially from 4 to 10 years of age with clinical interviews (n = 1,042). Prospective reciprocal relations between symptoms of disorders were analyzed with a dynamic panel model within a structural equation framework, adjusting for all unmeasured time-invariant confounders and time-varying negative life-events. Homotypic continuities in symptoms characterized all disorders; strongest for attention-deficit/hyperactivity disorder (ADHD) (r = .32-.62), moderate for behavioral disorders (r = .31-.48) and for anxiety and depression (r = .15-.40), and stronger between 8 and 10 than between 4 and 6 years. Heterotypic continuity also characterized all disorders. A dynamic panel model showed that most continuities were due to unmeasured time-invariant factors rather than effects of earlier symptoms on later symptoms, although symptoms of behavioral disorders, which evinced two-year homotypic continuity (B = .14, 95% CI: .04, .25), did influence later symptoms of ADHD (B = .13, CI: .03, .23), and earlier ADHD symptoms influenced later anxiety disorder symptoms (B = .07, CI: .01, .12). Homotypic and heterotypic continuities of symptoms of childhood psychiatric disorders are mostly due to unobserved time-invariant factors. Nonetheless, symptoms of earlier behavioral disorders may affect later symptoms of such disorders and of ADHD, and ADHD may increase the risk of later anxiety. Thus, even if interventions do not alter basic etiological factors, symptom reduction may itself cause later symptom reduction.


Probing tissue microstructure by diffusion skewness tensor imaging.
Probing the cellular structure of in vivo biological tissue is a fundamental problem in biomedical imaging and medical science. This work introduces an approach for analyzing diffusion magnetic resonance imaging data acquired by the novel tensor-valued encoding technique for characterizing tissue microstructure. Our approach first uses a signal model to estimate the variance and skewness of the distribution of apparent diffusion tensors modeling the underlying tissue. Then several novel imaging indices, such as weighted microscopic anisotropy and microscopic skewness, are derived to characterize different ensembles of diffusion processes that are indistinguishable by existing techniques. The contributions of this work also include a theoretical proof that shows that, to estimate the skewness of a diffusion tensor distribution, the encoding protocol needs to include full-rank tensor diffusion encoding. This proof provides a guideline for the application of this technique. The properties of the proposed indices are illustrated using both synthetic data and in vivo data acquired from a human brain.


Podocyte injuries exacerbate mesangial proliferative glomerulonephritis.
From the observations of morphology seen in early phases of the experimental models of the irreversible mesangial proliferative glomerulonephritis, we hypothesized that podocyte injury is one of the important factors in bringing upon irreversible glomerular alterations. To verify this hypothesis, we investigated whether podocyte injury induced by puromycin aminonucleoside (PAN) injection affects the mesangial alterations of anti-Thy 1.1 glomerulonephritis. Female Wistar rats were injected with 0.5 mg monoclonal antibody (mAb) 1-22-3 five days after the injection of 10 mg or 5 mg/100 g body weight (BW) of puromycin aminonucleoside (PAN), and sacrificed at 7 days or 8 weeks after the mAb 1-22-3 injection. Consecutive injections of 10 mg/100 g BW of PAN and mAb 1-22-3 caused the irreversible mesangial alteration with persistent proteinuria (at week 8, proteinuria 100.3 +/- 57.8 mg/24 h, matrix score 1.13 +/- 0.52, collagen type I score 2.04 +/- 0.53, mRNA for collagen type I 227 +/- 79% to the group with a single injection of 1-22-3). Although single injection of 5 mg/100 g BW of PAN was not capable of inducing abnormal proteinuria, consecutive injections of 5 mg/100 g BW of PAN and mAb 1-22-3 also caused irreversible mesangial alteration and persistent proteinuria. Podocyte injury might be an important factor that exacerbates mesangial proliferation and mesangial matrix expansion. The irreversible mesangial alterations caused by consecutive injections of PAN and mAb 1-22-3 may be a novel model that could be used to analyze the mechanism of progressive mesangial alteration.


Three-dimensional arm movements at constant equi-affine speed.
It has long been acknowledged that planar hand drawing movements conform to a relationship between movement speed and shape, such that movement speed is inversely proportional to the curvature to the power of one-third. Previous literature has detailed potential explanations for the power law's existence as well as systematic deviations from it. However, the case of speed-shape relations for three-dimensional (3D) drawing movements has remained largely unstudied. In this paper we first derive a generalization of the planar power law to 3D movements, which is based on the principle that this power law implies motion at constant equi-affine speed. This generalization results in a 3D power law where speed is inversely related to the one-third power of the curvature multiplied by the one-sixth power of the torsion. Next, we present data from human 3D scribbling movements, and compare the obtained speed-shape relation to that predicted by the 3D power law. Our results indicate that the introduction of the torsion term into the 3D power law accounts for significantly more of the variance in speed-shape relations of the movement data and that the obtained exponents are very close to the predicted values.


A workshop on urinalysis and a survey on urine microscopy among kidney centers of Iran.
Urinalysis is a mandatory diagnostic tool for the evaluation of patients with kidney diseases. A workshop on urinalysis was held for nephrologists in Isfahan, Iran, on October 11-12, 2012. After the presentation of the results of a survey of the nephrology centers of Iran on urine microscopy, the most important aspects of urinalysis were presented and discussed. These included the following: (1) urinalysis by dipstick, which provides results in a few seconds, is simple to use, has a low cost, and is used worldwide for screening purposes, in spite of some limitations; (2) measurement of proteinuria by 24-hour urine collection, which still represents the reference method in spite of limitations due to frequent over or under collection errors; (3) protein-creatinine ratio in a random urine sample, which is recommended by international guidelines as an alternative to the measurement of 24-hour protein excretion; (4) microalbuminuria, which is seen as a marker of systemic endothelial damage; and (5) the urinary sediment, which is underused even among nephrologists in spite of the relevant diagnostic information it can supply in a wide spectrum of kidney diseases.


What Is the Common Ground for Modern Psychotherapy? A Discussion Paper Based on EACLIPT's 1st Webinar.
Psychotherapy as it is implemented today, can be seen as the composition of unconnected groups of practitioners and scientists pursuing different theories. The idea of finding a common "umbrella" for all evidence-based treatments in the field of psychotherapy is gaining more interest. Based on this background, experts in clinical psychology from various backgrounds led a fundamental discussion about modern psychotherapy and its basic mechanisms. Process-Based Therapy (PBT) was presented by Stefan Hofmann as a possible novel approach to clinical research and practice. In this article we present the different perspectives of the four panelists on PBT and in how far the model builds a common ground for different treatment approaches. Learning mechanisms and the therapeutic alliance were almost unanimously considered as indispensable factors in a global model of psychotherapy. In conclusion, the panelists emphasized a much-needed focus on characteristics and competencies of therapists themselves e.g., in communication, listening and empathy. These core competencies should be trained and promoted independently of the therapeutic approach.


