A commentary on methodological issues in stroke caregiver research: lessons learned from three RESCUE intervention studies.
Stroke caregivers represent a distinct population and require unique considerations when conducting intervention research. Unfortunately, there are few published recommendations for conducting intervention trials with stroke caregivers. Thus, the goal of this paper is to provide foundational guidance for stroke caregiving researchers. We describe lessons learned from three trials of the RESCUE intervention to illustrate methodological issues in stroke caregiver research. We identify challenges encountered while conducting a clinical demonstration project, pilot study, and multi-site randomized controlled trial of a problem-solving and skills-building stroke caregiver intervention. We use our research experiences to exemplify or enhance understanding of each issue and describe the strategies we employed to overcome these obstacles. We present issues related to and recommendations for study design, theoretical frameworks, eligibility criteria, recruitment and retention, human subjects protection, intervention design, treatment fidelity, outcome measures, and qualitative methods. Identifying approaches to circumvent methodological challenges can help advance research on and implementation of stroke caregiver programs.


Longitudinal evaluation of periodontitis and tooth loss among older adults.
To evaluate pattern of change in periodontal variables and tooth loss in a twelve-year follow-up study of older adults living in Sweden. In a prospective population study of older adults, a clinical examination and radiographic dental examination were performed at baseline (2001-2003) and after 12 years (2013-2015). In 375 individuals, the number and proportion of sites with a distance ≥4 mm and ≥5 mm from cemento-enamel junction to the bone level, the number and proportion of teeth with pockets ≥5 mm and number of teeth lost were calculated. Dental caries was registered. Periodontitis was defined as having ≥2 sites with ≥5 mm distance from cemento-enamel junction to the marginal bone level and ≥1 tooth with pockets ≥5 mm. A diagnosis of periodontitis was evident in 39% of the individuals, and 23% of the individuals lost ≥3 teeth over the study period. The proportion of sites with ≥4 mm and ≥5 mm bone loss increased with age, while the proportion of teeth with pockets remained stable. Periodontitis was the strongest predictor for losing ≥3 teeth, OR 2.9 (p < .001) in the final model. Periodontitis is a risk factor for future tooth loss among older adults.


Astragaloside IV ameliorates early diabetic nephropathy by inhibition of MEK1/2-ERK1/2-RSK2 signaling in streptozotocin-induced diabetic mice.
Objective The aim of this study was to investigate the renoprotective effects and molecular mechanisms of astragaloside IV (AS-IV) in streptozotocin (STZ)-induced diabetic mice. Methods Male C57BL/6 mice were injected intraperitoneally with STZ at 200 mg/kg body weight. AS-IV was administered for 8 consecutive weeks, beginning 1 week after STZ injection. Body weight, 24-hour urinary albumin excretion, and fasting blood glucose were measured. Kidney tissues were examined by histopathological analyses. Total levels and phosphorylation of mitogen-activated protein kinase 1/2 (MEK1/2), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and ribosomal S6 kinase 2 (RSK2) were determined by Western blotting analysis. Results AS-IV treatment significantly reduced albuminuria and serum creatinine levels, ameliorated mesangial matrix expansion and greater foot process width, and decreased the levels of urinary N-acetyl-beta-D-glucosaminidase, neutrophil gelatinase-associated lipocalin, and transforming growth factor-beta 1 in STZ-induced diabetic mice. AS-IV also inhibited renal cortical phosphorylation of MEK1/2, ERK1/2 and RSK2. Conclusion Our results suggest that AS-IV attenuates renal injury in STZ-induced diabetic mice. This effect might be partially associated with inhibition of the activation of the MEK1/2-ERK1/2-RSK2 signaling pathway.


Medical education and family planning: developing future leaders and improving global health.
Well-trained medical professionals are key to improving global reproductive health and reducing rates of unsafe abortion, but medical training often fails to prepare practitioners to provide essential family planning services. The field of medical education is currently undergoing reformation to better meet the needs of a global population, and comprehensive, integrated family planning training will be an important part of those reforms. Family planning training is not only vital to address global reproductive healthcare demand, but integrates effectively with cornerstones of current medical education reform: competency-based education, leadership development, collaboration with practitioners of all levels, and global health context. Examples of successful integration of family planning education are outlined, and recommendations for integrating family planning into medical education detailed at the 2012 FIGO World Congress are discussed.


Acoustic analysis of a mechanical circulatory support.
Mechanical circulatory support technology is continually improving. However, adverse complications do occur with devastating consequences, for example, pump thrombosis that may develop in several parts of the pump system. The aim of this study was to design an experimental clot/thrombosis model to register and analyze acoustic signals from the left ventricular assist device (LVAD) HeartMate II (HMII) (Thoratec Corporation, Inc., Pleasanton, CA, USA) and detect changes in sound signals correlating to clots in the inflow, outflow, and pump housing. Using modern telecom techniques, it was possible to register and analyze the HMII pump-specific acoustic fingerprint in an experimental model of LVAD support using a mock loop. Increase in pump speed significantly (P<0.005) changed the acoustic fingerprint at certain frequency (0-23,000 Hz) intervals (regions: R1-3 and peaks: P1,3-4). When the ball valves connected to the tubing were narrowed sequentially by ∼50% of the inner diameter (to mimic clot in the out- and inflow tubing), the frequency spectrum changed significantly (P<0.005) in P1 and P2 and R1 when the outflow tubing was narrowed. This change was not seen to the same extent when the lumen of the ball valve connected to the inflow tube was narrowed by ∼50%. More significant (P<0.005) acoustic changes were detected in P1 and P2 and R1 and R3, with the largest dB figs. in the lower frequency ranges in R1 and P2, when artificial clots and blood clots passed through the pump system. At higher frequencies, a significant change in dB figs. in R3 and P4 was detected when clots passed through the pump system. Acoustic monitoring of pump sounds may become a valuable tool in LVAD surveillance.


Introduction and proliferation of multidrug-resistant Streptococcus pneumoniae serotype 19A clones that cause acute otitis media in an unvaccinated population.
Introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in the United States in 2000 was temporally associated with an increase in the incidence of disease caused by Streptococcus pneumoniae serotype 19A (Sp19A) and with increasing drug resistance within this serotype. A causative role of PCV7 was speculated. We prospectively studied the dynamics of acute otitis media (AOM) caused by Sp19A in southern Israel before the introduction of PCV7. AOM in children < 5 years old undergoing tympanocentesis during 1999-2006 was studied. Antibiotic prescriptions for approximately 20% of children < 5 years old were recorded. Sp19A isolates were studied for antibiotic-resistance and pulsed-field gel electrophoresis patterns; multilocus sequence typing of representative isolates was compared with that of international clones. Sp19A caused 438 (9.8%) of 4449 pneumococcal AOM episodes, increasing by 63.1% from 1999-2001 (mean +/- SD, 8.4% +/- 0.8%) to 2004-2006 (mean +/- SD, 13.7% +/- 0.9%) among Bedouin children, who were characterized by overcrowding and high antibiotic use. Penicillin, erythromycin, and multidrug resistance increased from < 10% to 78.6%, 50.0%, and 50.0%, respectively (P < .001), and was associated with the introduction and proliferation of 2 multidrug-resistant clones that were not previously associated with multidrug resistance. This was temporally associated with the introduction of and rapid increase in azithromycin use and the frequent use of oral cephalosporins. The introduction and proliferation of multidrug-resistant Sp19A occurred before the introduction of PCV7. The increasing proportion of antibiotic-resistant Sp19A suggests that antibiotic use plays an important role in the community.


Volumetric analysis and three-dimensional glucose metabolic mapping of the striatum and thalamus in patients with autism spectrum disorders.
In patients with autism, behavioral deficits as well as neuroimaging studies of the anterior cingulate cortex suggest ventral rather than dorsal striatal and thalamic abnormalities in structure and function. The authors used imaging studies to map volumetric and metabolic differences within the entire dorsoventral extent of the striatum and thalamus. Magnetic resonance imaging (MRI) and positron emission tomography (PET) were used to measure volumes and metabolic activity in the thalamus, caudate, and putamen in 17 patients with autism or Asperger's disorder and 17 age- and sex-matched comparison subjects. Subjects performed a serial verbal learning test during the [(18)F]-fluorodeoxyglucose uptake period. The regions of interest were outlined on contiguous axial MRI slices. After PET/MRI coregistration, region-of-interest coordinates were applied to the PET scan for each individual. Between-group differences in metabolism were assessed by three-dimensional statistical probability mapping. The patients with autism spectrum disorders had greater volumes of the right caudate nucleus than comparison subjects as well as a reversal of the expected left-greater-than-right hemispheric asymmetry. Patients also had lower relative glucose metabolic rates bilaterally in the ventral caudate, putamen, and thalamus. Patients with autism had lower metabolic activity in the ventral thalamus than those with Asperger's disorder, but they did not differ from comparison subjects in metabolic activity in the caudate nucleus. These results are consistent with a deficit in the anterior cingulate-ventral striatum-anterior thalamic pathway in patients with autism spectrum disorders. The results also suggest an important role for the caudate in helping support working-memory demands.


Coinfection with leptospirosis and scrub typhus in Taiwanese patients.
We retrospectively analyzed patients with leptospirosis (n = 35), scrub typhus (n = 45), and coinfection (leptospirosis and scrub typhus [n = 7]) to facilitate the detection of coinfection. Our data showed that factors favoring these disease entities included animal contact, an aspartate aminotransferase/alanine aminotransferase ratio > 2 (for leptospirosis); outdoor exposure, lymphadenopathy, splenomegaly, eschar, and elevated alkaline phosphatase levels (for scrub typhus and coinfection); calf tenderness, conjunctival suffusion, jaundice, oliguria, elevated total bilirubin levels and serum creatinine levels (for leptospirosis and coinfection); and maculopapular rash (for scrub typhus). Patients at risk for leptospirosis are often at increased risk for scrub typhus and vice versa. Lack of knowledge of coinfection may jeopardize the health of affected patients. Our study serves as a reminder of potential coinfection and provides clues for its detection.


