The role of leadership in implementing and sustaining an evidence-based intervention for osteoarthritis (ESCAPE-pain) in NHS physiotherapy services: a qualitative case study.
To explore the role of leadership by physiotherapists in implementing and sustaining an evidence-based complex intervention (ESCAPE-pain) for osteoarthritis. A qualitative case study approach using in-depth interviews with 23 clinicians and managers from 4 National Health Service (NHS) physiotherapy providers in England between 2016 and 2017. Data were analysed using thematic analysis. Different leadership roles and actions were characterised with four themes: (1) Clinical champions - clinicians driving the sustainability of ESCAPE-pain; (2) Supporters - junior clinicians directly supporting clinical champions' efforts to sustain ESCAPE-pain; (3) Senior Manager - clinical champions' senior managers influence on sustainability; (4) Decision-making - (in)formal processes underpinning decisions to (not) sustain the programme. The study characterises the role of leadership in physiotherapy to sustain an evidence-based intervention for osteoarthritis (OA) within the NHS. Sustaining the intervention required on-going leadership, it did not stop at implementation. Senior specialist physiotherapists (as Champions) had a critical leadership role in driving sustainability. Their structural position (bridging the operational and strategic) and personal attributes allowed them to integrate different levels of leadership (i.e., senior managers and operational staff) to mobilise the collective, on-going work required for sustaining the programme.IMPLICATIONS FOR REHABILITATIONSenior managers and clinicians in practice settings need to be aware that sustaining an intervention is an on-going, collective effort that continues post-implementation.Senior managers need to enable senior clinicians (who straddle strategic and operational functions) to have sufficient autonomy to access and mobilise resources and scope to restructure local systems and practice to support intervention sustainability.Operational staff need to be supported to have the practical know-how to deliver evidence-based intervention, which includes instilling the value of and a commitment for the interventions.Managers need to utilise dispersed leadership to empower and enthuse frontline clinicians to participate fully in the work to refine and sustain interventions, because it cannot be achieved by lone individuals.


Decoupled active contour (DAC) for boundary detection.
The accurate detection of object boundaries via active contours is an ongoing research topic in computer vision. Most active contours converge toward some desired contour by minimizing a sum of internal (prior) and external (image measurement) energy terms. Such an approach is elegant, but suffers from a slow convergence rate and frequently misconverges in the presence of noise or complex contours. To address these limitations, a decoupled active contour (DAC) is developed which applies the two energy terms separately. Essentially, the DAC consists of a measurement update step, employing a Hidden Markov Model (HMM) and Viterbi search, and then a separate prior step, which modifies the updated curve based on the relative strengths of the measurement uncertainty and the nonstationary prior. By separating the measurement and prior steps, the algorithm is less likely to misconverge; furthermore, the use of a Viterbi optimizer allows the method to converge far more rapidly than energy-based iterative solvers. The results clearly demonstrate that the proposed approach is robust to noise, can capture regions of very high curvature, and exhibits limited dependence on contour initialization or parameter settings. Compared to five other published methods and across many image sets, the DAC is found to be faster with better or comparable segmentation accuracy.


Energy expenditure in rock/pop drumming.
Despite the vigorous nature of rock/pop drumming, there are no precise data on the energy expenditure of this activity. The aim of this study was to quantify the energy cost of rock/pop drumming. Fourteen male drummers (mean±SD; age 27±8 yrs.) completed an incremental drumming test to establish the relationship between energy expenditure and heart rate for this activity and a ramped cycle ergometer test to exhaustion as a criterion measure for peak values (oxygen uptake and heart rate). During live concert performance heart rate was continuously measured and used to estimate energy expenditure (from the energy expenditure vs. heart rate data derived from the drumming test). During concert performance, estimated energy expenditure (mean±SD) was 623±168 kcal.h⁻¹ (8.1±2.2 METs) during performances of 38.6±15.6 min, and drummers achieved a peak heart rate of 186±16 b.min⁻¹. During the drumming test participants attained 78.7±8.3% of the cycle ergometer peak oxygen uptake. Rock/pop drumming represents a relatively high-intensity form of physical activity and as such involves significant energy expenditure. Rock/pop drumming should be considered as a viable alternative to more traditional forms of physical activity.


Living well to the end: A phenomenological analysis of life in extra care housing.
To understand older adults' experiences of moving into extra care housing which offers enrichment activities alongside social and healthcare support. A longitudinal study was conducted which adopted a phenomenological approach to data generation and analysis. Semi-structured interviews were conducted in the first 18 months of living in extra care housing. Interpretative phenomenological analysis was used because its commitment to idiography enabled an in-depth analysis of the subjective lived experience of moving into extra care housing. Themes generated inductively were examined against an existential-phenomenological theory of well-being. Learning to live in an extra care community showed negotiating new relationships was not straightforward; maintaining friendships outside the community became more difficult as capacity declined. In springboard for opportunity/confinement, living in extra care provided new opportunities for social engagement and a restored sense of self. Over time horizons began to shrink as incapacities grew. Seeking care illustrated reticence to seek care, due to embarrassment and a sense of duty to one's partner. Becoming aged presented an ontological challenge. Nevertheless, some showed a readiness for death, a sense of homecoming. An authentic later life was possible but residents required emotional and social support to live through the transition and challenges of becoming aged. Enhancement activities boosted residents' quality of life but the range of activities could be extended to cater better for quieter, smaller scale events within the community; volunteer activity facilitators could be used here. Peer mentoring may help build new relationships and opportunities for interactive stimulation. Acknowledging the importance of feeling-empathic imagination-in caregiving may help staff and residents relate better to each other, thus helping individuals to become ontologically secure and live well to the end.


Release of arachidonate from membrane phospholipids in cultured neonatal rat myocardial cells during adenosine triphosphate depletion. Correlation with the progression of cell injury.
The present study utilized a cultured myocardial cell model to evaluate the relationship between the release of arachidonate from membrane phospholipids, and the progression of cell injury during ATP depletion. High-energy phosphate depletion was induced by incubating cultured neonatal rat myocardial cells with various combinations of metabolic inhibitors (deoxyglucose, oligomycin, cyanide, and iodoacetate). Phospholipid degradation was assessed by the release of radiolabeled arachidonate from membrane phospholipids. In this model, the current study demonstrates that (a) cultured myocardial cells display a time-dependent progression of cell injury during ATP depletion; (b) the morphologic patterns of mild and severe cell injury in the cultured cells are similar to those found in intact ischemic canine myocardial models; (c) cultured myocardial cells release arachidonate from membrane phospholipids during ATP depletion; and (d) using two separate combinations of metabolic inhibitors, there is a correlation between the release of arachidonate, the development of severe cellular and sarcolemmal damage, the release of creatine kinase into the extracellular medium, and the loss of the ability of the myocardial cells to regenerate ATP when the metabolic inhibitors are removed. Thus, the present results suggest that during ATP depletion, in cultured neonatal rat myocardial cells, the release of arachidonate from myocardial membrane phospholipids is linked to the development of membrane defects and the associated loss of cell viability.