Functional subclasses of T-lymphocytes bearing different Ly antigens. I. The generation of functionally distinct T-cell subclasses is a differentiative process independent of antigen.
Ly alloantigens coded by two unlinked genetic loci (Ly-1 and Ly-2/Ly-3) are expressed on lymphoid cells undergoing thymus-dependent differentiation. Peripheral Thy-1+ cells from C57BL/6 mice can be divided into three subclasses on the basis of differential expression of Ly-1, Ly-2, and Ly-3; about 50% express all three Ly antigens (Ly -123+), about 33% only Ly-1 (Ly-1+), and about 6-8% Ly-2 and Ly-3 (Ly-23+). Cells of the Ly-123+ subclasses are the first peripheral Thy-1+ cells to appear in ontogeny, and are reduced in the periphery shortly after adult thymectomy. In contrast, Ly-1+ and Ly-23+ subclasses appear later in the peripheral tissues than do Ly-123+ cells, and are resistant to the early effects of adult thymectomymperiheral lymphoid populations depleted of Ly-1+ cells and Ly-123+ cells (and thereby enriched for Ly-23+ cells) were incapable of developing significant helper activity to SRBC but generated substantial levels of cytotoxic activity to allogeneic target cells. The same lymphoid populations, depleted of Ly-23+ cells and Ly-123+ cells (and thereby enriched for Ly-1+ cells), produced substantial helper responses but were unable to generate appreciable levels of killer activity. These experiments imply that commitment of T cells to participate exclusively in either helper or cytotoxic function is a differentiative process that takes place before they encounter antigen, and is accompanied by exclusion of different Ly groups, Lu-23 or Ly-1 respectively, from TL+Ly-123+ T-cell precursors. It is yet to be decided whether the TL-phase by Ly-123+ subclass is a transitional form or a separately differentiated subclass with a discrete immunologic function.


Original research: using guided imagery to manage pain in young children with sickle cell disease.
Despite innovations in treatment, disease-related pain is still the primary cause of hospitalization for children with sickle cell disease. Pharmacologic pain management relieves pain temporarily, but adverse effects are increasingly a concern. Cognitive behavioral therapies, which include the use of guided imagery, have shown promise in changing pain perception and coping patterns in people with chronic illnesses. Few studies have been done in children with sickle cell disease. The purposes of this study were to test the effects of guided imagery training on school-age children who had been diagnosed with sickle cell disease, and to describe changes in pain perception, analgesic use, self-efficacy, and imaging ability from the month before to the month after training. A quasi-experimental interrupted time-series design was used with a purposive sample of 20 children ages six to 11 years enrolled from one sickle cell disease clinic, where they had been treated for at least one year. Children completed pain diaries daily for two months, and investigators measured baseline and end-of-treatment imaging ability and self-efficacy. After training in the use of guided imagery, participants reported significant increases in self-efficacy and reductions in pain intensity, and use of analgesics decreased as well. Guided imagery is an effective technique for managing and limiting sickle cell disease-related pain in a pediatric population.


Drivers and barriers of vaccine acceptance among pregnant women in Kenya.
Maternal vaccination coverage remains suboptimal globally and is lowest in low- and middle-income countries. Attitudes toward maternal vaccines have been characterized in middle-high income settings, however data from African countries are limited. We assessed drivers and barriers of vaccine acceptance among pregnant women in Kenya. We conducted a cross-sectional survey among pregnant women aged 15-49 y. We enrolled a convenience sample of women presenting for antenatal care at seven health-care facilities in four diverse counties (Nairobi, Mombasa, Marsabit, Siaya) of Kenya and from the community in two counties (Nairobi, Siaya). We described frequencies of socio-demographic characteristics of participants and their knowledge, attitudes, and beliefs regarding maternal vaccination. We enrolled 604 pregnant women with a median age of 26.5 y, of whom 48.2% had primary education or less. More than 95% agreed that maternal vaccines are "important for my health" and that getting vaccinated is "a good way to protect myself from disease". The most commonly cited reason in favor of maternal vaccination was disease prevention (53.2%). Fear of side effects to mother/baby (15.1%) was the most frequently reported potential barrier. Influenza vaccine is not in routine use in Kenya; however, 77.8% reported willingness to accept influenza vaccination during pregnancy. Maternal vaccination is well accepted among Kenyan pregnant women. We identified the provision of adequate vaccine information and addressing safety concerns as opportunities to improve maternal vaccine uptake. The expressed willingness to receive a vaccine not currently in routine use bodes well for implementation of new maternal vaccines in Kenya.


PCB-47, PBDE-47, and 6-OH-PBDE-47 differentially modulate human GABAA and alpha4beta2 nicotinic acetylcholine receptors.
Polychlorinated biphenyls (PCBs) and the structurally related polybrominated diphenyl ethers (PBDEs) are abundant persistent organic pollutants that exert several comparable neurotoxic effects. Importantly, hydroxylated metabolites of PCBs and PBDEs have an increased neurotoxic potency. Recently, we demonstrated that PCBs can act as (partial) agonist on GABA(A) neurotransmitter receptors, with PCB-47 being the most potent congener. It is, however, unknown whether PBDE-47 and its metabolite 6-OH-PBDE-47 exert similar effects and if these effects are limited to GABA(A) receptors only. We therefore investigated effects of PCB-47, PBDE-47, and 6-OH-PBDE-47 on the inhibitory GABA(A) and excitatory α(4)β(2) nicotinic acetylcholine (nACh) receptor expressed in Xenopus oocytes using the two-electrode voltage-clamp technique. Since human exposure is generally not limited to individual compounds, experiments with binary mixtures were also performed. The results demonstrate that PCB-47 and 6-OH-PBDE-47 act as full and partial agonist on the GABA(A) receptor. However, both congeners act as antagonist on the nACh receptor. PBDE-47 does not affect either type of receptor. Binary mixtures of PCB-47 and 6-OH-PBDE-47 induced an additive activation as well as potentiation of GABA(A) receptors, whereas this mixture resulted in an additive inhibition of nACh receptors. Binary mixtures of PBDE-47 and 6-OH-PBDE-47 yielded similar effects as 6-OH-PBDE-47 alone. These findings demonstrate that GABA(A) and nACh receptors are affected differently by PCB-47 and 6-OH-PBDE-47, with inhibitory GABA(A)-mediated signaling being potentiated and excitatory α(4)β(2) nACh-mediated signaling being inhibited. Considering these opposite actions and the additive interaction of the congeners, these effects are likely to be augmented in vivo.