Newspaper coverage of biobanks.
Background. Biobanks are an important research resource that provides researchers with biological samples, tools and data, but have also been associated with a range of ethical, legal and policy issues and concerns. Although there have been studies examining the views of different stakeholders, such as donors, researchers and the general public, the media portrayal of biobanks has been absent from this body of research. This study therefore examines how biobanking has been represented in major print newspapers from Australia, Canada, the United Kingdom and the United States to identify the issues and concerns surrounding biobanks that have featured most prominently in the print media discourse. Methods. Using Factiva, articles published in major broadsheet newspapers in Canada, the US, the UK, and Australia were identified using specified search terms. The final sample size consisted of 163 articles. Results. Majority of articles mentioned or discussed the benefits of biobanking, with medical research being the most prevalent benefit mentioned. Fewer articles discussed risks associated with biobanking. Researchers were the group of people most quoted in the articles, followed by biobank employees. Biobanking was portrayed as mostly neutral or positive, with few articles portraying biobanking in a negative manner. Conclusion. Reporting on biobanks in the print media heavily favours discussions of related benefits over risks. Members of the scientific research community appear to be a primary source of this positive tone. Under-reporting of risks and a downtrend in reporting on legal and regulatory issues suggests that the print media views such matters as less newsworthy than perceived benefits of biobanking.


Choosing the best embryo by time lapse versus standard morphology.
Within the past few years the morphological evaluation of in vitro fertilized embryos has been extended to include continuous surveillance, enabled by the introduction of time-lapse incubators developed specifically for IVF treatment. As a result time-lapse monitoring has been implemented in many clinics worldwide. The proposed benefits compared with culture in a standard incubator and fixed time-point evaluation are uninterrupted culture, a flexible workflow in the laboratory, and improved embryo selection. The latter is based on the reasonable assumption that more frequent observations will provide substantially more information on the relationship between development, timing, and embryo viability. Several retrospective studies have confirmed a relationship between time-lapse parameters and embryo viability evaluated by developmental competence, aneuploidy, and clinical pregnancy. Furthermore a much anticipated randomized study has shown improved pregnancy rates (PRs) after culture in a time-lapse incubator combined with selection using a hierarchical time-lapse selection model. At present this is the only randomized study on possible benefits of time lapse in human embryology. Strict evidence may still seem too weak to introduce time lapse in routine clinical setting. This aim of this review is therefore to perform a balanced discussion of the evidence for time-lapse monitoring.


Quantification and localisation of FOXP3+ T lymphocytes and relation to hepatic inflammation during chronic HCV infection.
T lymphocyte-mediated immune reactions are closely involved in the pathogenesis of HCV-induced chronic liver disease. Regulatory T cells are able to suppress HCV-specific T lymphocyte proliferation and cytokine secretion during chronic HCV infection. We wished to address to what extent regulatory T cells exist in the livers of HCV+ individuals, and what the role of such cells might be in disease progression. We analysed the frequency and distribution of FOXP3+ cells, along with CD4, CD8 and CD20+ cells, in liver biopsies of 28 patients with chronic HCV and 14 patients with PBC, and correlated these data with histological parameters. A striking number of FOXP3+ cells were present in the portal tract infiltrates of HCV-infected livers. FOXP3+ cells were largely CD4+ and there was a remarkably consistent ratio of total CD4+:FOXP3+ cells in liver across a wide range of disease states of around 2:1. This differed substantially from the ratio observed in PBC (10:1, P=0.001). An unexpectedly high proportion of the cellular infiltrate in persistent HCV infection comprises FOXP3+ cells. The relative proportion of FOXP3+ cells remains similar in both mild and severe fibrosis. These cells are likely to play a critical role in intrahepatic immune regulation, although their overall role in disease progression remains to be determined.


The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing.
Epigenetic chromatin marks restrict the ability of differentiated cells to change gene expression programs in response to environmental cues and to transdifferentiate. Polycomb group (PcG) proteins mediate gene silencing and repress transdifferentiation in a manner dependent on histone H3 lysine 27 trimethylation (H3K27me3). However, macrophages migrated into inflamed tissues can transdifferentiate, but it is unknown whether inflammation alters PcG-dependent silencing. Here we show that the JmjC-domain protein Jmjd3 is a H3K27me demethylase expressed in macrophages in response to bacterial products and inflammatory cytokines. Jmjd3 binds PcG target genes and regulates their H3K27me3 levels and transcriptional activity. The discovery of an inducible enzyme that erases a histone mark controlling differentiation and cell identity provides a link between inflammation and reprogramming of the epigenome, which could be the basis for macrophage plasticity and might explain the differentiation abnormalities in chronic inflammation.


[Strategy for surgery in neonates with coexisting congenital heart diseases].
To determine the most appropriate treatment strategy for neonates with coexisting congenital heart diseases (CHD) requiring surgery, 408 neonates treated in our department between 2002 and 2009 were retrospectively reviewed. Of the 408 neonates, 37 (9.1%) had coexisting CHD. Among the pediatric diseases requiring surgery, esophageal atresia (46.7%), anorectal malformation (24.1%), and tracheobronchial anomalies (75.0%) were frequently associated with CHD, and the survival rate among patients with coexisting CDH was 24.3%, about 2-fold higher than among those without coexisting CHD. Clinical observations in the present series suggested that fatal conditions such as tracheoesophageal fistula should be repaired immediately after birth, followed by palliative cardiac surgery to stabilize the circulatory status if necessary. Thereafter, radical repair of cardiac and pediatric anomalies should be performed, taking into account the balance between surgical stress and cardiac reserve. For this purpose, proper assessment of surgical stress and cardiac function and collaboration among specialists in relevant fields are essential during the perinatal period to determine the treatment strategy for patients with multiple-organ anomalies.


Evolving therapeutic strategies to improve nonsteroidal anti-inflammatory drug safety.
Nonsteroidal anti-inflammatory drugs (NSAIDs) possess potent anti-inflammatory and analgesic properties through inhibition of cyclooxygenase enzymes (COX-1 and COX-2), which are responsible for synthesis of proinflammatory mediators. NSAIDs are frequently used for treatment of acute and chronic pain conditions. However, their use is associated with serious dose-dependent gastrointestinal (GI), cardiovascular, renal, and hepatic adverse effects, which pose a serious clinical concern for both patients and physicians. During the past 2 decades, approaches to improving the tolerability of NSAIDs were mainly directed toward discovery of COX-2 selective NSAIDs (coxibs), which were expected to minimize the risk of GI injury. Unfortunately, the results from multiple clinical studies have shown that treatment with coxibs may increase the risk for cardiovascular complications. This review summarizes current strategies used to reduce the toxicity of NSAIDs and outlines novel therapeutic approaches still in preclinical development. To minimize the risk of GI ulcerations and bleeding, combination therapies with gastroprotective agents are currently recommended. The new therapeutic agents anticipated to have similar effects include nitric oxide- and hydrogen sulfide-releasing NSAIDs. Novel manufacturing technologies enhance dissolution and absorption of NSAID products, allowing for their administration at low doses, which could lead to improved drug tolerability without diminishing the analgesic and anti-inflammatory efficacy of NSAIDs. This principle is in line with the current recommendation by the US Food and Drug Administration that NSAIDs should be used at the lowest effective dosage. Finally, NSAID formulations targeted directly to the site of inflammation are expected to reduce systemic drug exposure and thus decrease the risk of systemic adverse effects.


Common genetic effects of gender atypical behavior in childhood and sexual orientation in adulthood: a study of Finnish twins.
The existence of genetic effects on gender atypical behavior in childhood and sexual orientation in adulthood and the overlap between these effects were studied in a population-based sample of 3,261 Finnish twins aged 33-43 years. The participants completed items on recalled childhood behavior and on same-sex sexual interest and behavior, which were combined into a childhood gender atypical behavior and a sexual orientation variable, respectively. The phenotypic association between the two variables was stronger for men than for women. Quantitative genetic analyses showed that variation in both childhood gender atypical behavior and adult sexual orientation was partly due to genetics, with the rest being explained by nonshared environmental effects. Bivariate analyses suggested that substantial common genetic and modest common nonshared environmental correlations underlie the co-occurrence of the two variables. The results were discussed in light of previous research and possible implications for theories of gender role development and sexual orientation.


Bayesian Analysis of Individual Level Personality Dynamics.
A Bayesian technique with analyses of within-person processes at the level of the individual is presented. The approach is used to examine whether the patterns of within-person responses on a 12-trial simulation task are consistent with the predictions of ITA theory (Dweck, 1999). ITA theory states that the performance of an individual with an entity theory of ability is more likely to spiral down following a failure experience than the performance of an individual with an incremental theory of ability. This is because entity theorists interpret failure experiences as evidence of a lack of ability which they believe is largely innate and therefore relatively fixed; whilst incremental theorists believe in the malleability of abilities and interpret failure experiences as evidence of more controllable factors such as poor strategy or lack of effort. The results of our analyses support ITA theory at both the within- and between-person levels of analyses and demonstrate the benefits of Bayesian techniques for the analysis of within-person processes. These include more formal specification of the theory and the ability to draw inferences about each individual, which allows for more nuanced interpretations of individuals within a personality category, such as differences in the individual probabilities of spiraling. While Bayesian techniques have many potential advantages for the analyses of processes at the level of the individual, ease of use is not one of them for psychologists trained in traditional frequentist statistical techniques.


The management of severe alcoholic liver disease and variceal bleeding in the intensive care unit.
To address recent advances in the understanding and management of alcohol-related chronic liver disease and its acute complications. Refinements have been made in the prognosis and treatment of alcoholic hepatitis, and new insights have been gained into the pathophysiology of the hepatorenal syndrome. Further trial evidence has emerged concerning therapy in the hepatorenal syndrome, and there has been some clarification of the benefits and risks relating to albumin dialysis/extracorporeal liver support, and consensus in the early management of variceal haemorrhage. Recent developments have led to modifications in the standard of care of patients with severe alcoholic liver disease, many of which are highly applicable to the general critical care setting. These changes apply specifically to alcoholic hepatitis, the hepatorenal syndrome and variceal bleeding, common conditions with a high mortality rate, upon which changes in practice can have a significant impact.