Diabetes reporting as a cause of death: results from the Translating Research Into Action for Diabetes (TRIAD) study.
To determine the frequency of reporting of diabetes on death certificates of decedents with known diabetes, define factors associated with reporting of diabetes, and describe trends in reporting over time. Data were obtained from 11,927 participants with diabetes who were enrolled in the Translating Research Into Action for Diabetes study, a multicenter prospective observational study of diabetes care in managed care. Data on decedents (n = 540) were obtained from the National Death Index. The primary dependent variable was the presence of ICD-10 codes for diabetes on the death certificate. Covariates included age at death, sex, race/ethnicity, education, income, duration of diabetes, type of diabetes, diabetes treatment, smoking status, and number of comorbidities. Diabetes was recorded on 39% of death certificates and as the underlying cause of death for 10% of decedents with diabetes. Diabetes was significantly less likely to be reported on the death certificates of decedents with diabetes dying of cancer. Predictors of recording diabetes anywhere on the death certificate included longer duration of diabetes and insulin treatment. Longer duration of diabetes, insulin treatment, and fewer comorbidities were associated with recording of diabetes as the underlying cause of death. Diabetes is much more likely to be reported on the death certificates of diabetic individuals who die of cardiovascular causes. Reporting of diabetes on death certificates has been stable over time. Death certificates underestimate the prevalence of diabetes among decedents and present a biased picture of the causes of death among people with diabetes.


Black women receive less mammography even with similar use of primary care.
Black women with breast cancer have a decreased 5-year survival rate in comparison with white women, possibly because of less frequent use of mammography. Having a regular provider or source of health care is the most important determinant of mammography use. To examine whether the difference in mammography use between elderly black women and elderly white women is related to the number of visits made to a primary care physician. Retrospective review of 1990 Health Care Financing Administration billing files (Medicare part B) from 10 states. Outpatient mammography services in 10 states. Black women and white women, 65 years of age and older, residing in one of the 10 states. Any mammogram. Predictors included race, number of visits to a primary care physician (0, 1, 2, or 3 or more), median income of ZIP code of residence (a surrogate measure of income), and state. The following are findings from Georgia; similar results were found in each state studied. The mean age of the 335,680 women was 75 years; 20% were black. Sixty-eight percent of the black women and 69% of the white women made at least one visit to a primary care physician. Overall, 14% of the women had had mammography; black women had mammography less often than white women (9% compared with 15%). At each primary care visit level (1, 2, or 3 or more visits), black women had mammography less often than white women (1 visit, 7% compared with 15%; 2 visits, 12% compared with 21%; and 3 or more visits, 12% compared with 20%). Even among women who had made at least one visit to a primary care physician, a deficit for blacks occurred in each income quintile (lowest quintile, 13% compared with 20%; low, 10% compared with 18%; middle, 12% compared with 18%; high, 10% compared with 19%; and highest, 12% compared with 22%) and in each state (in Georgia, for example, the percentages were 14% compared with 21%). An age-, income-, and state-adjusted logistic model predicting mammography use for 2.9 million white women in all 10 states shows the powerful effect of primary care use on mammography (odds ratios for 1, 2, and 3 or more visits were, respectively, 2.73 [95% CI, 2.70 to 2.77]; 3.98 [CI, 3.93 to 4.03]; and 4.62 [CI, 4.58 to 4.67]). The same model fit to 250 000 black women shows a lesser effect (analogous odds ratios were 1.77 [CI, 1.67 to 1.87]; 2.49 [CI, 2.36 to 2.63]; and 3.15 [CI, 3.04 to 3.25]). Among older women, mammography is used less often for blacks than for whites. More frequent use of mammography is associated with more visits to a primary care physician in both groups, but the deficit for black women persists at each income level and in each state, even after primary care use is considered. Primary care visits are less likely to "boost" mammography use for black women than for white women.


Familiality of cardiovascular mortality in end-stage renal disease patients.
A very high rate of cardiovascular (CV) death is well recognized in individuals with end-stage renal disease (ESRD). Besides many other factors, this excess risk may also be related to familiality. We tested this hypothesis by estimating the risk of CV death among both ESRD patients and their relatives. In this case-control study, we used the Utah Population Database (UPDB), which includes genealogy records, state-wide death certificates as well as other data sets. These have been linked to the University of Utah Health Sciences Enterprise Data Warehouse which provides multiple diagnosis data sources. Patients with ESRD either on dialysis or who received a kidney transplant were identified in the clinical databases at the University of Utah Dialysis Program and Kidney Transplant Program or from Utah death certificates. CV deaths were identified by the reporting on the death certificates. The relative risks for CV death, adjusted for several potential confounders in the ESRD patients (n = 516) and in their first-degree (n = 2,418) and second-degree (n = 7,720) relatives were estimated in relation to the general population. Using information from death certificates, ESRD patients were found to have disproportionately increased risk for CV mortality (relative risk or RR = 2.4; 95% CI 2.11-2.72), compared to the general population. First-degree relatives of ESRD patients were also found to have an increased CV mortality risk (RR = 1.10; 95% CI 1.01-1.20). When the specific categories of CVD were analyzed, the first-degree relatives also had higher risks for death from acute myocardial infarction (RR = 1.20; 95% CI 1.03-1.40) or heart failure (RR = 1.32; 95% CI 1.12-1.56). An increased risk for CV mortality was, however, not observed in second-degree relatives of ESRD patients, except for the subcategory of hypertensive heart disease (RR = 1.24, 95% CI 1.01-1.49). In conclusion, this study suggests that, in addition to many putative risk factors, the increased risk of CV death in ESRD patients may have a familial contribution.


Isotopic composition of rare gases in lunar samples.
Data from total melt and step-by-step heating experiments on the Apollo 11 lunar samples suggest a close affinity between lunar and meteoritic rare gases. Trapped neon-20/neon-22 ratios range from 11.5 to approximately 15, resembling those for the gas-rich meteorites. Trapped krypton and xenon in the lunar fines and in the carbonaceous chondrites are similar except for an interesting underabundance of the heavy isotopes in both lunar gases which suggests that the fission component found in carbonaceous chondrites is depleted in lunar material. Spallation gases are in most cases quite close to meteoritic spallation gases in isotopic composition.


RNAi-mediated silencing of Myc transcription inhibits stem-like cell maintenance and tumorigenicity in prostate cancer.
Several studies link disease progression, recurrence, and treatment failures to the cancer stem-like cell (CSC) subpopulation within the heterogeneous tumor cell population. Myc is a transcription factor having a central function in stem cell biology and in human cancers. Hence, Myc represents an attractive target to develop CSC-specific therapies. Recent findings suggest that Myc transcription can be silenced using an RNA interference (RNAi)-based strategy that targets noncoding promoter-associated RNA (paRNA) overlapping the transcription start site. In this study, we investigated the effects of silencing Myc transcription on prostate CSC in cell culture and xenograft models of human prostate cancer. Treatment with an effective promoter-targeting siRNA reduced the fraction of CSCs, leading to reduced self-renewal, tumor-initiating, and metastatic capability. Combined analysis of stem-like cells and senescence markers indicated that Myc silencing triggered a phenotypic shift and senescence in the CSC subpopulation. Notably, systemic delivery of the promoter-targeting siRNA in the xenograft model produced a striking suppression in the development of prostate tumors. Our results support a pivotal role for Myc in CSC maintenance and show that Myc targeting via RNAi-based transcriptional silencing can trigger CSC senescence and loss of their tumor-initiating capability. More generally, our findings demonstrate the efficacy of RNAi-based transcriptional strategies and the potential to target regulatory noncoding paRNAs for therapeutic applications.