Vitamin D deficiency and muscle strength in male alcoholics.
1. Chronic alcoholism may be complicated by proximal muscle weakness associated with a selective atrophy of type II skeletal muscle fibres. The histopathological findings are non-specific as identical changes are seen in proximal muscle weakness associated with various metabolic myopathies, including osteomalacia. 2. The maximum voluntary contraction (MVC) of the dominant quadriceps and plasma 25-hydroxycholecalciferol [25-(OH)D] were measured in male alcoholics and control subjects to determine whether vitamin D deficiency contributed to proximal muscle weakness. 3. In both groups MVC declined with age and was related to body build. The distribution of plasma 25-(OH)D was skewed in alcoholics, with the mean significantly lower than in control subjects. Seventeen per cent of patients (but none of the control subjects) had pronounced biochemical deficiency [plasma 25-(OH)D less than 10 nmol/l]. 4. Alcoholics were significantly weaker than control subjects, even after correcting for the effects of age, height and weight. The severity of associated liver disease (cirrhosis vs no cirrhosis) did not influence muscle strength. Variation in plasma 25-(OH)D and albumin made an insignificant contribution to the difference in MVC observed between patients and control subjects. 5. We conclude that proximal muscle strength is reduced in chronic alcoholism but that this is not due to associated vitamin D [25-(OH)D] deficiency or alcoholic cirrhosis.


Iterative Subspace Screening for Rapid Sparse Estimation of Brain Tissue Microstructural Properties.
Diffusion magnetic resonance imaging (DMRI) is a powerful imaging modality due to its unique ability to extract microstructural information by utilizing restricted diffusion to probe compartments that are much smaller than the voxel size. Quite commonly, a mixture of models is fitted to the data to infer microstructural properties based on the estimated parameters. The fitting process is often non-linear and computationally very intensive. Recent work by Daducci et al. has shown that speed improvement of several orders of magnitude can be achieved by linearizing and recasting the fitting problem as a linear system, involving the estimation of the volume fractions associated with a set of diffusion basis functions that span the signal space. However, to ensure coverage of the signal space, sufficiently dense sampling of the parameter space is needed. This can be problematic because the number of basis functions increases exponentially with the number of parameters, causing computational intractability. We propose in this paper a method called iterative subspace screening (ISS) for tackling this ultrahigh dimensional problem. ISS requires only solving the problem in a medium-size subspace with a dimension that is much smaller than the original space spanned by all diffusion basis functions but is larger than the expected cardinality of the support of the solution. The solution obtained for this subspace is used to screen the basis functions to identify a new subspace that is pertinent to the target problem. These steps are performed iteratively to seek both the solution subspace and the solution itself. We apply ISS to the estimation of the fiber orientation distribution function (ODF) and demonstrate that it improves estimation robustness and accuracy.


Dietary choline supplementation improves behavioral, histological, and neurochemical outcomes in a rat model of traumatic brain injury.
Novel pharmacological approaches that safely and effectively lessen the degree of neurological impairment following traumatic brain injury (TBI) are sorely needed. Non-invasive approaches that could be used over an extended periods of time might be particularly useful. Previous studies from our lab have hypothesized that TBI-induced decreases in hippocampal and cortical alpha7 neuronal nicotinic cholinergic receptor (nAChR) expression might contribute to cognitive impairment that follows brain injury. The purpose of this study was to determine whether the low-potency, but selective alpha7 nAChR agonist choline might be a useful treatment for improvement of neurological outcome in a rat model of TBI. Male Sprague-Dawley rats were exposed to control or choline-supplemented diets for 2 weeks prior to experimental brain injury (1.5-mm cortical contusion injury) and throughout the recovery phase. Dietary choline supplementation resulted in a modest degree of improvement in spatial memory as assessed in the Morris water maze test. In addition, choline treatment resulted in significant cortical tissue sparing, reduced brain inflammation, and normalized some TBI-induced deficits in nAChR expression. The results of this study suggest that alpha7 nAChR agonists may be useful drugs to enhance recovery following brain injury.


Radiographic diagnosis of diaphragmatic hernia: review of 60 cases in dogs and cats.
Sixty cases of diaphragmatic hernia in dogs and cats were radiologically reviewed and categorized by their characteristic radiographic signs. Any particular predilection for age, sex, or breed was not observed. Liver, stomach and small intestine were more commonly herniated. At least two radiographs, at different angles, were required for a valid diagnosis, because some radiographic signs were not visible in a single radiographic view and more clearly detectable in two radiographic views. In addition to previously reported radiographic signs for diaphragmatic hernia, we found that the location of the stomach axis and the displacement of tracheal and bronchial segments were also useful radiographic signs.


Integrating the issues of global and veterinary public health into the veterinary education curriculum: an Australian perspective.
This article discusses the integration of global and veterinary public health issues into the Australian veterinary curriculum. Formal veterinary education in Australia has a history of over 100 years and veterinarians have played a major role in the control of zoonotic and transboundary diseases for an even longer period. Australia is the largest exporter of red meat and live animals in the world. Therefore, educating veterinarians to promote and ensure food safety and animal welfare is prominent in Australian veterinary curricula. Veterinary degrees are accredited to allow Australian graduates to work professionally overseas, including in the United Kingdom and United States of America, and, in recent years, globalisation of the student body at Australian veterinary schools has occurred. For this reason, an appropriately broad curriculum is required to produce graduates who are able to address challenges in veterinary public health throughout the world. A Public Health University Network has been established to harmonise the veterinary public health curricula at the various veterinary schools and to develop the 'Australian veterinary public health philosophy', with its links to global issues and the 'One World, One Health' concept. Finally, conclusions are drawn on the implications of veterinary public health teaching in Australia and the preparation of Australian graduates for the global profession.


Modification of the existing maximum residue levels for flupyradifurone and DFA in okra/lady's finger.
In accordance with Article 6 of Regulation (EC) No 396/2005, FPS Public Health, Food Chain Safety and Environment on behalf of Belgium (evaluating Member State, EMS) submitted an application to modify the existing maximum residue levels (MRLs) for the active substance flupyradifurone and its metabolite difluoroacetic acid (DFA) in okra/lady's finger. The data submitted in support of the request were found sufficient to derive MRL proposals for the crop under consideration. The potential contribution of DFA residues in okra/lady's finger from the soil uptake was also estimated. Adequate analytical methods for enforcement are available to control the relevant residues in the crop under consideration. Based on the risk assessment results, EFSA concluded that the long-term intake of residues of flupyradifurone and of its soil metabolite DFA resulting from the use of flupyradifurone is unlikely to present a risk to consumer health. Due to the lack of proper consumption data of okra/lady's finger, the acute exposure assessment could not be reliably undertaken but due to this crop being a minor commodity it is unlikely that acute consumer intake concerns will be associated with this crop.