Wham: Identifying Structural Variants of Biological Consequence.
Existing methods for identifying structural variants (SVs) from short read datasets are inaccurate. This complicates disease-gene identification and efforts to understand the consequences of genetic variation. In response, we have created Wham (Whole-genome Alignment Metrics) to provide a single, integrated framework for both structural variant calling and association testing, thereby bypassing many of the difficulties that currently frustrate attempts to employ SVs in association testing. Here we describe Wham, benchmark it against three other widely used SV identification tools-Lumpy, Delly and SoftSearch-and demonstrate Wham's ability to identify and associate SVs with phenotypes using data from humans, domestic pigeons, and vaccinia virus. Wham and all associated software are covered under the MIT License and can be freely downloaded from github (https://github.com/zeeev/wham), with documentation on a wiki (http://zeeev.github.io/wham/). For community support please post questions to https://www.biostars.org/.


Impact of direct-acting antiviral agents on liver function in patients with chronic hepatitis C virus infection.
Whilst the benefit of direct-acting antiviral agents (DAAs) in achieving sustained virological response (SVR) is now well-accepted, their impact on liver function, particularly in relation to achievement of SVR, has not been well documented. We studied 2394 patients with chronic HCV infection, 1276 receiving DAAs and 1118 interferon-based therapy. Liver function was assessed by the albumin-bilirubin (ALBI) score or grade. Overall survival according to SVR status and baseline ALBI grade was examined. We also studied time to first decompensation according to ALBI grade, as well as longitudinal changes in ALBI score over time according to SVR. Among the patients receiving DAAs, 89% achieved SVR (Japan = 99%, UK = 78%). Amongst the decompensated patients in the UK cohort, three distinct risk groups according to ALBI grade at baseline were observed. The UK patients receiving DAAs, who had predominantly decompensated disease, showed clear evidence of improvement of liver function detectable within 2 years of the start of treatment, especially in those achieving SVR. These early changes in liver function were very similar to those observed in the first 2-3 years after interferon-based therapy. DAAs improve liver function especially in those with decompensated disease who achieve SVR. Experience with interferon-based therapy suggests that failure to achieve SVR is associated with long-term decline in liver function and, in contrast, patients who do achieve SVR can expect long-term disease improvement and subsequent stabilization of liver function. Our initial analysis suggests that those receiving DAAs are likely, in the long term, to follow a similar course.


Effects of live yeast dietary supplementation on nutrient digestibility and fecal microflora in beagle dogs.
The effects of live yeast (strain CNCM I-4407; Actisaf Sc 47; Phileo Lesaffre Animal Care, Marcq-en-Baroeul, France) administration on nutrient digestibility and fecal microflora in dogs were investigated. The study included 24 young beagle dogs. They were allocated in control and live yeast (LY) groups (6 males and 6 females in each). During the Adaptation (d 1 to 28) and Trial (d 29 to 70) periods, the dogs received a standard dry pelleted diet. In the Trial period, the LY dogs were given capsuled Actisaf Sc 47 at 1 g/kg live weight with at 2.9 × 10 cfu/g. The control dogs received empty capsules. Live weight and feed consumption were recorded. Blood samples for complete blood count (CBC) and serum biochemistry (urea, creatinine, alkaline phosphatase, and alanine aminotransferase) and fecal samples for pH, microbiology, DM, lactic acid, and ammonia and digestibility evaluation were collected during the Trial period from each dog. The LY dogs had a higher ( < 0.05) weight gain during the Trial period than the control ones. Feed consumption was not adversely affected by LY. The CBC values and urea, creatinine, alkaline phosphatase, and alanine aminotransferase were not adversely affected by LY. Live yeast did not significantly influence pH of fresh feces. Fecal lactic acid and ammonia concentrations were not affected. The LY dogs showed lower ( < 0.05) Escherichia coli and fecal enterococci counts in feces than the control ones. Lactic acid bacteria, Clostridium perfringens, and total coliforms did not show any significant differences between the treatments. The LY dogs showed a higher ( < 0.05) apparent digestibility of NDF. Digestibilities of DM, ash, crude fiber, CP, and fat were not influenced.


Membrane proteomic analysis reveals overlapping and independent functions of Streptococcus mutans Ffh, YidC1, and YidC2.
A comparative proteomic analysis was utilized to evaluate similarities and differences in membrane samples derived from the cariogenic bacterium Streptococcus mutans, including the wild-type strain and four mutants devoid of protein translocation machinery components, specifically ∆ffh, ∆yidC1, ∆yidC2, or ∆ffh/yidC1. The purpose of this work was to determine the extent to which the encoded proteins operate individually or in concert with one another and to identify the potential substrates of the respective pathways. Ffh is the principal protein component of the signal recognition particle (SRP), while yidC1 and yidC2 are dual paralogs encoding members of the YidC/Oxa/Alb family of membrane-localized chaperone insertases. Our results suggest that the co-translational SRP pathway works in concert with either YidC1 or YidC2 specifically, or with no preference for paralog, in the insertion of most membrane-localized substrates. A few instances were identified in which the SRP pathway alone, or one of the YidCs alone, appeared to be most relevant. These data shed light on underlying reasons for differing phenotypic consequences of ffh, yidC1 or yidC2 deletion. Our data further suggest that many membrane proteins present in a ∆yidC2 background may be non-functional, that ∆yidC1 is better able to adapt physiologically to the loss of this paralog, that shared phenotypic properties of ∆ffh and ∆yidC2 mutants can stem from impacts on different proteins, and that independent binding to ribosomal proteins is not a primary functional activity of YidC2. Lastly, genomic mutations accumulate in a ∆yidC2 background coincident with phenotypic reversion, including an apparent W138R suppressor mutation within yidC1.


Amino acids and proteins at ZnO-water interfaces in molecular dynamics simulations.
We determine potentials of the mean force for interactions of amino acids with four common surfaces of ZnO in aqueous solutions. The method involves all-atom molecular dynamics simulations combined with the umbrella sampling technique. The profiled nature of the density of water with the strongly adsorbed first layer affects the approach of amino acids to the surface and generates either repulsion or weak binding. The largest binding energy is found for tyrosine interacting with the surface in which the Zn ions are at the top. It is equal to 7 kJ mol(-1) which is comparable to that of the hydrogen bonds in a protein. This makes the adsorption of amino acids onto the ZnO surface much weaker than onto the well studied surface of gold. Under vacuum, binding energies are more than 40 times stronger (for one of the surfaces). The precise manner in which water molecules interact with a given surface influences the binding energies in a way that depends on the surface. Among the four considered surfaces the one with Zn at the top is recognized as binding almost all amino acids with an average binding energy of 2.60 kJ mol(-1). Another (O at the top) is non-binding for most amino acids. For binding situations the average energy is 0.66 kJ mol(-1). The remaining two surfaces bind nearly as many amino acids as they do not and the average binding energies are 1.46 and 1.22 kJ mol(-1). For all of the surfaces the binding energies vary between amino acids significantly: the dispersion in the range of 68-154% of the mean. A small protein is shown to adsorb onto ZnO only intermittently and with only a small deformation. Various adsorption events lead to different patterns in mobilities of amino acids within the protein.


Cardioprotection in ischaemia-reperfusion injury: novel mechanisms and clinical translation.
In recent decades, robust successes have been achieved in conquering the acutely lethal manifestations of heart disease. Nevertheless, the prevalence of heart disease, especially heart failure, continues to rise. Among the precipitating aetiologies, ischaemic disease is a leading cause of heart failure. In the context of ischaemia, the myocardium is deprived of oxygen and nutrients, which elicits a cascade of events that provokes cell death. This ischaemic insult is typically coupled with reperfusion, either spontaneous or therapeutically imposed, wherein blood supply is restored to the previously ischaemic tissue. While this intervention limits ischaemic injury, it triggers a new cascade of events that is also harmful, viz. reperfusion injury. In recent years, novel insights have emerged regarding mechanisms of ischaemia-reperfusion injury, and some hold promise as targets of therapeutic relevance. Here, we review a select number of these pathways, focusing on recent discoveries and highlighting prospects for therapeutic manipulation for clinical benefit.


Plasma isoflavones and fibrocystic breast conditions and breast cancer among women in Shanghai, China.
Proliferative benign breast conditions are associated with elevated risk of breast cancer, whereas nonproliferative conditions are not strongly associated with risk. Factors acting before onset of hyperplasia might be associated with both benign conditions and breast cancer, whereas those on the proliferative disease-to-cancer pathway would be associated only with cancer. Soy isoflavone exposure may influence breast cancer risk, but little is known of its association with benign conditions. We examined possible relationships between plasma genistein and daidzein concentrations and risk of breast disease in women, in a breast self-examination trial in Shanghai, China, diagnosed with breast cancer (n = 196) or a benign breast condition (n = 304), and 1,002 age-matched controls with no known breast disease. Benign conditions were classified as nonproliferative (n = 131) or proliferative with or without atypia (n = 173). Isoflavone concentrations were inversely associated with risk of nonproliferative and proliferative benign fibrocystic conditions, as well as with breast cancer, both with and without concomitant proliferative changes in ipsilateral noncancerous mammary epithelium (P(trend) < 0.01 for all comparisons with controls). Women in the highest quartile of plasma genistein (>76.95 ng/mL) were less likely to have breast cancer (odds ratio, 0.26; 95% confidence interval, 0.13-0.50) or benign conditions (odds ratio, 0.40; 95% confidence interval, 0.23-0.70) compared with women in the lowest quartile (<9.42 ng/mL). Observed risks for breast cancer with and without surrounding proliferative changes were not different, respectively, from observed risks for benign proliferative and nonproliferative conditions alone. Isoflavone exposure was inversely associated with fibrocystic breast conditions and breast cancer, and the results suggest that effects on cancer risk occur early in carcinogenesis.