Seroprevalence of toxoplasmosis, leptospirosis and brucellosis in sugarcane field-workers in Trinidad and Tobago.
Sugarcane field-workers, like rice field-workers, livestock farmers and abattoir workers are known to be occupationally exposed to zoonotic agents. The study determined the seroprevalence of immunoglobulins to Toxoplasma gondii (IgM), Leptospira spp (IgM) and Brucella abortus (IgG) in sugarcane field-workers across weighing stations in the island of Trinidad. In addition, the association of risk factors to infections by the three zoonoses was investigated. Blood samples were collected from consenting apparently healthy sugarcane field-workers across the island of Trinidad. Current/acute infection in individuals was determined in the sera of individuals using the enzyme immunoassay (EIA) for T gondii IgM antibodies, enzyme-linked immunosorbent assay (ELISA) for Leptospira spp IgM immunoglobulins and both buffered plate agglutination test (BPAT) and competitive ELISA for B abortus IgG antibodies. The seroprevalence of IgM immunoglobulins to T gondii was 15.7% (64 of 407) and to Leptospira spp was 0.7% (5 of 704) and the difference was statistically significant (p 0 < 0.05; chi2). All 704 samples tested for B abortus IgG immunoglobulins were negative. All risk factors (age, gender race and type of work done) were not statistically significantly (p > 0.05; chi2) associated with infections by T gondii and Leptospira spp. It was concluded that sugarcane field-workers in Trinidad were at high risk of acute toxoplasmosis and, to a lesser extent, to leptospirosis. The fact that the four risk factors studied were not significantly associated with T gondii and Leptospira spp infections suggests that they may not be important in the epidemiology of both diseases in the population studied.


Posttraumatic stress disorder in the World Mental Health Surveys.
Traumatic events are common globally; however, comprehensive population-based cross-national data on the epidemiology of posttraumatic stress disorder (PTSD), the paradigmatic trauma-related mental disorder, are lacking. Data were analyzed from 26 population surveys in the World Health Organization World Mental Health Surveys. A total of 71 083 respondents ages 18+ participated. The Composite International Diagnostic Interview assessed exposure to traumatic events as well as 30-day, 12-month, and lifetime PTSD. Respondents were also assessed for treatment in the 12 months preceding the survey. Age of onset distributions were examined by country income level. Associations of PTSD were examined with country income, world region, and respondent demographics. The cross-national lifetime prevalence of PTSD was 3.9% in the total sample and 5.6% among the trauma exposed. Half of respondents with PTSD reported persistent symptoms. Treatment seeking in high-income countries (53.5%) was roughly double that in low-lower middle income (22.8%) and upper-middle income (28.7%) countries. Social disadvantage, including younger age, female sex, being unmarried, being less educated, having lower household income, and being unemployed, was associated with increased risk of lifetime PTSD among the trauma exposed. PTSD is prevalent cross-nationally, with half of all global cases being persistent. Only half of those with severe PTSD report receiving any treatment and only a minority receive specialty mental health care. Striking disparities in PTSD treatment exist by country income level. Increasing access to effective treatment, especially in low- and middle-income countries, remains critical for reducing the population burden of PTSD.


Quercetin Attenuates Cell Survival, Inflammation, and Angiogenesis via Modulation of AKT Signaling in Murine T-Cell Lymphoma.
AKT signaling is important to maintaining normal physiology. Hyperactivation of AKT signaling is frequent in cancer, which maintains a high oxidative state in a tumor microenvironment that is needed for tumor adaptation. Therefore, antioxidants are proposed to exhibit anticancer properties by interfering with the tumor microenvironment. Quercetin is an ubiquitous bioactive antioxidant rich in vegetables and beverages. The present study aimed to analyze cancer preventive property of quercetin in ascite cells of Dalton's lymphoma-bearing mice. Protein level was determined by Western blotting. Nitric oxide (NO) level was estimated spectrophotometrically using Griess reagent. Results show downregulation in phosphorylation of AKT and PDK1 by quercetin, which was consistent with decreased phosphorylation of downstream survival factors such as BAD, GSK-3β, mTOR, and IkBα. Further, quercetin attenuated the levels of angiogenic factor VEGF-A and inflammatory enzymes COX-2 and iNOS as well as NO levels, whereas it increased the levels of phosphatase PTEN. Overall results suggest that quercetin modulates AKT signaling leading to attenuation of cell survival, inflammation, and angiogenesis in lymphoma-bearing mice.


Dietary intake of soy genistein is associated with lung function in patients with asthma.
To determine if micronutrient intake is associated with asthma severity, we administered the Block food frequency questionnaire to participants in a randomized clinical trial of the safety of influenza vaccine for asthmatics. The nutrition substudy included 1033 participants, aged 12-75. Intake of antioxidant vitamins, soy isoflavones, total fruits and vegetables, fats, and fiber was compared with asthma severity at baseline [forced expiratory volume in 1 second (FEV1), peak expiratory flow rate (PEF), asthma symptoms] and the rate of asthma exacerbations during the 2 weeks following influenza vaccination. The only nutrient that had a consistent association with asthma severity was genistein, a soy isoflavone. None of the nutrients evaluated were related to asthma exacerbation rate when adjusted for known confounders. The FEV1 in genistein consumers of at least 250 microg/1000 Kcal/day was 82.1% predicted, 79.9% predicted for those who consumed between 1 and 249 microg/1000 kcal, and 76.2% predicted in genistein nonconsumers (p=0.006); the PEF was 82.7% predicted, 80.8% predicted, and 78.3% predicted, respectively (p=0.009). There were no differences in the Asthma Symptom Utility Index (ASUI). We could not account for these results based on differences in demographics, body mass index, or consumption of other nutrients. Thus, increasing consumption of genistein is associated with better lung function in patients with asthma. Further studies are needed to determine whether dietary supplementation with genistein can reduce asthma severity.