Scaled particle theory for hard sphere pairs. I. Mathematical structure.
We develop an extension of the original Reiss-Frisch-Lebowitz scaled particle theory that can serve as a predictive method for the hard sphere pair correlation function g(r). The reversible cavity creation work is analyzed both for a single spherical cavity of arbitrary size, as well as for a pair of identical such spherical cavities with variable center-to-center separation. These quantities lead directly to a prediction of g(r). Smooth connection conditions have been identified between the small-cavity situation where the work can be exactly and completely expressed in terms of g(r), and the large-cavity regime where macroscopic properties become relevant. Closure conditions emerge which produce a nonlinear integral equation that must be satisfied by the pair correlation function. This integral equation has a structure which straightforwardly generates a solution that is a power series in density. The results of this series replicate the exact second and third virial coefficients for the hard sphere system via the contact value of the pair correlation function. The predicted fourth virial coefficient is approximately 0.6% lower than the known exact value. Detailed numerical analysis of the nonlinear integral equation has been deferred to the subsequent paper.


Mistranslation drives the evolution of robustness in TEM-1 β-lactamase.
How biological systems such as proteins achieve robustness to ubiquitous perturbations is a fundamental biological question. Such perturbations include errors that introduce phenotypic mutations into nascent proteins during the translation of mRNA. These errors are remarkably frequent. They are also costly, because they reduce protein stability and help create toxic misfolded proteins. Adaptive evolution might reduce these costs of protein mistranslation by two principal mechanisms. The first increases the accuracy of translation via synonymous "high fidelity" codons at especially sensitive sites. The second increases the robustness of proteins to phenotypic errors via amino acids that increase protein stability. To study how these mechanisms are exploited by populations evolving in the laboratory, we evolved the antibiotic resistance gene TEM-1 in Escherichia coli hosts with either normal or high rates of mistranslation. We analyzed TEM-1 populations that evolved under relaxed and stringent selection for antibiotic resistance by single molecule real-time sequencing. Under relaxed selection, mistranslating populations reduce mistranslation costs by reducing TEM-1 expression. Under stringent selection, they efficiently purge destabilizing amino acid changes. More importantly, they accumulate stabilizing amino acid changes rather than synonymous changes that increase translational accuracy. In the large populations we study, and on short evolutionary timescales, the path of least resistance in TEM-1 evolution consists of reducing the consequences of translation errors rather than the errors themselves.


Augmented laminography, a correlative 3D imaging method for revealing the inner structure of compressed fossils.
Non-destructive imaging techniques can be extremely useful tools for the investigation and the assessment of palaeontological objects, as mechanical preparation of rare and valuable fossils is precluded in most cases. However, palaeontologists are often faced with the problem of choosing a method among a wide range of available techniques. In this case study, we employ x-ray computed tomography (CT) and computed laminography (CL) to study the first fossil xiphosuran from the Muschelkalk (Middle Triassic) of the Netherlands. The fossil is embedded in micritic limestone, with the taxonomically important dorsal shield invisible, and only the outline of its ventral part traceable. We demonstrate the complementarity of CT and CL which offers an excellent option to visualize characteristic diagnostic features. We introduce augmented laminography to correlate complementary information of the two methods in Fourier space, allowing to combine their advantages and finally providing increased anatomical information about the fossil. This method of augmented laminography enabled us to identify the xiphosuran as a representative of the genus Limulitella.


The influence of episodic foresight on delay discounting and demand for alcohol.
There is a near-universal tendency to discount the value of delayed rewards relative to those available in the here and now. The rate at which future rewards become devalued over time, delay discounting, is an important individual difference variable related to impulsivity and is elevated in externalising disorders, including alcohol use disorders. Recent research suggests that vividly imagining personally relevant future events (episodic foresight) during an intertemporal choice task can attenuate the rate at which delayed rewards are discounted. The present study sought to extend these findings by examining the effect of episodic foresight on both delay discounting and alcohol-related decision-making. Forty-eight college students were administered both modified intertemporal choice and hypothetical alcohol purchase tasks during which personally relevant episodic future event cues or control imagery cues were presented. Engaging in episodic foresight reduced both the rate at which delayed monetary rewards were discounted and initial alcohol demand intensity (but not other demand indices) relative to control imagery. Findings suggest that the attenuating effect of episodic foresight on impulsivity may be limited to particular aspects of impulsive choice.


Effects of ghrelin on circulating neuropeptide Y levels in humans.
Ghrelin is a 28 amino-acid peptide with a strong GH-releasing activity and a complex role in regulation of appetite, fuel utilization, body weight and composition. Neuropeptide Y (NPY) is a well-known stimulator of pathways favouring food intake and energy storage. Recently, studies in rodents suggested a possible mediation of ghrelin action by NPY. In contrast, until now no evidence of ghrelin-NPY interaction in humans has been provided. In the present study, we examined whether ghrelin influences NPY secretion in normal men. Twelve healthy normal men (aged 24-35 years; body mass index (BMI) 22.3+/-0.93 kg/m2) were tested twice at 08.00 AM on two different days, in random order at weekly intervals, after an overnight fast and rest in bed. An intravenous bolus of 1 microg/kg body weight ghrelin (esperimental test) or an equal amount of normal saline (control test) was injected at time 0. Blood was taken before and over 90 minutes after injections, and was used for the measurement of plasma NPY levels. Plasma levels of NPY slightly, but significantly rose in response to ghrelin, with a mean peak level at 15 min after injection, whereas no significant change was observed after saline administration. Our results show a significant enhancement of plasma NPY levels under ghrelin stimulation. To our knowledge, this is the first demonstration of a ghrelin-NPY interaction in humans, which may suggest a possible mediation of ghrelin action by NPY in humans.