Light-Cone Spreading of Perturbations and the Butterfly Effect in a Classical Spin Chain.
We find that the effects of a localized perturbation in a chaotic classical many-body system-the classical Heisenberg chain at infinite temperature-spread ballistically with a finite speed even when the local spin dynamics is diffusive. We study two complementary aspects of this butterfly effect: the rapid growth of the perturbation, and its simultaneous ballistic (light-cone) spread, as characterized by the Lyapunov exponents and the butterfly speed, respectively. We connect this to recent studies of the out-of-time-ordered commutators (OTOC), which have been proposed as an indicator of chaos in a quantum system. We provide a straightforward identification of the OTOC with a natural correlator in our system and demonstrate that many of its interesting qualitative features are present in the classical system. Finally, by analyzing the scaling forms, we relate the growth, spread, and propagation of the perturbation with the growth of one-dimensional interfaces described by the Kardar-Parisi-Zhang equation.


Enhancement of motor imagery-related cortical activation during first-person observation measured by functional near-infrared spectroscopy.
It is known that activity in secondary motor areas during observation of human limbs performing actions is affected by the observer's viewpoint, with first-person views generally leading to stronger activation. However, previous neuroimaging studies have displayed limbs in front of the observer, providing an offset view of the limbs without a truly first-person viewpoint. It is unknown to what extent these pseudo-first-person viewpoints have affected the results published to date. In this experiment, we used a horizontal two-dimensional mirrored display that places virtual limbs at the correct egocentric position relative to the observer. We compared subjects using the mirrored and conventional displays while recording over the premotor cortex with functional near-infrared spectroscopy. Subjects watched a first-person view of virtual arms grasping incoming balls on-screen; they were instructed to either imagine the virtual arm as their own [motor imagery during observation (MIO)] or to execute the movements [motor execution (ME)]. With repeated-measures anova, the hemoglobin difference as a direct index of cortical oxygenation revealed significant main effects of the factors hemisphere (P = 0.005) and condition (P ≤ 0.001) with significant post hoc differences between MIO-mirror and MIO-conventional (P = 0.024). These results suggest that the horizontal mirrored display provides a more accurate first-person view, enhancing subjects' ability to perform motor imagery during observation. Our results may have implications for future experimental designs involving motor imagery, and may also have applications in video gaming and virtual reality therapy, such as for patients following stroke.


Suppressor T cells activated in a primary in vitro response to non-major histocompatibility alloantigens.
Normal mouse spleen cells are not capable of mounting a primary cytotoxic T lymphocyte (Tc) response to non-H-2 alloantigens in vitro, although a good secondary H-2-restricted response is observable after in vivo immunization of the responder animals. Suppressor cells are generated in such a primary responses provided a Mls incompatibility exists between the responder and stimulator. These suppressors are not antigen specific, are Thy-1+, Lyt-1+, 2-, I-J-, and are highly radiosensitive. The suppressor cell precursors in normal spleen express the same phenotype. These suppressor cells are probably implicated in the lack of a primary Tc response in a primary mixed lymphocyte reaction across non-H-2 incompatibilities that include an Mls difference.


Out-of-hospital cardiac arrest in high-rise buildings: delays to patient care and effect on survival.
The increasing number of people living in high-rise buildings presents unique challenges to care and may cause delays for 911-initiated first responders (including paramedics and fire department personnel) responding to calls for out-of-hospital cardiac arrest. We examined the relation between floor of patient contact and survival after cardiac arrest in residential buildings. We conducted a retrospective observational study using data from the Toronto Regional RescuNet Epistry database for the period January 2007 to December 2012. We included all adult patients (≥ 18 yr) with out-of-hospital cardiac arrest of no obvious cause who were treated in private residences. We excluded cardiac arrests witnessed by 911-initiated first responders and those with an obvious cause. We used multivariable logistic regression to determine the effect on survival of the floor of patient contact, with adjustment for standard Utstein variables. During the study period, 7842 cases of out-of-hospital cardiac arrest met the inclusion criteria, of which 5998 (76.5%) occurred below the third floor and 1844 (23.5%) occurred on the third floor or higher. Survival was greater on the lower floors (4.2% v. 2.6%, p = 0.002). Lower adjusted survival to hospital discharge was independently associated with higher floor of patient contact, older age, male sex and longer 911 response time. In an analysis by floor, survival was 0.9% above floor 16 (i.e., below the 1% threshold for futility), and there were no survivors above the 25th floor. In high-rise buildings, the survival rate after out-of-hospital cardiac arrest was lower for patients residing on higher floors. Interventions aimed at shortening response times to treatment of cardiac arrest in high-rise buildings may increase survival.


Repeatability of lameness, fear and slipping scores to assess animal welfare upon arrival in pig slaughterhouses.
The EU project Welfare Quality® proposes an overall assessment system for animal welfare based on animal outcomes. The objective of this study was to test inter-observer reliability (IOR) when assessing lameness, fear and slipping and falling scores as parameters for monitoring the welfare of killing pigs during arrival at the slaughterhouse. Two Belgian and two Spanish slaughterhouses were visited by six to seven observers. Lameness, slipping and falling were assessed twice; during unloading and in the passageway to the lairage zone (lairage). Fear, which was assessed in the unloading area, was based on four indicators: reluctance to move, retreat attempts, turning back and vocalisations. Lameness had low-to-moderate IOR when observed in the passageway to lairage (r = 0.46), but the IOR was low during unloading (r = 0.25). IOR for slipping and falling was moderate to high (r = 0.71 and r = 0.50, respectively), when assessed in the unloading area, but low for observations in the passageway (r = 0.13). Fear indicators had only moderate or low IOR. Turning back was the measure with the highest IOR (r = 0.43) and retreat attempts had the lowest IOR (r = 0.25). Based on these results, we concluded that scoring lameness could be reliable when assessed from the unloading bay to lairage, whereas slipping and falling should be scored in the unloading area of the slaughterhouse. We suggest scoring a maximum of two measures of fear on the same animals at the unloading area, with the most reliable parameters being turning back and reluctance to move. The three indicators of animal welfare (lameness, fear and slipping and falling) should be measured in a way to reduce overtax of the observers in order to achieve accurate results.


Continuous shear stress alters metabolism, mass-transport, and growth in electroactive biofilms independent of surface substrate transport.
Electroactive bacteria such as Geobacter sulfurreducens and Shewanella onedensis produce electrical current during their respiration; this has been exploited in bioelectrochemical systems. These bacteria form thicker biofilms and stay more active than soluble-respiring bacteria biofilms because their electron acceptor is always accessible. In bioelectrochemical systems such as microbial fuel cells, corrosion-resistant metals uptake current from the bacteria, producing power. While beneficial for engineering applications, collecting current using corrosion resistant metals induces pH stress in the biofilm, unlike the naturally occurring process where a reduced metal combines with protons released during respiration. To reduce pH stress, some bioelectrochemical systems use forced convection to enhance mass transport of both nutrients and byproducts; however, biofilms' small pore size limits convective transport, thus, reducing pH stress in these systems remains a challenge. Understanding how convection is necessary but not sufficient for maintaining biofilm health requires decoupling mass transport from momentum transport (i.e. fluidic shear stress). In this study we use a rotating disc electrode to emulate a practical bioelectrochemical system, while decoupling mass transport from shear stress. This is the first study to isolate the metabolic and structural changes in electroactive biofilms due to shear stress. We find that increased shear stress reduces biofilm development time while increasing its metabolic rate. Furthermore, we find biofilm health is negatively affected by higher metabolic rates over long-term growth due to the biofilm's memory of the fluid flow conditions during the initial biofilm development phases. These results not only provide guidelines for improving performance of bioelectrochemical systems, but also reveal features of biofilm behavior. Results of this study suggest that optimized reactors may initiate operation at high shear to decrease development time before decreasing shear for steady-state operation. Furthermore, this biofilm memory discovered will help explain the presence of channels within biofilms observed in other studies.


First Report of Soybean Vein Necrosis Disease Caused by Soybean vein necrosis-associated virus in Wisconsin and Iowa.
Several viral diseases of soybean (Glycine max) have been identified in the north-central U.S. soybean production area, which includes Wisconsin and Iowa (2). Previously, Soybean vein necrosis disease (SVND) caused by Soybean vein necrosis-associated virus was reported in Arkansas, Tennessee, and other southern states (4). In September 2012, soybean plants with symptoms similar to those reported for SVND (4) were observed in fields across Wisconsin and Iowa. Symptoms included leaf-vein and leaf chlorosis, followed by necrosis of the leaf veins and eventually necrosis of the entire leaf. Six samples with symptoms indicative of SVNaV were collected from research plots located at the West Madison Agricultural Research Station located in Madison, WI. An additional three samples were collected from three locations in central Iowa. Total RNA extracted from each sample using the Trizol Plus RNA purification kit (Invitrogen, Carlsbad, CA) was used to generate complementary DNA (cDNA) using the iScript cDNA synthesis kit (Bio-Rad Laboratories, Hercules, CA) following the manufacturers' suggested protocols. The resulting cDNA was used as template in a PCR with SVNaV-specific primers, SVNaV-f1 and SVNaV-r1 (3). PCRs of two of the six Wisconsin samples and two Iowa samples were positive. Amplification products were not detected in the other five samples. The amplification products from the four strongly positive samples were purified using the Wizard SV Gel and PCR Purification Kit (Promega, Madison, WI) following the manufacturer's suggested protocol and were subjected to automated sequencing (University of Wisconsin Biotechnology Center or Iowa State University, DNA Sequencing Facilities). BLASTn (1) alignments of the 915-bp consensus sequence revealed 98% and >99% identity of the Wisconsin and Iowa samples, respectively, with the 'S' segment of the SVNaV 'TN' isolate (GenBank Accession No. GU722319.1). Samples from the same leaf tissue used above, were subjected to serological tests for SVNaV using antigen coated-indirect ELISA (3). Asymptomatic soybeans grown in the greenhouse were used as a source of leaves for negative controls. These tests confirmed the presence of SVNaV in eight symptomatic soybean leaflets collected in Wisconsin and Iowa. The asymptomatic control and one Iowa sample, which was also PCR-negative, were also negative by serological testing. Six additional samples from soybean fields in as many Wisconsin counties (Fond Du Lac, Grant, Green, Juneau, Richland, Rock) tested positive for SVNaV using specific primers that amplify the 'L' segment (4). The sequenced amplification products (297-bp) showed 99 to 100% homology to the L segment of the TN isolate (GU722317.1). To our knowledge, this is the first report of SVNaV associated with soybean and the first report of SVND in Wisconsin and Iowa. Considering that little is known about SVNaV, it is assumed that it is like other Tospoviruses and can cause significant yield loss (4). Soybean is a major cash crop for Wisconsin and Iowa, and infection by SVNaV could result in potential yield loss in years where epidemics begin early and at a high initial inoculum level. References: (1) S. F. Altschul et al. J. Mol. Biol. 215:403, 1990. (2) G. L. Hartman et al. Compendium of Soybean Diseases, 4th ed, 1999. (3) B. Khatabi et al. Eur. J. Plant Pathol. 133:783, 2012. (4) J. Zhou et al. Virus Genes 43:289, 2011.