Spatial genetic structure in a crustacean herbivore highlights the need for local considerations in Baltic Sea biodiversity management.
Incorporating species' eco-evolutionary responses to human-caused disturbances remains a challenge in marine management efforts. A prerequisite is knowledge of geographic structure and scale of genetic diversity and connectivity-the so-called seascape genetic patterns. The Baltic Sea is an excellent model system for studies linking seascape genetics with effects of anthropogenic stress. However, seascape genetic patterns in this area are only described for a few species and are completely unknown for invertebrate herbivores, which constitute a critical part of the ecosystem. This information is crucial for sustainable management, particularly under future scenarios of rapid environmental change. Here, we investigate the population genetic structure among 31 locations throughout the Baltic Sea, of which 45% were located in marine protected areas, in one of the most important herbivores of this region, the isopod crustacean Idotea balthica, using an array of 33,774 genome-wide SNP markers derived from 2b-RAD sequencing. In addition, we generate a biophysical connectivity matrix for I. balthica from a combination of oceanographic current models and estimated life history traits. We find population structure on scales of hundreds of kilometers across the Baltic Sea, where genomic patterns in most cases closely match biophysical connectivity, indicating passive transport with oceanographic currents as an important mean of dispersal in this species. We also find a reduced genetic diversity in terms of heterozygosity along the main salinity gradient of the Baltic Sea, suggesting periods of low population size. Our results provide crucial information for the management of a key ecosystem species under expected changes in temperature and salinity following global climate change in a marine coastal area.


Population-based study of presbyopia in Shahroud, Iran.
There is limited information regarding the prevalence of presbyopia in different parts of the world. The add power and the prevalence of presbyopia by age and gender in general population of Shahroud, north of Iran, were studied. Population-based cross-sectional study. Using random cluster sampling, 6311 people from the 40- to 64-year-old population of Shahroud were invited. Of the invited population, 5190 individuals (82.2%) participated in the study. Presbyopia was defined as the correction of near vision to logMAR 1 (N8 point) with at least 1 D of add power. Near visual acuity of participants was evaluated with a logMAR chart at a distance of 40 cm. Mean add power in the age groups of 40-44, 45-49, 50-54, 55-59 and 60-64 years was 0.65, 1.30, 1.70, 1.87 and 2.08 D, respectively. For each 5-year increase in age, a 0.35 D increase in add power was noted. The prevalence of presbyopia was 58.15% (95% confidence interval: 56.46-59.84). Presbyopia was more prevalent in women (P < 0.001) and increased with ageing more in women than in men (P < 0.001). Furthermore, in the 60-64-year-old age group, 11% of men and 23% of women were not presbyopic. Compared with other reports, the add power in different age groups was 0.5 D less, and presbyopia was less prevalent. More than 50% of the over 45-year-old individuals were presbyopic and 17% of the over 60 individuals were free of this condition.


Crystal structures of ligand complexes of P450eryF exhibiting homotropic cooperativity.
Several mammalian cytochrome P450 (P450) isoforms demonstrate homotropic cooperativity with a number of substrates, including steroids and polycyclic aromatic hydrocarbons. To identify structural factors contributing to steroid and polycyclic aromatic hydrocarbon binding to P450 enzymes and to determine the location of the allosteric site, we investigated interactions of the macrolide hydroxylase P450eryF from Saccharopolyspora erythraea with androstenedione and 9-aminophenanthrene. Spectroscopic binding assays indicate that P450eryF binds androstenedione with an affinity of 365 microM and a Hill coefficient of 1.31 +/- 0.6 and coordinates with 9-aminophenanthrene with an affinity of 91 microM and a Hill coefficient of 1.38 +/- 0.2. Crystals of complexes of androstenedione and 9-aminophenanthrene with P450eryF were grown and diffracted to 2.1 A and 2.35 A, respectively. Electron density maps indicate that for both complexes two ligand molecules are simultaneously present in the active site. The P450eryF/androstenedione model was refined to an r = 18.9%, and the two androstenedione molecules have similar conformations. The proximal androstenedione is positioned such that the alpha-face of carbon-6 is closest to the heme iron, and the second steroid molecule is positioned 5.5 A distal in the active site. The P450eryF/9-aminophenanthrene model was refined to an r = 19.7% with the proximal 9-aminophenanthrene coordinated with the heme iron through the 9-amino group and the second ligand positioned approximately 6 A distal in the active site. These results establish that homotropic cooperativity in ligand binding can result from binding of two substrate molecules within the active site pocket without major conformational changes in the protein.


A Kunitz trypsin inhibitor gene family from trembling aspen (Populus tremuloides Michx.): cloning, functional expression, and induction by wounding and herbivory.
Three Kunitz trypsin inhibitor genes were isolated from trembling aspen (Populus tremuloides) by PCR and cDNA screening. Based on sequence similarity, they were grouped into two classes. Southern blots showed complex banding patterns and a high level of restriction fragment polymorphism between different aspen genotypes, suggesting that these trypsin inhibitors are members of a large, rapidly evolving gene family. One of the trypsin inhibitor genes, PtTI2. was over-expressed in Escherichia coli and its product shown to inhibit bovine trypsin in vitro. Both classes of PtTI genes are induced by wounding and herbivory, permitting rapid adaptive responses to herbivore pressure. The response appears to be mediated by an octadecanoid-based signaling pathway, as methyl jasmonate treatments induced the trypsin inhibitors. Wound-induced accumulation of trypsin inhibitor protein was also observed by western blot analysis. The pattern of expression, the apparent rapid evolution of TI genes, and the in vitro trypsin inhibitory activity are consistent with a role in herbivore defense. This work establishes the presence of a functional protein-based inducible defense system in trembling aspen.


Gene Expansion and Positive Selection as Bacterial Adaptations to Oligotrophic Conditions.
We examined the genomic adaptations of prevalent bacterial taxa in a highly nutrient- and ion-depleted freshwater environment located in the secondary cooling water system of a nuclear research reactor. Using genome-centric metagenomics, we found that none of the prevalent bacterial taxa were related to typical freshwater bacterial lineages. We also did not identify strong signatures of genome streamlining, which has been shown to be one of the ecoevolutionary forces shaping the genome characteristics of bacterial taxa in nutrient-depleted environments. Instead, focusing on the dominant taxon, a novel Ramlibacter sp. which we propose to name Ramlibacter aquaticus, we detected extensive positive selection on genes involved in phosphorus and carbon scavenging pathways. These genes were involved in the high-affinity phosphate uptake and storage into polyphosphate granules, metabolism of nitrogen-rich organic matter, and carbon/energy storage into polyhydroxyalkanoate. In parallel, comparative genomics revealed a high number of paralogs and an accessory genome significantly enriched in environmental sensing pathways (i.e., chemotaxis and motility), suggesting extensive gene expansions in R. aquaticus The type strain of R. aquaticus (LMG 30558T) displayed optimal growth kinetics and productivity at low nutrient concentrations, as well as substantial cell size plasticity. Our findings with R. aquaticus LMG 30558T demonstrate that positive selection and gene expansions may represent successful adaptive strategies to oligotrophic environments that preserve high growth rates and cellular productivity.IMPORTANCE By combining a genome-centric metagenomic approach with a culture-based approach, we investigated the genomic adaptations of prevalent populations in an engineered oligotrophic freshwater system. We found evidence for widespread positive selection on genes involved in phosphorus and carbon scavenging pathways and for gene expansions in motility and environmental sensing to be important genomic adaptations of the abundant taxon in this system. In addition, microscopic and flow cytometric analysis of the first freshwater representative of this population (Ramlibacter aquaticus LMG 30558T) demonstrated phenotypic plasticity, possibly due to the metabolic versatility granted by its larger genome, to be a strategy to cope with nutrient limitation. Our study clearly demonstrates the need for the use of a broad set of genomic tools combined with culture-based physiological characterization assays to investigate and validate genomic adaptations.