HIGH PREVALENCE OF VOLUNTARY STERILIZATION AMONG AMERICAN WOMEN EXPLAINED BY TRADE-OFFS RESULTING FROM MALE PARENTAL COMMITMENT.
Tubal ligation is the modal form of family planning among American women aged 30 and older. As the preference for tubal ligation over cheaper, lower risk and more reliable methods, such as vasectomy, has puzzled experts, a theoretical approach that explains this preference would be useful. The present study investigates the high prevalence of voluntary sterilization among American women from the perspective of life history theory, arguing that the trade-offs between investing in current and future offspring will favour tubal ligation when women cannot obtain reliable male commitment to future parental investment. Data came from the National Survey of Fertility Barriers (NSFB), a nationally representative survey of 4712 American women aged 25-45 conducted between 2004 and 2007. Four novel predictions of the prevalence of tubal ligation, drawn from life history theory, were developed and tested: 1) it is most common among unpartnered women with children, and least common among married women with children; 2) it is negatively correlated with age at first birth; 3) it is least common among highly educated women without children, and most common among less educated women with children; and 4) among women with two or more children, it is positively correlated with lifetime number of long-term partners. These predictions were tested using multivariate regression analysis. The first prediction was not supported: women with children were more likely to be sterilized, regardless of their marital status. The other three predictions were all supported by the data. The results suggest that trade-offs influence women's decisions to undergo voluntary sterilization. Women are most likely to opt for tubal ligation when the costs of an additional child will impinge on their ability to invest in existing offspring, especially in the context of reduced male commitment.


Vorapaxar in acute coronary syndrome patients undergoing coronary artery bypass graft surgery: subgroup analysis from the TRACER trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome).
This study evaluated effects of protease-activated receptor-1 antagonist vorapaxar (Merck, Whitehouse Station, New Jersey) versus placebo among the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) study patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass grafting (CABG). Platelet activation may play a key role in graft occlusion, and antiplatelet therapies may reduce ischemic events, but perioperative bleeding risk remains a major concern. Although the TRACER study did not meet the primary quintuple composite outcome in the overall population with increased bleeding, an efficacy signal with vorapaxar was noted on major ischemic outcomes, and preliminary data suggest an acceptable surgical bleeding profile. We aimed to assess efficacy and safety of vorapaxar among CABG patients. Associations between treatment and ischemic and bleeding outcomes were assessed using time-to-event analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox hazards model. Event rates were estimated using the Kaplan-Meier method. Among 12,944 patients, 1,312 (10.1%) underwent CABG during index hospitalization, with 78% on the study drug at the time of surgery. Compared with placebo CABG patients, vorapaxar-treated patients had a 45% lower rate of the primary endpoint (i.e., a composite of death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization during index hospitalization) (HR: 0.55; 95% CI: 0.36 to 0.83; p = 0.005), with a significant interaction (p = 0.012). The CABG-related Thrombolysis In Myocardial Infarction major bleeding was numerically higher with vorapaxar, but not significantly different between vorapaxar and placebo (9.7% vs. 7.3%; HR: 1.36; 95% CI: 0.92 to 2.02; p = 0.12), with no excess in fatal bleeding (0% vs. 0.3%) or need for reoperation (4.7% vs. 4.6%). In non-ST-segment elevation acute coronary syndrome patients undergoing CABG, vorapaxar was associated with a significant reduction in ischemic events and no significant increase in major CABG-related bleeding. These data show promise for protease-activated receptor 1 antagonism in patients undergoing CABG and warrant confirmatory evidence in randomized trials. (Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome [TRA·CER] [Study P04736AM3]; NCT00527943).


Tumor progression in patients receiving adjuvant whole-brain radiotherapy vs localized radiotherapy after surgical resection of brain metastases.
Surgery followed by adjuvant radiotherapy is a well-established treatment paradigm for brain metastases. To examine the effect of postsurgical whole-brain radiotherapy (WBRT) or localized radiotherapy (LRT), including stereotactic radiosurgery and intraoperative radiotherapy, on the rate of recurrence both local and distal to the resection site in the treatment of brain metastases. We retrospectively identified patients who underwent surgery for brain metastasis at the Cleveland Clinic between 2004 and 2012. Institutional review board-approved chart review was conducted, and patients who had radiation before surgery, who had nonmetastatic lesions, or who lacked postadjuvant imaging were excluded. The final analysis included 212 patients. One hundred fifty-six patients received WBRT, 37 received stereotactic radiosurgery only, and 19 received intraoperative radiotherapy. One hundred forty-six patients were deceased, of whom 60 (41%) died with no evidence of recurrence. Competing risks methodology was used to test the association between adjuvant modality and progression. Multivariable analysis revealed no significant difference in the rate of recurrence at the resection site (hazard ratio [HR] 1.46, P = .26) or of unresected, radiotherapy-treated lesions (HR 1.70, P = .41) for LRT vs WBRT. Patients treated with LRT had an increased hazard of the development of new lesions (HR 2.41, P < .001) and leptomeningeal disease (HR 2.45, P = .04). Median survival was 16.5 months and was not significantly different between groups. LRT as adjuvant treatment to surgical resection of brain metastases is associated with an increased rate of development of new distant metastases and leptomeningeal disease compared with WBRT, but not with recurrence at the resection site or of unresected lesions treated with radiation.


Population-Level Density Dependence Influences the Origin and Maintenance of Parental Care.
Parental care is a defining feature of animal breeding systems. We now know that both basic life-history characteristics and ecological factors influence the evolution of care. However, relatively little is known about how these factors interact to influence the origin and maintenance of care. Here, we expand upon previous work and explore the relationship between basic life-history characteristics (stage-specific rates of mortality and maturation) and the fitness benefits associated with the origin and the maintenance of parental care for two broad ecological scenarios: the scenario in which egg survival is density dependent and the case in which adult survival is density dependent. Our findings suggest that high offspring need is likely critical in driving the origin, but not the maintenance, of parental care regardless of whether density dependence acts on egg or adult survival. In general, parental care is more likely to result in greater fitness benefits when baseline adult mortality is low if 1) egg survival is density dependent or 2) adult mortality is density dependent and mutant density is relatively high. When density dependence acts on egg mortality, low rates of egg maturation and high egg densities are less likely to lead to strong fitness benefits of care. However, when density dependence acts on adult mortality, high levels of egg maturation and increasing adult densities are less likely to maintain care. Juvenile survival has relatively little, if any, effect on the origin and maintenance of egg-only care. More generally, our results suggest that the evolution of parental care will be influenced by an organism's entire life history characteristics, the stage at which density dependence acts, and whether care is originating or being maintained.