Polarization-resolved spatial characterization of birefringent Fiber Bragg Gratings.
A method that enables polarization-resolved spatial characterization of fiber Bragg gratings is presented. The polarization-resolved reflection spectrum of the grating is measured using optical-frequency domain reflectometry. A polarization-resolved layer-peeling algorithm is used to compute the spatial profile, including the local birefringence and the local polarization-dependent index modulation. A strain-tuned distributed feedback fiber laser is used as source. With closed-loop control of the laser sweep, 0.14% maximum deviation from constant sweep rate is achieved, which is much better than commercial available tunable lasers. The polarization of the source is modulated synchronous with the laser sweep by passing the light through a three-armed Mach-Zehnder-type interferometer having different retardation. The method is used to investigate the polarization-dependence of the index modulation amplitude of a fiber Bragg grating.


Ethical aspects of registry-based research in the Nordic countries.
National health care registries in the Nordic countries share many attributes, but different legal and ethical frameworks represent a challenge to promoting effective joint research. Internationally, there is a lack of knowledge about how ethical matters are considered in Nordic registry-based research, and a lack of knowledge about how Nordic ethics committees operate and what is needed to obtain an approval. In this paper, we review ethical aspects of registry-based research, the legal framework, the role of ethics review boards in the Nordic countries, and the structure of the ethics application. We discuss the role of informed consent in registry-based research and how to safeguard the integrity of study participants, including vulnerable subjects and children. Our review also provides information on the different government agencies that contribute registry-based data, and a list of the major health registries in Denmark, Finland, Iceland, Norway, and Sweden. Both ethical values and conditions for registry-based research are similar in the Nordic countries. While Denmark, Finland, Iceland, Norway, and Sweden have chosen different legal frameworks, these differences can be resolved through mutual recognition of ethical applications and by harmonizing the different systems, likely leading to increased collaboration and enlarged studies.


Short-term caloric restriction augments age-related decreases in gastrin content and release.
Aging is associated with significant structural and functional changes in the gastrointestinal tract. Gastrin, a hormone produced by G cells in the antrum of the stomach, stimulates proliferation of gastric mucosa; its synthesis appears to decrease with age. Life-long restriction of caloric intake is the only experimental manipulation that has been shown to retard aging processes in rats. The purpose of this study was to examine the effect of short-term caloric restriction (CR) on the production and release of the hormone gastrin with aging. Aging causes a fall in both fasting plasma levels of gastrin and antral content of gastrin in Fischer 344 rats; short-term CR appears to augment this age-related decrease. Steady state levels of antral gastrin mRNA were decreased with aging, and short-term CR resulted in an augmented decrease in aged, but not in young rats. Our findings indicate that gastrin release, synthesis and gene expression decrease with age. Restriction of the caloric intake for a short period (i.e. 8 weeks) augments this age-related decrease in antral gastrin and fasting plasma levels. Short-term CR appears to decrease the production of gastrin at the level of gene expression.


Modular engineering of cellular signaling proteins and networks.
Living cells respond to their environment using networks of signaling molecules that act as sensors, information processors, and actuators. These signaling systems are highly modular at both the molecular and network scales, and much evidence suggests that evolution has harnessed this modularity to rewire and generate new physiological behaviors. Conversely, we are now finding that, following nature's example, signaling modules can be recombined to form synthetic tools for monitoring, interrogating, and controlling the behavior of cells. Here we highlight recent progress in the modular design of synthetic receptors, optogenetic switches, and phospho-regulated proteins and circuits, and discuss the expanding role of combinatorial design in the engineering of cellular signaling proteins and networks.


Ensuring research integrity: setting standards for robust and ethical conduct and reporting of research.
We present an account of why we decided to retract a paper. We discovered a lack of adherence to conventional trials registration, execution, interpretation and reporting, and consequently, with the authors, needed to correct the scientific record. We set out our responses in general to strengthen research integrity.Declaration of interestK.S.B. is Editor-in-Chief of the British Journal of Psychiatry. W.L., K.R.K. and S.M.L. are members of the senior editorial committee and the research integrity committee for the journal. In the past three years, S.M.L. has received research support from Janssen and Lundbeck, and personal support from Janssen, Otsuka and Sunovion.


The S-locus receptor kinase gene in a self-incompatible Brassica napus line encodes a functional serine/threonine kinase.
An S-receptor kinase (SRK) cDNA, SRK-910, from the active S-locus in a self-incompatible Brassica napus W1 line has been isolated and characterized. The SRK-910 gene is predominantly expressed in pistils and segregates with the W1 self-incompatibility phenotype in an F2 population derived from a cross between the self-incompatible W1 line and a self-compatible Westar line. Analysis of the predicted amino acid sequence demonstrated that the extracellular receptor domain is highly homologous to S-locus glycoproteins, whereas the cytoplasmic kinase domain contains conserved amino acids present in serine/threonine kinases. An SRK-910 kinase protein fusion was produced in Escherichia coli and found to contain kinase activity. Phosphoamino acid analysis confirmed that only serine and threonine residues were phosphorylated. Thus, the SRK-910 gene encodes a functional serine/threonine receptor kinase.


Quantitative analysis of methylation status of the PAX1 gene for detection of cervical cancer.
Although aided by high-risk human papillomavirus (HPV) DNA test, early detection of cervical cancer is still a challenge. Hypermethylation of the paired boxed gene 1 (PAX1) was recently reported as a characteristic of cervical cancer. This study designed a quantitative measure of PAX1 methylation and compared its efficacy to the currently available Hybrid Capture 2 (HC2) HPV test in detection of cervical cancer. Using real-time quantitative methylation-specific polymerase chain reaction, we measured the percentage of PAX1 methylation in cervical scrapings obtained from a hospital-based cohort of women with cervical neoplasia of different severities and compared the efficacy of diagnosis of cervical cancer to that of the HC2 HPV test. From 73 cervical scrapings, with diagnoses of normal (n = 17), cervical intraepithelial neoplasm 1 (CIN1; n = 10), CIN2 (n = 18), CIN3 (n = 14), and invasive cancer (n = 14), the percentage of PAX1 methylation was determined. The percent of methylated reference of invasive cancer (mean [SE], 56.7 [7.1]) was significantly higher than CIN3 (6.5 [2.3]) and the other milder lesions (1.0 [0.3]; P < 0.0001). At a cutoff percent of methylated reference value of 4.5, PAX1 methylation was found in 100% of invasive cancer tissue as compared with 0% of normal tissue, 10% of CIN1, 11% of CIN2, and 43% of CIN3 (P < 0.0001). As a comparison, the HC2 HPV test result was positive in 5.9% of normal tissue, 70% of CIN1, 55.6% of CIN2, 71.4% of CIN3, and 100% of invasive cancer. In addition to cancer tissue, methylation of PAX1 was also found in normal tissue adjacent to the cancer lesion (9/11, 82%) but much less in the remote normal tissues (2/5, 40%), indicating a field methylation. In this hospital-based study, quantitative measurement of PAX1 hypermethylation in cervical scrapings is highly sensitive and is more specific than HC2 in detection of cervical cancer.


Is long-term use of benzodiazepine a risk for cancer?
The carcinogenicity of benzodiazepines (BZDs) is still unclear. We aimed to assess whether long-term benzodiazepines use is risk for cancer.We conducted a longitudinal population-based case-control study by using 12 years from Taiwan National Health Insurance database and investigated the association between BZDs use and cancer risk of people aged over 20 years. During the study period, 42,500 cases diagnosed with cancer were identified and analyzed for BZDs use. For each case, six eligible controls matched for age, sex, and the index date (ie, free of any cancer in the date of case diagnosis) by using propensity score. For appropriate risk estimation, we observed the outcomes according to their length of exposure (LOE) and defined daily dose (DDD). To mimic bias, we adjusted with potential confounding factors such as medications and comorbid diseases which could influence for cancer risk during the study period. The data was analyzed by using Cox proportional hazard regression and conditional logistic regression.The finding unveils benzodiazepines use into safe and unsafe groups for their carcinogenicity. The use of diazepam (HR, 0.96; 95%CI, 0.92-1.00), chlorodizepoxide (HR, 0.98; 95%CI, 0.92-1.04), medazepam (HR, 1.01; 95%CI, 0.84-1.21), nitrazepam (HR, 1.06; 95%CI, 0.98-1.14), oxazepam (HR, 1.05; 95%CI, 0.94-1.17) found safer among BZDs. However, clonazepam (HR, 1.15; 95%CI, 1.09-1.22) were associated with a higher risk for cancers. Moreover, specific cancer risk among BZDs use was observed significantly increased 98% for brain, 25% for colorectal, and 10% for lung, as compared with non-BZDs use.Diazepam, chlordiazepoxide, medazepam, nitrazepam, and oxazepam are safe among BZDs use for cancer risk. Our findings could help physicians to select safer BZDs and provide an evidence on the carcinogenic effect of benzodiazepines use by considering the LOE and DDD for further research.