Accuracy of haplotype reconstruction from haplotype-tagging single-nucleotide polymorphisms.
Many investigators are now using haplotype-tagging single-nucleotide polymorphism (htSNPs) as a way of screening regions of the genome for association with disease. A common approach is to genotype htSNPs in a study population and to use this information to draw inferences about each individual's haplotypic makeup, including SNPs that were not directly genotyped. To test the validity of this approach, we simulated the exercise of typing htSNPs in a large sample of individuals and compared the true and inferred haplotypes. The accuracy of haplotype inference varied, depending on the method of selecting htSNPs, the linkage-disequilibrium structure of the region, and the amount of missing data. At the stage of selection of htSNPs, haplotype-block-based methods required a larger number of htSNPs than did unstructured methods but gave lower levels of error in haplotype inference, particularly when there was a significant amount of missing data. We present a Web-based utility that allows investigators to compare the likely error rates of different sets of htSNPs and to arrive at an economical set of htSNPs that provides acceptable levels of accuracy in haplotype inference.


Comparative evaluation of aqueous and plasma concentration of topical moxifloxacin alone and with flurbiprofen in patients of cataract surgery.
To determine the aqueous and plasma concentrations of moxifloxacin administered topically alone and with flurbiprofen in patients undergoing cataract surgery. A total of 50 subjects scheduled for routine cataract surgery were randomly allocated to two groups (n = 25 each). Group-1 patients were treated with topical moxifloxacin alone: One drop 6 times/day for 3 days before surgery and one drop 4 times on the day of surgery: Group-2 patients were treated with topical moxifloxacin as in Group-1 and with topical flurbiprofen: One drop 4 times/day for 3 days before and on the day of surgery. The interval between two drugs was 30 min for last 3 days and 15 min on the day of surgery. Last dose was administered 1 h before aqueous humor and blood sampling for both the groups. The antibiotic concentration in aqueous humor and plasma were determined by using high performance liquid chromatography. The mean concentration of moxifloxacin in aqueous humor was 1.71 ± 0.82 mg/ml in Group-1 and 2.39 ± 1.34 mg/ml in Group-2. Concentrations of moxifloxacin in aqueous humor were significantly higher in Group-2 than that of Group-1. Flurbiprofen may increase the concentration of moxifloxacin in aqueous humor.


Behavioral and electrophysiological investigation of speech perception deficits in silence, noise and envelope conditions in developmental dyslexia.
The present study investigated whether children with developmental dyslexia showed specific deficits in the perception of three phonetic features (voicing, place, and manner of articulation) in optimal (silence) and degraded listening conditions (envelope-coded speech versus noise), using both standard behavioral and electrophysiological measures. Performance of children with dyslexia was compared to that of younger typically developing children who were matched in terms of reading age. Results showed no significant group differences in response accuracy except for the reception of place-of-articulation in noise. However, dyslexic children responded more slowly than typically developing children across all conditions with larger deficits in noise than in envelope than in silence. At the neural level, dyslexic children exhibited reduced N1 components in silence and the reduction of N1 amplitude was more pronounced for voicing than for the other phonetic features. In the envelope condition, the N1 was localized over the right hemisphere and it was larger for typically developing readers than for dyslexic children. Finally, in stationary noise, the N1 to place of articulation was clearly delayed in children with dyslexia, which suggests a temporal de-organization in the most adverse listening conditions. The results clearly show abnormal neural processing to speech sounds in all conditions. They are discussed in the context of recent theories on perceptual noise exclusion, neural noise and temporal sampling.


Using ecological indicators and a decision support system for integrated ecological assessment at two national park units in the mid-Atlantic region, USA.
We implemented an integrated ecological assessment using a GIS-based decision support system model for Upper Delaware Scenic and Recreational River (UPDE) and Delaware Water Gap National Recreation Area (DEWA)-national park units with the mid-Atlantic region of the United States. Our assessment examined a variety of aquatic and terrestrial indicators of ecosystem components that reflect the parks' conservation purpose and reference condition. Our assessment compared these indicators to ecological thresholds to determine the condition of park watersheds. Selected indicators included chemical and physical measures of water quality, biologic indicators of water quality, and landscape condition measures. For the chemical and physical measures of water quality, we used a water quality index and each of its nine components to assess the condition of water quality in each watershed. For biologic measures of water quality, we used the Ephemeroptera, Plecoptera, Trichoptera aquatic macroinvertebrate index and, secondarily, the Hilsenhoff aquatic macroinvertebrate index. Finally, for the landscape condition measures of our model, we used percent forest and percent impervious surface. Based on our overall assessment, UPDE and DEWA watersheds had an ecological assessment score of 0.433 on a -1 to 1 fuzzy logic scale. This score indicates that, in general, the natural resource condition within watersheds at these parks is healthy or ecologically unimpaired; however, we had only partial data for many of our indicators. Our model is iterative and new data may be incorporated as they become available. These natural parks are located within a rapidly urbanizing landscape-we recommend that natural resource managers remain vigilant to surrounding land uses that may adversely affect natural resources within the parks.


Association of C-reactive protein and metabolic risk with cognitive effects of lurasidone in patients with schizophrenia.
Accumulating evidence has implicated insulin resistance and inflammation in the pathophysiology of cognitive impairments associated with neuropsychiatric disorders. This post-hoc analysis based on a placebo-controlled trial investigated the effect of inflammation (indexed by CRP) and metabolic risk factors on cognitive performance in patients with schizophrenia treated with lurasidone. Acutely exacerbated patients with schizophrenia were randomized to lurasidone (80 or 160 mg/day), quetiapine XR 600 mg/day, or placebo. A wide range CRP test and a cognitive assessment using the CogState computerized battery were performed at baseline and week 6 study endpoint. Associations between log-transformed CRP, high density lipoprotein (HDL), homeostatic model assessment of insulin resistance (HOMA-IR) and treatment response were evaluated. CRP combined with HDL, triglyceride-to-HDL (TG/HDL) ratio, or HOMA-IR at study baseline were significant moderators of the improvement in cognitive performance associated with lurasidone 160 mg/day (vs. placebo) treatment (p < .05). Greater placebo-corrected treatment effect size on the CogState composite score was observed for patients in the lurasidone 160 mg/day treatment group who had either low CRP and high HDL (d = 0.43), or low CRP and low HOMA-IR (d = 0.46). Interactive relationships between CRP, HDL, TG/HDL, HOMA-IR and the antipsychotic efficacy of lurasidone or quetiapine XR were not significant. There were no significant associations between antipsychotic treatment and changes in CRP level at study endpoint. Findings of this post-hoc analysis based on a placebo-controlled trial in patients with schizophrenia suggest that baseline CRP level combined with measures of metabolic risk significantly moderated the improvement in cognitive performance associated with lurasidone 160 mg/day (vs. placebo) treatment. Our findings underscore the importance of maintaining a low metabolic risk profile in patients with schizophrenia.