Effects of astaxanthin on oxidative stress in overweight and obese adults.
Oxidative stress is caused by an imbalance between the antioxidant and the reactive oxygen species, which results in damage to cells or tissues. Recent studies have reported that oxidative stress is involved in obesity, in addition to many other human diseases and aging. A prospective, randomized, double-blind study was performed to investigate the effect of astaxanthin (ASX), which is known to be a potent antioxidant, on oxidative stress in overweight and obese adults in Korea. Twenty-three adults with BMI > 25.0 kg/m(2) enrolled in this study and were randomly assigned to two dose groups: ASX 5 mg and 20 mg once daily for 3 weeks. Malondialdehyde (MDA), isoprostane (ISP), superoxide dismutase (SOD) and total antioxidant capacity (TAC), as oxidative stress biomarkers, were measured at baseline and 1, 2 and 3 weeks after ASX administration. Compared with baseline, the MDA (by 34.6% and 35.2%) and ISP (by 64.9% and 64.7%) levels were significantly lowered, whereas SOD (by 193% and 194%) and TAC (by 121% and 125%) levels were significantly increased in two dose groups after the 3 week intervention. This study revealed that supplemental ASX for 3 weeks improved oxidative stress biomarkers by suppressing lipid peroxidation and stimulating the activity of the antioxidant defense system.


Temporal events underlying arterial remodeling after chronic flow reduction in mice: correlation of structural changes with a deficit in basal nitric oxide synthesis.
To define the cellular events of vascular remodeling in mice, we measured blood flow and analyzed the morphology of remodeled vessels at defined points after a flow-reducing remodeling stimulus for 3, 7, 14, and 35 days. Acute ligation of the left external carotid artery reduced blood flow in the left common carotid artery (LC) compared with sham and contralateral right common carotid arteries (RCs). In morphometric analyses, the decrease in diameter in LCs was reversible by vasodilator perfusion 3 days after ligation, whereas ligation for 7 days or greater resulted in a permanent diameter reduction. Coincident with structural remodeling at day 7 was an increase in cell death in remodeled LCs. Functionally, rings from remodeled LCs contracted to prostaglandin F(2alpha) and relaxed to acetylcholine in a manner identical to that of control arteries. However, remodeled LCs were hypersensitive to the nitrovasodilator sodium nitroprusside (at day 7) and exhibited a marked reduction in basal NO synthesis at 7 and 14 days after ligation. The impairment of endothelial NO synthase function was likely due to post-translational mechanisms, given that endothelial NO synthase mRNA and protein levels did not change in remodeled LCs. These data define the ontogeny of flow-triggered luminal remodeling in adult mice and suggest that endothelial dysfunction occurs during reorganization of the vessel wall.


Submerged Osmotic Processes: Design and Operation to Mitigate Mass Transfer Limitations.
Submerged forward osmosis (FO) is of high interest for bioreactors, such as osmotic membrane bioreactor, microalgae photobioreactor, food or bioproduct concentration where pumping through pressurized modules is a limitation due to viscosity or breakage of fragile components. However, so far, most FO efforts have been put towards cross flow configurations. This study provides, for the first time, insights on mass transfer limitations in the operation of submerged osmotic systems and offer recommendations for optimized design and operation. It is demonstrated that operation of the submerged plate and frame FO module requires draw circulation in the vacuum mode (vacuum assisted osmosis) that is in favor of the permeation flux. However, high pressure drops and dead zones occurring in classical U-shape FO draw channel strongly disadvantage this design; straight channel design proves to be more effective. External concentration polarization (ECP) is also a crucial element in the submerged FO process since mixing of the feed solution is not as optimized as in the cross flow module unless applying intense stirring. Among the mitigation techniques tested, air scouring proves to be more efficient than feed solution circulation. However, ECP mitigation methodology has to be adapted to application specificities with regards to combined/synergetic effects with fouling mitigation.


The inhibition of human farnesyl pyrophosphate synthase by nitrogen-containing bisphosphonates. Elucidating the role of active site threonine 201 and tyrosine 204 residues using enzyme mutants.
Farnesyl pyrophosphate synthase (FPPS) is the major molecular target of nitrogen-containing bisphosphonates (N-BPs), used clinically as bone resorption inhibitors. We investigated the role of threonine 201 (Thr201) and tyrosine 204 (Tyr204) residues in substrate binding, catalysis and inhibition by N-BPs, employing kinetic and crystallographic studies of mutated FPPS proteins. Mutants of Thr201 illustrated the importance of the methyl group in aiding the formation of the Isopentenyl pyrophosphate (IPP) binding site, while Tyr204 mutations revealed the unknown role of this residue in both catalysis and IPP binding. The interaction between Thr201 and the side chain nitrogen of N-BP was shown to be important for tight binding inhibition by zoledronate (ZOL) and risedronate (RIS), although RIS was also still capable of interacting with the main-chain carbonyl of Lys200. The interaction of RIS with the phenyl ring of Tyr204 proved essential for the maintenance of the isomerized enzyme-inhibitor complex. Studies with conformationally restricted analogues of RIS reaffirmed the importance of Thr201 in the formation of hydrogen bonds with N-BPs. In conclusion we have identified new features of FPPS inhibition by N-BPs and revealed unknown roles of the active site residues in catalysis and substrate binding.


Some sex hormone profiles are consistent over time in normal menstruating women: implications for sports injury epidemiology.
It is unclear whether sex hormone profiles obtained in two consecutive months are consistent within women. Month-to-month consistency in daily, nadir, peak and mean hormone concentrations during the early follicular and luteal phases in recreationally active, young eumenorrheic women was prospectively examined. 60 healthy, non-smoking women who reported normal and consistent menstrual cycles lasting 26-32 days for the past 6 months were followed prospectively to obtain serum samples for the first 6 days of menses and for 8 days after a positive ovulation test over two consecutive months. Month-to-month consistency of daily concentrations of oestradiol (pg/ml), progesterone (ng/ml), testosterone (ng/dl), sex hormone-binding globulin (nmol/l) and free androgen index were determined using linear mixed models. Month-to-month consistency in nadir, peak and mean concentrations were then assessed using intraclass correlation coefficients and SEM to more precisely examine intraindividual consistency. Linear mixed models revealed stable hormone concentrations across cycles and cycles by day. Reliability estimates for nadir, peak, mean menses and mean postovulatory concentrations range from 0.56 to 0.86 for oestradiol, 0.44 to 0.91 for progesterone, 0.60 to 0.86 for testosterone, 0.88 to 0.97 for sex hormone-binding globulin and 0.78 to 0.91 for free androgen index. Hormone profiles were reproducible over two consecutive months. To reduce month-to-month intraindividual variations and improve measurement consistency, it is recommended that multiple samples be taken over consecutive days as opposed to a single sample.