Advantage of specialism: reproductive output is related to prey choice in a small raptor.
Predatory species' usage of different prey types is affected by both prey availability and selectivity. The diet during the breeding season may affect the reproductive success of individual pairs. We studied the prey use of a small reversed size-dimorphic raptor, the Eurasian sparrowhawk Accipiter nisus, with respect to prey weight on two organizational levels. Using 13 years of data from southern Norway, we related reproductive output of individual breeding events to prey size taken. Further, we assessed the regional variation in prey usage between five Fennoscandian populations. This was done by fitting optimum-type functions to the prey species' numbers or relative predation risks. Pairs that successfully completed the season with more fledglings displayed less variation in prey size, suggesting a possible adaptive benefit of diet specialism, or possibly a correlative effect due to higher prey availability or lower female hunting effort. This finding contrasts with earlier raptor studies, which have suggested benefits of dietary (and hence nutritional) diversity. Indeed, our results might be limited to nutritionally substitutable prey items. We also found a tendency suggesting that older females raised more fledglings than 1-year-old females. In the population-level analysis, we found that optimum-type functions with constant width and spatially variable average best described the relationship between relative predation risk and log weight. This can reflect local conditions, such as prey availability. Our findings and new methodological tools could apply to a broader spectrum of predators. They also highlight the role of viewing usage or choice of prey at several spatial scales.


American Society of Clinical Oncology clinical expert statement on cancer survivorship care planning.
The seminal report from the Institute of Medicine, "From Cancer Patient to Cancer Survivor: Lost in Transition," identified four essential components of survivorship care and recommended that a survivorship care plan (SCP), consisting of a treatment summary and follow-up care plan, be developed and used as a tool to deliver patient-centered care by enhancing communication between the oncology team and the patient as well as communication and coordination of care between the oncology team and the primary care provider (PCP). Nearly a decade ago, the American Society of Clinical Oncology (ASCO) initiated a series of activities to promote chemotherapy treatment plans and summaries and SCPs. Unfortunately, there has been limited success in implementing SCPs in oncology practice because of barriers including, but not limited to, the time-consuming process of completing an SCP, lack of role clarity, and lack of reimbursement for preparation time. ASCO developed this statement and revised template to provide a framework for completing and sharing SCPs and to set clear expectations for survivorship care planning in the oncology setting. This statement is intended to help clinicians recognize the importance of developing patient-centered SCPs and delivering the information to both the patient and PCP and to identify barriers that may exist in completing and delivering these documents effectively.


Credentialing for public health nurses: personally valued ... But not well recognized.
This study examined the extent to which public health nurses (PHNs) see value in credentialing and perceive specific barriers related to a community/public health nursing (C/PHN) credential. A cross-sectional exploratory survey was used to examine the perceived value of credentialing for PHNs and the perceived barriers to obtaining or maintaining the C/PHN credential as the primary variables of interest. Data were collected from 655 PHN members of national public health nursing organizations who participated in an online survey. Responses related to the perceived value of credentialing were analyzed using factor analysis and descriptive statistics. Data regarding perceived barriers to the C/PHN credential were analyzed through descriptive statistics and through the Borda Count Method for analysis of ranked data (Tannenbaum, 1995). Similar to nurses in other specialties, study participants perceived that credentialing has a high personal value for PHNs, but that certification provides less value in terms of extrinsic recognition. Respondents identified issues related to the lack of external recognition as particular barriers to the C/PHN credential. These findings provide guidance to public health nursing leaders and inform discussions regarding the development of credentialing systems within the field of public health.


The inter-annual variability of heat-related mortality in nine European cities (1990-2010).
The association between heat and daily mortality and its temporal variation are well known. However, few studies have analyzed the inter-annual variations in both the risk estimates and impacts of heat. The aim is to estimate inter-annual variations in the effect of heat for a fixed temperature range, on mortality in 9 European cities included in the PHASE (Public Health Adaptation Strategies to Extreme weather events) project for the period 1990-2010. The second aim is to evaluate overall summer effects and heat-attributable deaths for each year included in the study period, considering the entire air temperature range (both mild and extreme temperatures). A city-specific daily time-series analysis was performed, using a generalized additive Poisson regression model, restricted to the warm season (April-September). To study the temporal variation for a fixed air temperature range, a Bayesian Change Point analysis was applied to the relative risks of mortality for a 2 °C increase over the 90th percentile of the city-specific distribution. The number of heat attributable deaths in each summer were also calculated for mild (reference to 95th percentile) and extreme heat (95th percentile to maximum value). A decline in the effects of heat over time was observed in Athens and Rome when considering a fixed interval, while an increase in effects was observed in Helsinki. The greatest impact of heat in terms of attributable deaths was observed in the Mediterranean cities (Athens, Barcelona and Rome) for extreme air temperatures. In the other cities the impact was mostly related to extreme years with 2003 as a record breaking year in Paris (+ 1900 deaths) and London (+ 1200 deaths). Monitoring the impact of heat over time is important to identify changes in population vulnerability and evaluate adaptation measures.


Nonpromoting 12-deoxyphorbol 13-esters inhibit phorbol 12-myristate 13-acetate induced tumor promotion in CD-1 mouse skin.
Prostratin and 12-deoxyphorbol 13-phenylacetate (dPP) form a new class of protein kinase C activators of unique biological activity. Although they bind to and activate protein kinase C, in mouse skin they either fail to induce typical phorbol ester (PMA) effects (e.g., hyperplasia) or induce only partial response (e.g., inflammation). Furthermore, pretreatment with these agents inhibits a range of PMA induced effects (acute and chronic hyperplasia, inflammation, etc.) These observations suggested that prostratin and dPP would function as inhibitors of phorbol ester tumor promotion. Here we verify that prediction. We report that both compounds reduced both the average number of papillomas and the tumor incidence in a tumor promotion schedule in CD-1 mouse skin, in which each PMA application was preceded by 12-deoxyphorbol 13-monoester pretreatment. The highest dose of prostratin used (2.56 mumol or 1 mg/pretreatment) caused a 96% (23-fold) reduction in the average number of papillomas with a decrease of tumor incidence from 97 to 40%. The highest dose of dPP used (21.4 nmol or 10 micrograms/pretreatment) induced an 86% (7-fold) reduction in the average number of papillomas with a 53% reduction of tumor incidence from 100 to 47%. The inhibitory effect was dose dependent. The dose causing 50% inhibition was 11 nmol/pretreatment for prostratin and 0.8 nmol/pretreatment for dPP. Maximal inhibition of tumor promotion was accompanied by a block of epidermal hyperplasia; however, significant inhibition of tumor induction was observed at doses without any apparent effect on the PMA induced hyperplasia.


Protein arginine methyltransferase 5 accelerates tumor growth by arginine methylation of the tumor suppressor programmed cell death 4.
Programmed cell death 4 (PDCD4) has been described as a tumor suppressor, with high expression correlating with better outcomes in a number of cancer types. Yet a substantial number of cancer patients with high PDCD4 in tumors have poor survival, suggesting that oncogenic pathways may inhibit or change PDCD4 function. Here, we explore the significance of PDCD4 in breast cancer and identify protein arginine methyltransferase 5 (PRMT5) as a cofactor that radically alters PDCD4 function. Specifically, we find that coexpression of PDCD4 and PRMT5 in an orthotopic model of breast cancer causes accelerated tumor growth and that this growth phenotype is dependent on both the catalytic activity of PRMT5 and a site of methylation within the N-terminal region of PDCD4. In agreement with the xenograft model, elevated PDCD4 expression was found to correlate with worse outcome within the cohort of breast cancer patients whose tumors contain higher levels of PRMT5. These results reveal a new cofactor for PDCD4 that alters its tumor suppressor functions and point to the utility of PDCD4/PRMT5 status as both a prognostic biomarker and a potential target for chemotherapy.


Plant versus animal based diets and insulin resistance, prediabetes and type 2 diabetes: the Rotterdam Study.
Vegan or vegetarian diets have been suggested to reduce type 2 diabetes (T2D) risk. However, not much is known on whether variation in the degree of having a plant-based versus animal-based diet may be beneficial for prevention of T2D. We aimed to investigate whether level of adherence to a diet high in plant-based foods and low in animal-based foods is associated with insulin resistance, prediabetes, and T2D. Our analysis included 6798 participants (62.7 ± 7.8 years) from the Rotterdam Study (RS), a prospective population-based cohort in the Netherlands. Dietary intake data were collected with food-frequency questionnaires at baseline of three sub-cohorts of RS (RS-I-1: 1989-1993, RS-II-1: 2000-2001, RS-III-1: 2006-2008). We constructed a continuous plant-based dietary index (range 0-92) assessing adherence to a plant-based versus animal-based diet. Insulin resistance at baseline and follow-up was assessed using homeostasis model assessment of insulin resistance (HOMA-IR). Prediabetes and T2D were collected from general practitioners' records, pharmacies' databases, and follow-up examinations in our research center until 2012. We used multivariable linear mixed models to examine association of the index with longitudinal HOMA-IR, and multivariable Cox proportional-hazards regression models to examine associations of the index with risk of prediabetes and T2D. During median 5.7, and 7.3 years of follow-up, we documented 928 prediabetes cases and 642 T2D cases. After adjusting for sociodemographic and lifestyle factors, a higher score on the plant-based dietary index was associated with lower insulin resistance (per 10 units higher score: β = -0.09; 95% CI: - 0.10; - 0.08), lower prediabetes risk (HR = 0.89; 95% CI: 0.81; 0.98), and lower T2D risk [HR = 0.82 (0.73; 0.92)]. After additional adjustment for BMI, associations attenuated and remained statistically significant for longitudinal insulin resistance [β = -0.05 (- 0.06; - 0.04)] and T2D risk [HR = 0.87 (0.79; 0.99)], but no longer for prediabetes risk [HR = 0.93 (0.85; 1.03)]. In conclusion, a more plant-based and less animal-based diet may lower risk of insulin resistance, prediabetes and T2D. These findings strengthen recent dietary recommendations to adopt a more plant-based diet.Clinical Trial Registry number and website NTR6831, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6831 .