Polyphenolic extract from maple syrup potentiates antibiotic susceptibility and reduces biofilm formation of pathogenic bacteria.
Phenolic compounds are believed to be promising candidates as complementary therapeutics. Maple syrup, prepared by concentrating the sap from the North American maple tree, is a rich source of natural and process-derived phenolic compounds. In this work, we report the antimicrobial activity of a phenolic-rich maple syrup extract (PRMSE). PRMSE exhibited antimicrobial activity as well as strong synergistic interaction with selected antibiotics against Gram-negative clinical strains of Escherichia coli, Proteus mirabilis, and Pseudomonas aeruginosa. Among the phenolic constituents of PRMSE, catechol exhibited strong synergy with antibiotics as well as with other phenolic components of PRMSE against bacterial growth. At sublethal concentrations, PRMSE and catechol efficiently reduced biofilm formation and increased the susceptibility of bacterial biofilms to antibiotics. In an effort to elucidate the mechanism for the observed synergy with antibiotics, PRMSE was found to increase outer membrane permeability of all bacterial strains and effectively inhibit efflux pump activity. Furthermore, transcriptome analysis revealed that PRMSE significantly repressed multiple-drug resistance genes as well as genes associated with motility, adhesion, biofilm formation, and virulence. Overall, this study provides a proof of concept and starting point for investigating the molecular mechanism of the reported increase in bacterial antibiotic susceptibility in the presence of PRMSE.


Differences in Intertidal Microbial Assemblages on Urban Structures and Natural Rocky Reef.
Global seascapes are increasingly modified to support high levels of human activity in the coastal zone. Modifications include the addition of defense structures and boating infrastructure, such as seawalls and marinas that replace natural habitats. Artificial structures support different macrofaunal communities to those found on natural rocky shores; however, little is known about differences in microbial community structure or function in urban seascapes. Understanding how artificial constructions in marine environments influence microbial communities is important as these assemblages contribute to many basic ecological processes. In this study, the bacterial communities of intertidal biofilms were compared between artificial structures (seawalls) and natural habitats (rocky shores) within Sydney Harbour. Plots were cleared on each type of habitat at eight locations. After 3 weeks the newly formed biofilm was sampled and the 16S rRNA gene sequenced using the Illumina Miseq platform. To account for differences in orientation and substrate material between seawalls and rocky shores that might have influenced our survey, we also deployed recruitment blocks next to the habitats at all locations for 3 weeks and then sampled and sequenced their microbial communities. Intertidal bacterial community structure sampled from plots differed between seawalls and rocky shores, but when substrate material, age and orientation were kept constant (with recruitment blocks) then bacterial communities were similar in composition and structure among habitats. This suggests that changes in bacterial communities on seawalls are not related to environmental differences between locations, but may be related to other intrinsic factors that differ between the habitats such as orientation, complexity, or predation. This is one of the first comparisons of intertidal microbial communities on natural and artificial surfaces and illustrates substantial ecological differences with potential consequences for biofilm function and the recruitment of macrofauna.


Promoting quality use of medicines in South-East Asia: reports from country situational analyses.
Irrational use of medicines is widespread in the South-East Asia Region (SEAR), where policy implementation to encourage quality use of medicines (QUM) is often low. The aim was to determine whether public-sector QUM is better in SEAR countries implementing essential medicines (EM) policies than in those not implementing them. Data on six QUM indicators and 25 EM policies were extracted from situational analysis reports of 20 country (2-week) visits made during 2010-2015. The average difference (as percent) for the QUM indicators between countries implementing versus not implementing specific policies was calculated. Policies associated with better (> 1%) QUM were included in regression of a composite QUM score versus total number of policies implemented. Twenty-two policies were associated with better (> 1%) QUM. Twelve policies were associated with 3.6-9.5% significantly better use (p < 0.05), namely: standard treatment guidelines; formulary; a government unit to promote QUM; continuing health worker education on prescribing by government; limiting over-the-counter (OTC) availability of systemic antibiotics; disallowing public-sector prescriber revenue from medicines sales; not charging fees at the point of care; monitoring advertisements of OTC medicines; public education on QUM; and a good drug supply system. There was significant correlation between the number of policies implemented out of 22 and the composite QUM score (r = 0.71, r2 = 0.50, p < 0.05). Country situational analyses allowed rapid data collection that showed EM policies are associated with better QUM. SEAR countries should implement all such policies.


Do Vitamin D Level and Dietary Calcium Intake Modify the Association Between Loop Diuretics and Bone Health?
Loop diuretics (LD) may affect bone health by inhibiting renal calcium reuptake. However, whether vitamin D status and dietary calcium intake modify the association between LD and bone outcome is unclear. Therefore, this study aimed to evaluate whether vitamin D level or calcium intake modify the association between LD and various indices of bone health including bone mineral density (BMD) and Trabecular Bone Score (TBS). From The Rotterdam Study, a prospective population-based cohort study, we used data from 6990 participants aged > 45 year with a DXA scan (2002-2008), 6908 participants with femoral neck (FN)-BMD, 6677 participants with lumbar spine (LS)-BMD and 6476 participants with LS-TBS measurements. Use of LD was available from pharmacy dispensing records. Vitamin D (25(OH)D) level was measured in serum, and dietary calcium intake was measured with a validated food frequency questionnaire. Almost eight percent of the participants used LD. The association between LD (past-users compared to never-users) and LS-TBS was significantly different by 25(OH)D concentrations (P for interaction = 0.04). A significantly lower LS-TBS among LD past-users was observed for 25(OH)D ≥ 50 nmol/l compared to ≤ 20 and 20-50 nmol/l (β = - 0.036, 95% CI - 0.060; - 0.013 vs. β = - 0.012, 95% CI - 0.036; 0.013 and β = - 0.031, 95% CI - 0.096; 0.034, respectively). However, no other significant effect modification by 25(OH)D and dietary calcium intake was found in the associations between LD use and bone health outcomes (P-interaction > 0.13). This study suggests that the association between LD use and indices of bone health is not consistently modified by vitamin D or dietary calcium intake.


Endocannabinoid 2-arachidonylglycerol protects primary cultured neurons against LPS-induced impairments in rat caudate nucleus.
Inflammation plays a pivotal role in the pathogenesis of many diseases in the central nervous system. Caudate nucleus (CN), the largest nucleus in the brain, is also implicated in many neurological disorders. 2-Arachidonoylglycerol (2-AG), the most abundant endogenous cannabinoid and the true natural ligand for CB1 receptors, has been shown to exhibit neuroprotective effects through its anti-inflammatory action from proinflammatory stimuli in hippocampus. However, it is still not clear whether 2-AG is also able to protect CN neurons from proinflammation stimuli. In the present study, we discovered that 2-AG significantly protects CN neurons in culture against lipopolysaccharide (LPS)-induced inflammatory response. 2-AG is capable of suppressing elevation of LPS-induced cyclooxygenase-2 expression associated with ERK/p38MAPK/NF-κB signaling pathway in CB1 receptor-dependant manner in primary cultured CN neurons. Moreover, 2-AG inhibits LPS-induced increase in voltage-gated sodium channel currents and hyperpolarizing shift of activation curves through CB1 receptor-dependant pathway. Our study suggests the therapeutic potential of 2-AG for the treatment of some inflammation-induced neurological disorders and pain.