Haemodynamic and endocrine changes during anti-hypertensive treatment with clonidine and its derivative St 600.
1. The cardio-renal haemodynamic and endocrine effects of the anti-hypertensive agents 2-(2,6-dichlorophenylamine)-2-imidazoline hydrochloride (clonidine, St 155) and 2-(5-fluor-o-toluidine)-2-imidazoline hydrochloride (St 600) were investigated in twelve patients with essential hypertension. 2. The anti-hypertensive action of both compounds was similar and was accompanied by a reduction in heart rate and in cardiac output, total peripheral resistance being unchanged. There was no alteration in renal blood flow and glomerular filtration rate, and renal vascular resistance showed a significant decrease. Blood volume and plasma renin concentration did not change significantly. An inverse relation changes in plasma volume and plasma aldosterone concentration was observed. In the face of similar reductions in blood pressure, no differences were observed between systemic and renal haemodynamic and endocrine responses after clonidine and St 600.


Upregulation of endothelial cell adhesion molecules characterizes veins close to granulomatous infiltrates in the renal cortex of cats with feline infectious peritonitis and is indirectly triggered by feline infectious peritonitis virus-infected monocytes in vitro.
One of the most characteristic pathological changes in cats that have succumbed to feline infectious peritonitis (FIP) is a multifocal granulomatous phlebitis. Although it is now well established that leukocyte extravasation elicits the inflammation typically associated with FIP lesions, relatively few studies have aimed at elucidating this key pathogenic event. The upregulation of adhesion molecules on the endothelium is a prerequisite for stable leukocyte-endothelial cell (EC) adhesion that necessarily precedes leukocyte diapedesis. Therefore, the present work focused on the expression of the EC adhesion molecules and possible triggers of EC activation during the development of FIP. Immunofluorescence analysis revealed that the endothelial expression of P-selectin, E-selectin, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) was elevated in veins close to granulomatous infiltrates in the renal cortex of FIP patients compared to non-infiltrated regions and specimens from healthy cats. Next, we showed that feline venous ECs become activated when exposed to supernatant from feline infectious peritonitis virus (FIPV)-infected monocytes, as indicated by increased adhesion molecule expression. Active viral replication seemed to be required to induce the EC-stimulating activity in monocytes. Finally, adhesion assays revealed an increased adhesion of naive monocytes to ECs treated with supernatant from FIPV-infected monocytes. Taken together, our results strongly indicate that FIPV activates ECs to increase monocyte adhesion by an indirect route, in which proinflammatory factors released from virus-infected monocytes act as key intermediates.


A Failure to Communicate? Doctors and Nurses in American Hospitals.
This article showcases the realities and challenges of teamwork in American hospitals based on the in situ comparison with France. Drawing on observation of nurse-physician interactions in hospitals in the two nations, this article highlights a troubling conflict between teamwork rhetoric and realities on the ward. Although the use of informatics systems such as electronic health records is supposed to increase cooperation, the observations presented here show that on the contrary, it inhibits communication that is becoming mainly virtual. While the nursing profession is more developed and provides stronger education in the United States, this story highlights the challenges in creating a shared environment of work and suggests the importance of balancing professional autonomy and effective teamwork.


Human immunodeficiency virus (HIV) type 1 infection status and in vitro susceptibility to HIV infection among high-risk HIV-1-seronegative hemophiliacs.
Blood samples were obtained from 16 hemophiliacs who had a 50%-94% defined risk of human immunodeficiency virus (HIV) type 1 infection on the basis of treatment history and from 14 controls not at risk for HIV infection. HIV-1 was not detected in any of 12 patient samples by cocultivation nor in 14 patient samples by the polymerase chain reaction. Peripheral blood cells from 7 seronegative hemophiliacs at highest risk of seroconversion (94%) were less susceptible to HIV-1 infection in vitro than were cells from healthy controls (P < .025, one-tailed Wilcoxon rank sum test). In contrast, the susceptibility to HIV-1 infection of lymphocytes from 6 seronegative hemophiliacs at moderate risk (50%-56%) of seroconversion did not differ from that of cells from controls or from high-risk hemophiliacs. Therefore, prolonged periods of seronegative HIV-1 infection are not common in this high-risk population. In addition, among hemophiliacs there may exist heterogeneity in susceptibility to HIV-1 infection in vitro and in vivo.


Water stress deforms tracheids peripheral to the leaf vein of a tropical conifer.
Just as a soggy paper straw is prone to yielding under the applied suction of a thirsty drinker, the xylem tracheids in leaves seem prone to collapse as water potential declines, impeding their function. Here we describe the collapse, under tension, of lignified cells peripheral to the leaf vein of a broad-leaved rainforest conifer, Podocarpus grayi de Laub. Leaves of Podocarpus are characterized by an array of cylindrical tracheids aligned perpendicular to the leaf vein, apparently involved in the distribution of water radially through the mesophyll. During leaf desiccation the majority of these tracheids collapsed from circular to flat over the water potential range -1.5 to -2.8 MPa. An increase in the percentage of tracheids collapsed during imposed water stress was mirrored by declining leaf hydraulic conductivity (K(leaf)), implying a direct effect on water transport efficiency. Stomata responded to water stress by closing at -2.0 MPa when 45% of cells were collapsed and K(leaf) had declined by 25%. This was still substantially before the initial indications of cavitation-induced loss of hydraulic conductance in the leaf vein, at -3 MPa. Plants droughted until 49% of tracheids had collapsed were found to fully recover tracheid shape and leaf function 1 week after rewatering. A simple mechanical model of tracheid collapse, derived from the theoretical buckling pressure for pipes, accurately predicted the collapse dynamics observed in P. grayi, substantiating estimates of cell wall elasticity and measured leaf water potential. The possible adaptive advantages of collapsible vascular tissue are discussed.