Molecular detection of genomic regions associated with grain yield and yield-related components in an elite bread wheat cross evaluated under irrigated and rainfed conditions.
Grain yield and grain weight of wheat are often decreased by water-limitation in the north-eastern cropping belt of Australia. Based on knowledge that CIMMYT lines are well-adapted in this region, a recombinant inbred line (RIL) population between two elite CIMMYT bread wheats (Seri M82 and Babax) was evaluated under water-limited environments. Fourteen productivity traits were evaluated in 192 progeny in up to eight trials. For three aggregations of the environments (all, high yield or low yield), multiple quantitative trait loci (QTL) were detected, each explaining <15% of variation. Co-location of multiple trait QTL was greatest on linkage groups 1B-a, 1D-b, 4A-a, 4D-a, 6A-a, 6B-a, 7A-a and an unassigned linkage group. Two putative QTL (LOD > 3) from Seri (6D-b and UA-d) increased grain yield and co-located with a suggestive (2 < LOD < 3) and a putative QTL for increased stem carbohydrate content (WSC), respectively; the latter QTL also co-located with a putative anthesis QTL for earlier flowering. Both QTL were detected only in high yield (>4t ha(-1)) environments. A third increased grain yield QTL (7A-a) from Babax co-located with QTL for increased grain number. Six putative QTL increased grain weight and co-located with QTL for harvest index, grains per spike and spike number. Three putative QTL for increased grains per spike co-located with strong QTL for earlier flowering, increased grain weight and fewer spikes. A group of progeny that exceeded the mean grain yield and grain weight of commercial checks had an increased frequency of QTL for high WSC, large grain size, increased harvest index and greater height, but fewer stems, when compared to low yielding (20% less), low grain weight progeny. These findings were consistent with agronomic analyses of the germplasm and demonstrate that there should be opportunities to independently manipulate grain number and grain size which is typically difficult due to strong negative correlations.


Predicting the distribution of urinary schistosomiasis in Tanzania using satellite sensor data.
In this paper, remotely sensed (RS) satellite sensor environmental data, using logistic regression, are used to develop prediction maps of the probability of having infection prevalence exceeding 50%, and warranting mass treatment according to World Health Organization (WHO) guidelines. The model was developed using data from one area of coastal Tanzania and validated with independent data from different areas of the country. Receiver operating characteristic (ROC) analysis was used to evaluate the model's predictive performance. The model allows reasonable discrimination between high and low prevalence schools, at least within those geographical areas in which they were originally developed, and performs reasonably well in other coastal areas, but performs poorly by comparison in the Great Lakes area of Tanzania. These results may be explained by reference to an ecological zone map based on RS-derived environmental data. This map suggests that areas where the model reliably predicts a high prevalence of schistosomiasis fall within the same ecological zone, which has common intermediate-host snail species responsible for transmission. By contrast, the model's performance is poor near Lake Victoria, which is in a different ecological zone with different snail species. The ecological map can potentially define a template for those areas where existing models can be applied, and highlight areas where further data and models are required. The developed model was then used to provide estimates of the number of schoolchildren at risk of high prevalence and associated programme costs.


SPECT imaging in head injury interpreted with statistical parametric mapping.
This study investigated regional cerebral blood flow in head-injured patients using statistical parametric mapping (SPM) to detect hypoperfusion on (99m)Tc-hexamethylpropyleneamine oxime (HMPAO) SPECT scans. Acute and follow-up SPECT and MRI scans from 61 patients who were admitted to a regional neurosurgical unit were examined. Patients had acute MRI and SPECT at 2-18 d after injury and on follow-up between 130 and 366 d after injury. Thirty-two scans from non-head-injured patients were used as a SPECT control group. The SPECT images were first aligned to the Talairach-Tournoux atlas and then analyzed statistically with SPM. SPECT detected more extensive abnormality than MRI in acute and follow-up stages. This effect was more pronounced on follow-up of patients with diffuse injury. Examination of a focal injury group indicated the involvement of frontal and temporal lobes and the anterior cingulate. Blood flow abnormalities persist, to a lesser extent, on follow-up scans. The diffuse group displayed low blood flow in the frontal and temporal lobes, including cingulate involvement, which persists at follow-up with additional involvement of the thalamus. SPM has a role in SPECT image interpretation because it allows better visualization than other methods of quantitative analysis of the spatial distribution of abnormalities in focal and diffuse head injury. Frontal lobe blood flow abnormality (particularly anterofrontal regions and mesiofrontal areas) is common after head injury.


Public Perceptions of Doctors of Chiropractic: Results of a National Survey and Examination of Variation According to Respondents' Likelihood to Use Chiropractic, Experience With Chiropractic, and Chiropractic Supply in Local Health Care Markets.
The purpose of this study was to determine whether general perceptions of doctors of chiropractic (DCs) varied according to likeliness to use chiropractic care, whether particular demographic characteristics were associated with chiropractic care use, and whether perception of DCs varied according to the per-capita supply of DCs in local health care markets. We performed a secondary analysis of results from a 26-item nationally representative survey of 5422 members of The Gallup Panel that was conducted in the spring of 2015 (response rate, 29%) that sought to elicit the perceptions and use of DCs by US adults. We compared survey responses across: (1) respondents who had different likelihoods to use DCs for treatment of neck or back pain and (2) respondents who had different experiences using DCs. We linked respondents' zip codes to hospital referral regions for which we had the per-capita supply of DCs. Using the χ(2) test, we examined relationships between likeliness to use a DC, experience using a DC, respondent demographic variables, perceptions of DCs, and the per-capita supply of DCs in the local health care market. Most (61.4%) respondents believed that chiropractic care was effective at treating neck and back pain, 52.6% thought DCs were trustworthy, and 24.2% thought chiropractic care was dangerous; however, as respondents' likelihood to use a DC increased, perceptions of effectiveness and trustworthiness increased, and perceptions of danger decreased. Of all 5422 survey respondents, 744 or 13.7% indicated that they had seen a DC within the last 12 months. As one moved from distant to more recent experience using a DC, respondents were more likely to be female, married, white, and employed; those who had a distant history of using a DC were older and more likely to be retired than the other groups. A higher per-capita supply of DCs was associated with higher utilization rates and showed a more favorable regard for DCs. US adults often use chiropractic care, generally regard DCs favorably, and largely perceive that chiropractic care is safe. Where there is a higher per-capita supply of DCs in the local health care market, utilization and positive perceptions of chiropractic are higher.


Percentage of subjects with no heavy drinking days: evaluation as an efficacy endpoint for alcohol clinical trials.
Percent subjects with no heavy drinking days (PSNHDDs), an efficacy end point recommended by the Food and Drug Administration, considers abstinent individuals or those engaging in low-risk drinking behavior as successful responders to treatment. As PSNHDD has been used infrequently in previous alcohol clinical trials, we evaluated the utility and validity of the PSNHDD outcome measure in 2 large alcohol clinical trials. Data sets from 2 alcohol trials, COMBINE and a multisite topiramate trial, were used to analyze PSNHDDs and other traditional end points for the topiramate, naltrexone, acamprosate, and placebo groups. Effect sizes of PSNHDDs were determined for each month of active treatment and by varying grace periods-early periods in the trial where outcome is not considered in the analysis-and were compared with that of other traditional outcome measures. Long-term outcomes were compared for groups that had no heavy drinking days versus those that had heavy drinking days during active treatment. PSNHDD effect sizes were significant for both topiramate (0.34 and 0.25 at months 2 and 3, respectively) and naltrexone (0.24 and 0.26 at months 3 and 4, respectively). Given a 2-month grace period for naltrexone, the effect size of PSNHDDs was comparable to the effect sizes using traditional outcome measures. With a 1-month grace period for topiramate, it was greater than the majority of traditional outcome measures. Little is gained by allowing up to 1, 2, or 3 heavy drinking days as an end point. Subjects with no HDDs during treatment fared better than those with some HDDs on drinking outcomes and alcohol-related consequences during a 1-year follow-up. PSNHDD appears to be a clinically informative end point measure, especially when used with a grace period, and is as sensitive as most traditional outcome measures in detecting differences between the medication and placebo groups. Nonetheless, these findings should be replicated in other clinical data sets, particularly with medications that work via different mechanisms.


Prediction of bioconcentration factors in fish and invertebrates using machine learning.
The application of machine learning has recently gained interest from ecotoxicological fields for its ability to model and predict chemical and/or biological processes, such as the prediction of bioconcentration. However, comparison of different models and the prediction of bioconcentration in invertebrates has not been previously evaluated. A comparison of 24 linear and machine learning models is presented herein for the prediction of bioconcentration in fish and important factors that influenced accumulation identified. R2 and root mean square error (RMSE) for the test data (n = 110 cases) ranged from 0.23-0.73 and 0.34-1.20, respectively. Model performance was critically assessed with neural networks and tree-based learners showing the best performance. An optimised 4-layer multi-layer perceptron (14 descriptors) was selected for further testing. The model was applied for cross-species prediction of bioconcentration in a freshwater invertebrate, Gammarus pulex. The model for G. pulex showed good performance with R2 of 0.99 and 0.93 for the verification and test data, respectively. Important molecular descriptors determined to influence bioconcentration were molecular mass (MW), octanol-water distribution coefficient (logD), topological polar surface area (TPSA) and number of nitrogen atoms (nN) among others. Modelling of hazard criteria such as PBT, showed potential to replace the need for animal testing. However, the use of machine learning models in the regulatory context has been minimal to date and is critically discussed herein. The movement away from experimental estimations of accumulation to in silico modelling would enable rapid prioritisation of contaminants that may pose a risk to environmental health and the food chain.


[Psychophysical parallelism. On a discursive figure in the field of scientific changes in the late 19th century].
The article traces the rise and fall of "psychophysical parallelism" - which was the most advanced scientific formulation of the mind / body relationship in the second half of the 19th century - through an interdisciplinary and broad geographical spectrum. It sheds light on the extremely different positions that rallied round this discursive figure, ranging from Fechner, Hering, Mach, Wundt, Bain, Hughlings Jackson, and Taine to Freud and Saussure. The article develops the thesis that the psychophysical parallelism functioned as a 'hot zone' within and a symptom of the changes in the order of sciences at that time. Against that background, the criticism of the psychophysical parallelism which became prominent around 1900 (Stumpf, Busse, Bergson, Mauthner et. al.) indicates the cooling of this 'hot zone' and the establishment of a new order within the scientific disciplines. The article pays particular attention to the position of this figure in contemporaneous language theories. Its basic assumption is that the relationship between the body and the psyche is itself constituted by language.