[Ureteral duplications and ureteroceles - surgical treatment].
To study clinical and radiological data and surgical treatment for symptomatic ureteral duplications in childhood, especially the results for superior polar heminephrectomies. Prospective observational study concerning 15 pediatric patients surgically treated following a protocol with a minimum follow-up of 6 months. 93% of the patients presented urinary infection and/or fetal hydronephrosis during their first year of life. These were the usual reasons for evaluation. Superior polar heminephrectomy was indicated for 80% of the patients, all of whom presented clinical and radiological improvement after the surgery. There were no significant complications. All children with severe vesicoureteral reflux to the duplicated superior pole presented symptomatic reflux to the stump after the surgery and were submitted to stumpectomy. None of the patients without preoperative reflux needed any other surgical procedure. Superior polar heminephrectomy is safe and efficient in order to treat ureteral duplications in childhood. If the patient does not present vesicoureteral reflux this will probably be the only surgery needed. Most patients with reflux to the resected superior pole will need stumpectomy subsequently.


Environmental enrichment reduces neuronal intranuclear inclusion load but has no effect on messenger RNA expression in a mouse model of Huntington disease.
Huntington disease (HD) is a fatal neurodegenerative disease with no effective treatment. In the R6/1 mouse model of HD, environmental enrichment delays the neurologic phenotype onset and prevents cerebral volume loss by unknown molecular mechanisms. We examined the effects of environmental enrichment on well-characterized neuropathological parameters in a mouse model of HD. We found a trend toward preservation of downregulated neurotransmitter receptors in striatum of environmentally enriched mice and assessed possible enrichment-related modifications in gene expression using microarrays. We observed similar gene expression changes in R6/1 and R6/2 transgenic mice but found no specific changes in enrichment-related microarray expression profiles in either transgenic or wild-type mice. Furthermore, specific corrections in transprotein-induced transcriptional dysregulation in R6/1 mice were not detected by microarray profiling. However, gene-specific analyses suggested that long-term environmental enrichment may beneficially modulate gene expression dysregulation. Finally, environmental enrichment significantly decreased neuronal intranuclear inclusion load, despite unaffected transgene expression levels. Thus, the therapeutic effects of environmental enrichment likely contribute to decreasing aggregated polyglutamine protein levels without exerting strong effects on gene expression.


Proof of concept: endogenous antiangiogenic factors predict the occurrence of symptomatic vasospasm post subarachnoid hemorrhage.
The pathogenesis of vasospasm (VS) post aneurysmal subarachnoid hemorrhage (SAH) is multifactorial and not completely understood. The authors hypothesize that circulating antiangiogenic factors play an important role in brain injury post SAH and that elevated levels predict the occurrence of symptomatic vasospasm. In this study the authors measured the serum and cerebrospinal fluid (CSF) levels of soluble endoglin (sEng) and soluble fms-like tyrosine kinase 1 (sFlt1) in controls and SAH patients within 48 h of the bleed. Patients were prospectively followed and subcategorized into those with (sVS) and without symptomatic vasospasm (no-sVS). Compared to healthy controls, SAH patients had higher CSF levels of sEng (0.037 vs. 0.251 ng/ml; P = 0.02) and sFlt1 (0.068 vs. 0.679 ng/ml; P = 0.001). In the subgroup analysis, sVS patients had higher CSF levels of sEng and sFlt1 than no-sVS patients (sEng: 0.380 vs. 0.159 ng/ml, P = 0.02; sFlt1: 1.277 vs. 0.343 ng/ml, P = 0.01). The serum levels of sEng and sFlt1 were not statistically different among the different groups. Based on these results the authors conclude that elevated CSF levels of sFlt1 and sEng herald the occurrence of symptomatic VS post SAH.


Retention of a posterior resin-bonded fixed partial denture with a modified design: an in vitro study.
The aim of this study was to test in vitro the resistance of a modified resin-bonded fixed partial denture (RBFPD) to detachment using a laboratory setup simulating load fatigue of mastication forces. The effect of varying the cement type was also investigated. Extracted teeth were used to prepare specimens each consisting of a premolar and a molar with a space equivalent to a molar in between. Five test groups were prepared (n = 7). Specimens in group 1 were prepared to receive conventional RBFPDs with proximal grooves, occlusal rests, and lingual wings. Specimens in groups 2 and 3 were prepared to receive modified RBFPDs with retentive-slot restorations. Specimens in group 4 were prepared to receive RBFPDs with retentive-slot restorations only, whereas specimens in group 5 were prepared similarly to the ones in groups 2 and 3 but with inlay preparations instead of the retentive slots. Castings were made and their fit surfaces microetched. In groups 1, 2, 4, and 5 castings were cemented with Cement-It, whereas castings of group 3 were cemented with Panavia 21. Slot cavities of groups 2, 3, and 4 were restored with a resin composite. Specimens were subjected to compressive load cycling for 230,000 cycles at 4 Hz under water. Castings were then separated from the abutments under tensile loading. Mean separation forces were: group 1 = 361 N, group 2 = 525 N, group 3 = 562 N, group 4 = 449 N, and group 5 = 417 N. Groups 2 and 3 had significantly higher mean separation forces than groups 1 and 5. Separation of castings in groups 2 and 3 was associated with a higher frequency of cohesive fracture of the abutments than in group 1. Adhesive failure was uncommon among specimens of groups 2, 3, and 4. The modified RBFPDs of groups 2 and 3 had better potential for retention. Increased resistance to dislodgment of the modified RBFPDs was not directly related to the surface area of the castings, nor was it related to the type of resin cement, but rather to mechanical interlocking of the castings with the retentive-slot resin composite restorations.


Paravertebral and Retroperitoneal Vascular Tumour Presenting with Kasabach-Merritt Phenomenon in Childhood, Diagnosed with Magnetic Resonance Imaging.
Kasabach-Merritt phenomenon (KMP) is characterized by vascular tumour and consumptive coagulopathy with life-threatening thrombocytopenia, prolonged prothrombin time and partial thromboplastin time, hypofibrinogenemia, and the presence of high fibrin split products. We report a case of 3-year-old boy with local aggressive vascular lesions associated with KMP. Magnetic resonance imaging revealed an extensive lesion at paravertebral and retroperitoneal regions that was infiltrating vertebrae. Although we did not get any response to steroid or propranolol treatment, partial response was observed radiologically with interferon-alpha treatment. Unfortunately, the patient died because of the uncontrolled consumptive coagulopathy that led to intracranial hemorrhage which was caused by huge knee hematoma after minor trauma.