Tobacco control environment: cross-sectional survey of policy implementation, social unacceptability, knowledge of tobacco health harms and relationship to quit ratio in 17 low-income, middle-income and high-income countries.
This study examines in a cross-sectional study 'the tobacco control environment' including tobacco policy implementation and its association with quit ratio. 545 communities from 17 high-income, upper-middle, low-middle and low-income countries (HIC, UMIC, LMIC, LIC) involved in the Environmental Profile of a Community's Health (EPOCH) study from 2009 to 2014. Community audits and surveys of adults (35-70 years, n=12 953). Summary scores of tobacco policy implementation (cost and availability of cigarettes, tobacco advertising, antismoking signage), social unacceptability and knowledge were associated with quit ratios (former vs ever smokers) using multilevel logistic regression models. Average tobacco control policy score was greater in communities from HIC. Overall 56.1% (306/545) of communities had >2 outlets selling cigarettes and in 28.6% (154/539) there was access to cheap cigarettes (<5cents/cigarette) (3.2% (3/93) in HIC, 0% UMIC, 52.6% (90/171) LMIC and 40.4% (61/151) in LIC). Effective bans (no tobacco advertisements) were in 63.0% (341/541) of communities (81.7% HIC, 52.8% UMIC, 65.1% LMIC and 57.6% LIC). In 70.4% (379/538) of communities, >80% of participants disapproved youth smoking (95.7% HIC, 57.6% UMIC, 76.3% LMIC and 58.9% LIC). The average knowledge score was >80% in 48.4% of communities (94.6% HIC, 53.6% UMIC, 31.8% LMIC and 35.1% LIC). Summary scores of policy implementation, social unacceptability and knowledge were positively and significantly associated with quit ratio and the associations varied by gender, for example, communities in the highest quintile of the combined scores had 5.0 times the quit ratio in men (Odds ratio (OR) 5·0, 95% CI 3.4 to 7.4) and 4.1 times the quit ratio in women (OR 4.1, 95% CI 2.4 to 7.1). This study suggests that more focus is needed on ensuring the tobacco control policy is actually implemented, particularly in LMICs. The gender-related differences in associations of policy, social unacceptability and knowledge suggest that different strategies to promoting quitting may need to be implemented in men compared to women.


Immobilization of Keggin polyoxovanadoniobate in crystalline solids to produce effective heterogeneous catalysts towards selective oxidation of benzyl-alkanes.
Two ionic organic-inorganic hybrid compounds, [CuII(C2N2H8)2]4[CuII(C2N2H8)2(H2O)2]2[PNb12O40VVVIVO2]·(OH)2·11H2O (1) and [CoIII(C2N2H8)3]2[CoIII(C2N2H8)2(H2O)2]0.5[H2.5PNb12O40 VVVIVO2]·20H2O (2), based on P-centered dicapped polyoxoniobates and organometallic cations were isolated and structurally characterized by routine techniques. The trivalent cobalt complex-containing compound exhibits a looser arrangement compared with its divalent copper complex-containing counterpart, with a space volume of 34.9% for the former and 17.0% for the latter. The two compounds were proved to be effective in facilitating the oxidation of benzyl-alkanes to ketone products in a heterogeneous manner, evidencing the feasiblity of the strategy of self-immobilization of catalytically active, readily soluble PNb12O40(VO)2 species in crystalline solids.


Electronics manufacturing infrastructures for education and commercialization.
Many medical and biological applications require custom integrated hardware. Infrastructures for the design of CMOS and MEMS hardware allow the education and commercialization at a low cost and in a short time. This paper is reviewing the most recent developments at CMP for the manufacturing of ICs and MEMS. These custom hardware vehicles allow to target many medical and biological applications. Examples are provided through the paper. Such infrastructures may help the Medical and Biological community the same way they helped the Microelectronics community at the time of the VLSI revolution.


A physiological approach to the simulation of bone remodeling as a self-organizational control process.
Although the capacity of bone to adapt to functional mechanical requirements has been known for more than a century, it is still unclear how the bone adaptation processes are regulated. We hypothesize that osteocytes are sensitive to mechanical loading and control the regulation of bone mass in their environment. Recently, simulation models of such a process were developed, using the finite element method. It was discovered that these models produce discontinuous structures, not unlike trabecular bone. However, it was also found that severe discontinuities violate the continuum assumption underlying the finite element method and that the solutions were element mesh dependent. We have developed a simulation model (which is physiologically and mechanically more consistent) which maintains the self-organizational characteristics but does not produce these discontinuities. This was accomplished by separating the sensor density and range of action from the mesh. The results clearly show that predicted trabecular morphology, i.e. sizes and branching of struts, depend on the actual relationship between local load, sensor density and range of influence. We believe that the model is suitable to study the relationship between trabecular morphology and load and can also explain adaptation of morphology, in the sense of 'Wolff's law'.


Clinical and social outcomes of adolescent self harm: population based birth cohort study.
To investigate the mental health, substance use, educational, and occupational outcomes of adolescents who self harm in a general population sample, and to examine whether these outcomes differ according to self reported suicidal intent. Population based birth cohort study. Avon Longitudinal Study of Parents and Children (ALSPAC), a UK birth cohort of children born in 1991-92. Data on lifetime history of self harm with and without suicidal intent were available for 4799 respondents who completed a detailed self harm questionnaire at age 16 years. Multiple imputation was used to account for missing data. Mental health problems (depression and anxiety disorder), assessed using the clinical interview schedule-revised at age 18 years, self reported substance use (alcohol, cannabis, cigarette smoking, and illicit drugs) at age 18 years, educational attainment at age 16 and 19 years, occupational outcomes at age 19 years, and self harm at age 21 years. Participants who self harmed with and without suicidal intent at age 16 years were at increased risk of developing mental health problems, future self harm, and problem substance misuse, with stronger associations for suicidal self harm than for non-suicidal self harm. For example, in models adjusted for confounders the odds ratio for depression at age 18 years was 2.21 (95% confidence interval 1.55 to 3.15) in participants who had self harmed without suicidal intent at age 16 years and 3.94 (2.67 to 5.83) in those who had self harmed with suicidal intent. Suicidal self harm, but not self harm without suicidal intent, was also associated with poorer educational and employment outcomes. Adolescents who self harm seem to be vulnerable to a range of adverse outcomes in early adulthood. Risks were generally stronger in those who had self harmed with suicidal intent, but outcomes were also poor among those who had self harmed without suicidal intent. These findings emphasise the need for early identification and treatment of adolescents who self harm.


Use of therapeutic hypothermia and extracorporeal life support after an unusual response to the ajmaline challenge in a patient with Brugada syndrome.
Brugada syndrome is a cardiac disorder associated with a high risk of sudden cardiac death, especially in young subjects. The incidence and prevalence are likely underestimated. The diagnosis is based on a characteristic electrocardiography (ECG) pattern. The most commonly performed confirmatory test in cases of equivocal ECG is the intravenous ajmaline challenge. Although relatively safe, it carries the risk of ventricular arrhythmias that could potentially degenerate into a refractory electrical storm. A 27-year-old man developed sustained ventricular fibrillation after ajmaline challenge. He was rescued on extracorporeal life support after 108 min of cardiopulmonary resuscitation. Extracorporeal life support allowed recovery of spontaneous circulation and resulted in a positive neurological outcome.<Learning objective: This case is an example of how extracorporeal life support was instituted after prolonged and unsuccessful cardiopulmonary resuscitation resulting in a positive central neurological outcome.>.