A mathematical model of the sterol regulatory element binding protein 2 cholesterol biosynthesis pathway.
Cholesterol is one of the key constituents for maintaining the cellular membrane and thus the integrity of the cell itself. In contrast high levels of cholesterol in the blood are known to be a major risk factor in the development of cardiovascular disease. We formulate a deterministic nonlinear ordinary differential equation model of the sterol regulatory element binding protein 2 (SREBP-2) cholesterol genetic regulatory pathway in a hepatocyte. The mathematical model includes a description of genetic transcription by SREBP-2 which is subsequently translated to mRNA leading to the formation of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a main regulator of cholesterol synthesis. Cholesterol synthesis subsequently leads to the regulation of SREBP-2 via a negative feedback formulation. Parameterised with data from the literature, the model is used to understand how SREBP-2 transcription and regulation affects cellular cholesterol concentration. Model stability analysis shows that the only positive steady-state of the system exhibits purely oscillatory, damped oscillatory or monotic behaviour under certain parameter conditions. In light of our findings we postulate how cholesterol homeostasis is maintained within the cell and the advantages of our model formulation are discussed with respect to other models of genetic regulation within the literature.


Detection of Serum miRNAs Affecting Liver Apoptosis in a Periodontitis Rat Model.
miRNA molecules have been attracting attention as genetic modifiers between organs. We examined the relationship between serum miRNA and targeted liver mRNA profiles in a periodontitis rat model, and the influence of periodontitis on the liver. Male Wistar rats (n=16, 8 weeks old) were randomly divided into two groups (8 rats each): control and periodontitis (ligature placement for 4 weeks). Serum miRNA and liver mRNA profiles were compared. Periodontal destruction and hepatocyte apoptosis were induced in the periodontitis group. Microarray analysis indicated that 52 serum miRNAs and 33 liver mRNAs were expressed with a >1.5-fold change (FC) and a >2.0-FC (p<0.05), respectively, between the two groups. From the miRNA target genes, 12 genes equivalented to liver mRNAs with a >2.0-FC, among which, Hyou1, Chac1, and Bloc1s3 have apoptotic functions in our model. miRNAs upstream of these 3 mRNAs are miR-3591, miR-181a-2-3p and miR-6321. miR-3591, miR-181a-2-3p and miR-6321 induced hepatocyte apoptosis in our periodontitis rat model.


YKL-40 levels are independently associated with albuminuria in type 2 diabetes.
YKL-40 is involved in inflammation and endothelial dysfunction, and is increased in patients with type 1 diabetes, with an independent association between increasing YKL-40 levels and increasing levels of albuminuria. YKL-40 is associated with atherosclerosis and an increased cardiovascular mortality in the general population. In the present study YKL-40 levels were examined in patients with type 2 diabetes (T2D) with increasing levels of albuminuria, known to be associated with an increased risk of cardiovascular disease. One-hundred-five patients with T2D were examined: 49 with normoalbuminuria (N, U-albumin/creatinine < 2.5 mg/mmol), 35 with persistent microalbuminuria (MA, 2.5-25 mg/mmol) and 21 with persistent macroalbuminuria/diabetic nephropathy (DN, > 25 mg/mmol). The control group consisted of 20 healthy individuals (C). Groups were matched according to age, gender and known duration of diabetes. Median levels (interquartile range) of serum YKL-40 were significantly higher in N and MA vs. C (86 (55-137) ng/ml and 84 (71-147) ng/ml, respectively vs. 41 (33-55) ng/ml, p < 0.01) and even higher in patients with DN (120 (83-220) ng/ml, p < 0.001 for all comparisons). YKL-40 levels correlated with urinary albumin/creatinine-ratio in the total group of participants (r = 0.41, p < 0.001). Significant intercorrelations of YKL-40 were found with age, duration of diabetes, systolic blood pressure, lipid levels, HbA1c and HOMA-IR. After adjustment for significant covariates, albuminuria was significantly associated with YKL-40 levels (r = 0.32, p = 0.006). YKL-40 levels are elevated in patients with T2D with an independent association between increasing YKL-40 levels and increasing levels of albuminuria. The study suggests a role of YKL-40 in the progressing vascular complications in patients with T2D.


Experimental realization of a minimal microscopic heat engine.
Microscopic heat engines are microscale systems that convert energy flows between heat reservoirs into work or systematic motion. We have experimentally realized a minimal microscopic heat engine. It consists of a colloidal Brownian particle optically trapped in an elliptical potential well and simultaneously coupled to two heat baths at different temperatures acting along perpendicular directions. For a generic arrangement of the principal directions of the baths and the potential, the symmetry of the system is broken, such that the heat flow drives a systematic gyrating motion of the particle around the potential minimum. Using the experimentally measured trajectories, we quantify the gyrating motion of the particle, the resulting torque that it exerts on the potential, and the associated heat flow between the heat baths. We find excellent agreement between the experimental results and the theoretical predictions.


Sparse estimation of gene-gene interactions in prediction models.
Current assessment of gene-gene interactions is typically based on separate parallel analysis, where each interaction term is tested separately, while less attention has been paid on simultaneous estimation of interaction terms in a prediction model. As the number of interaction terms grows fast, sparse estimation is desirable from statistical and interpretability reasons. There is a large literature on sparse estimation, but there is a natural hierarchy between the interaction and its corresponding main effects that requires special considerations. We describe random-effect models that impose sparse estimation of interactions under both strong and weak-hierarchy constraints. We develop an estimation procedure based on the hierarchical-likelihood argument and show that the modelling approach is equivalent to a penalty-based method, with the advantage of the models being more transparent and flexible. We compare the procedure with some standard methods in a simulation study and illustrate its application in an analysis of gene-gene interaction model to predict body-mass index.


Role of mRNA gestation and senescence in noise reduction during the cell cycle.
Recent innovations in experimental techniques on single molecule detection resulted in advances in the quantification of molecular noise in several systems, and provide suitable data for defining stochastic computational models of biological processes. Some of the latest stochastic models of cell cycle regulation analyzed the effect of noise on cell cycle variability. In their study, Kar et al. (Proc. Natl. Acad. Sci. USA 106, 6471-6476, 2009) found that the observed variances of cell cycle time and cell division size distributions cannot be matched with the measured long half-lives of mRNAs. Here, we investigate through modeling and simulation how the noise created by the transcription and degradation processes of a key cell cycle controller mRNA affect the statistics of cell cycle time and cell size at division. Our model consists of an encoding of the model of Kar et al. into a stochastic Petri net, with the extensions necessary to represent multiple synthesis (gestation) and degradation (senescence) steps in the regulation of mRNAs. We found that few steps of gestation and senescence of mRNA are enough to give a good match for both the measured half-lives and variability of cell cycle-statistics. This result suggests that the complex process of transcription can be more accurately approximated by multi-step linear processes.


Evolutionary dynamics of paroxysmal nocturnal hemoglobinuria.
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal blood disorder characterized by hemolysis and a high risk of thrombosis, that is due to a deficiency in several cell surface proteins that prevent complement activation. Its origin has been traced to a somatic mutation in the PIG-A gene within hematopoietic stem cells (HSC). However, to date the question of how this mutant clone expands in size to contribute significantly to hematopoiesis remains under debate. One hypothesis posits the existence of a selective advantage of PIG-A mutated cells due to an immune mediated attack on normal HSC, but the evidence supporting this hypothesis is inconclusive. An alternative (and simpler) explanation attributes clonal expansion to neutral drift, in which case selection neither favours nor inhibits expansion of PIG-A mutated HSC. Here we examine the implications of the neutral drift model by numerically evolving a Markov chain for the probabilities of all possible outcomes, and investigate the possible occurrence and evolution, within this framework, of multiple independently arising clones within the HSC pool. Predictions of the model agree well with the known incidence of the disease and average age at diagnosis. Notwithstanding the slight difference in clonal expansion rates between our results and those reported in the literature, our model results lead to a relative stability of clone size when averaging multiple cases, in accord with what has been observed in human trials. The probability of a patient harbouring a second clone in the HSC pool was found to be extremely low ([Formula: see text]). Thus our results suggest that in clinical cases of PNH where two independent clones of mutant cells are observed, only one of those is likely to have originated in the HSC pool.


Signatures of mutational processes in human cancer.
All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.


Transcatheter aortic valve implantation (TAVI) for treatment of aortic valve stenosis: an evidence update.
One-year mortality outcomes in the PARTNER trial showed that transcatheter aortic valve implantation (TAVI) was noninferior to surgical aortic valve replacement (sAVR) in patients who were eligible for sAVR (cohort A), and superior to standard treatment in patients who were ineligible for sAVR (cohort B). To update a previous report on the safety, effectiveness, and cost-effectiveness of TAVI, published in 2012. A literature search was performed on September 11, 2012, using OVID MEDLINE, OVID MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, EBSCO Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Wiley Cochrane Library, and the Centre for Reviews and Dissemination database, for studies published from January 1, 2011, until September 11, 2012. Randomized controlled trials investigating TAVI in comparison to sAVR or standard treatment were included for analysis. Results were summarized descriptively. At 2-year follow-up, mortality in cohort A was similar between the TAVI and sAVR groups. Rates of stroke/transient ischemic attack, major vascular complications, and moderate/severe paravalvular aortic regurgitation were significantly higher in the TAVI group, but rate of major bleeding was significantly higher in the sAVR group. Mortality in cohort B was significantly lower with transfemoral (TF) TAVI than with standard treatment, but rate of stroke was significantly higher with TF TAVI. TF TAVI resulted in a more rapid improvement in quality of life scores than sAVR, but this difference was not sustained at 6 and 12 months. Patients who underwent transapical TAVI did not have a greater early improvement in quality of life compared to sAVR patients. Compared to standard treatment, TF TAVI resulted in a greater improvement in quality of life scores at all time points. Incremental cost-effectiveness ratios were in favour of TAVI for inoperable patients in the base-case analysis, but varied widely for operable patients. The findings of the 2-year follow-up with respect to mortality and adverse events were consistent with those of the 1-year follow-up. TAVI was also associated with improvement in quality of life, although results varied by cohort. Consistent with the 2012 report, TAVI may be cost-effective for patients who are not candidates for surgery.