Shape-controlled syntheses of metal oxide nanoparticles by the introduction of rare-earth metals.
Here, we report the size- and shape-controlled synthesis of metal oxide nanoparticles through the introduction of rare-earth metals. The addition of gadolinium oleate in the synthesis of iron oxide nanoparticles induced sphere-to-cube shape changes of nanoparticles and generated iron oxide nanocubes coated with gadolinium. Based on experimental investigations and density functional theory (DFT) calculations, we attribute the shape change to the facet-selective binding of undecomposed gadolinium oleates. While many previous studies on the shape-controlled syntheses of nanoparticles rely on the stabilization of specific crystal facets by anionic surfactants or their decomposition products, this study shows that the interaction between growing transition metal oxide nanoparticles and rare-earth metal complexes can be used as a robust new mechanism for shape-controlled syntheses. Indeed, we demonstrated that this approach was applicable to other transition metal oxide nanoparticles (i.e., manganese oxide and manganese ferrite) and rare earth metals (i.e., gadolinium, europium, and cerium). This study also demonstrates that the nature of metal-ligand bonding can play an important role in the shape control of nanoparticles.


Stretchable, Transparent Electrodes as Wearable Heaters Using Nanotrough Networks of Metallic Glasses with Superior Mechanical Properties and Thermal Stability.
Mechanical robustness, electrical and chemical reliabilities of devices against large deformations such as bending and stretching have become the key metrics for rapidly emerging wearable electronics. Metallic glasses (MGs) have high elastic limit, electrical conductivity, and corrosion resistance, which can be promising for applications in wearable electronics. However, their applications in wearable electronics or transparent electrodes have not been extensively explored so far. Here, we demonstrate stretchable and transparent electrodes using CuZr MGs in the form of nanotrough networks. MG nanotroughs are prepared by electrospinning and cosputtering process, and they can be transferred to various desired substrates, including stretchable elastomeric substrates. The resulting MG nanotrough network is first utilized as a stretchable transparent electrode, presenting outstanding optoelectronic (sheet resistance of 3.8 Ω/sq at transmittance of 90%) and mechanical robustness (resistance change less than 30% up to a tensile strain of 70%) as well as excellent chemical stability against hot and humid environments (negligible degradation in performance for 240 h in 85% relative humidity and 85 °C). A stretchable and transparent heater based on the MG nanotrough network is also demonstrated with a wide operating temperature range (up to 180 °C) and excellent stretchability (up to 70% in the strain). The excellent mechanical robustness of these stretchable transparent electrode and heater is ascribed to the structural configuration (i.e., a nanotrough network) and inherent high elastic limit of MGs, as supported by experimental results and numerical analysis. We demonstrate their real-time operations on human skin as a wearable, transparent thermotherapy patch controlled wirelessly using a smartphone as well as a transparent defroster for an automobile side-view mirror, suggesting a promising strategy toward next-generation wearable electronics or automobile applications.


A systematic review and meta-analysis of diabetes and risk of physical disability and functional impairment - protocol.
Diabetes and increased age are known risk factors for physical disability. With the increasing prevalence of diabetes within our aging population, the future burden of disability is expected to increase. To date, there has not been a pooled estimate of the risk for disability associated with diabetes or its precursor states, impaired glucose tolerance and impaired fasting glucose. We aim to conduct a systematic review and meta-analysis of the association between prediabetes and diabetes with disability, and quantify the risk of association. We will search for relevant studies in Medline via Pubmed, Embase, Cochrane library and Cumulative Index to Nursing and Allied Health Literature (CINAHL), as well as scan reference lists from relevant reviews and publications included in our review. We will review all publications that include studies on human adults (18 years and older) where information is included on diabetes status and at least one measure of disability (Activities of Daily Living (ADL), Instrumental ADL (IADL) or functional/mobility limitation), and where a risk association is available for the relationship between diabetes and/or prediabetes with disability, with reference to those without diabetes.We will further conduct a meta-analysis to pool estimates of the risk of disability associated with prediabetes and diabetes. Sensitivity analysis will be conducted to assess for publication bias and study quality.Findings from this systematic review and meta-analysis will be widely disseminated through discussions with stake-holders, publication in a peer-reviewed journal and conference presentation.


The use of routine preoperative magnetic resonance imaging in identifying intraspinal anomalies in patients with idiopathic scoliosis: a 10-year review.
This study sought to quantify the frequency of previously unidentified spinal cord anomalies identified by routine preoperative magnetic resonance imaging (MRI), in patients planned for surgical scoliosis correction. Our study group comprised 206 patients with idiopathic scoliosis who underwent deformity correction from 1998 to 2008. Clinical records of all the patients were retrospectively reviewed to ascertain the proportion having a neural abnormality on preoperative MRI scan. Twenty of 206 patients (9.7 %) were diagnosed with an unexpected intraspinal anomaly on routine preoperative MRI. In all cases, a neurosurgical opinion was sought prior to further intervention. Of the 20 patients, 11 underwent a neurosurgical procedure (de-tethering of cord, decompression of Chiari, decompression of syrinx). There was no statistically significant difference between the group of patients who had intrinsic spinal cord anomalies on preoperative MRI and those did not have a cord abnormality with regard to age at presentation, gender, side of dominant curve and degree of curve (p < 0.05). The high frequency of spinal cord abnormalities unidentified by preoperative neurological examination, and the frequent need for subsequent neurosurgical intervention, suggests that MRI assessment prior to deformity correction is important in the management of idiopathic scoliosis.


Effectiveness of the Veteran X peer-led mental health recovery program: A quasi-experimental study.
The inclusion of peer-delivered services in organizations providing behavioral health care has significantly increased in recent years, and substantial resources are being directed toward implementing recovery-oriented mental health services using peer-provided programs. Previous research found that participants in such programs have improved recovery outcomes. While there are demonstrated positive associations between recovery outcomes and peer-provided services, there is limited research on the effectiveness of specific peer-provided interventions. Veteran X is a peer-led program developed in the Department of Veterans Affairs in which participants serve as a recovery team for a fictitious Veteran who faces numerous social and mental health issues. This study compared the effectiveness of the Veteran X program with treatment as usual on measures of recovery wellbeing, symptoms and functioning, and risk and protective factors for substance use disorders. Participants were recruited (N = 80) over a period of ten months, and had self-selected into treatment as usual (TAU, N = 37), or treatment as usual plus Veteran X (N = 43). No baseline differences were found on the pretest measures. Both groups improved on all measures after 60 days of participation, however Veteran X participants improved significantly more than TAU participants on the measures of recovery wellbeing and symptoms and functioning. The results of this study appear to support the positive contribution of the Veteran X program in improving recovery wellbeing and symptoms and functioning among participating veterans. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Effects of continuity of care on emergency department utilization in children with asthma.
To examine whether continuity of ambulatory asthma care can lower asthma-specific emergency department (ED) utilization by children with asthma in Taiwan. Retrospective cohort study based on claims data. We used the Taiwan National Health Insurance Dataset, 2006 to 2009. The study population was new asthma patients aged 0 to 17 years in 2007, and every case was observed for 2 years. We used the Continuity of Care Index (COCI) to calculate the continuity of ambulatory asthma care in the first year, and estimated the asthma-specific ED utilization in the second year. Two-part hurdle regression was used for statistical analysis. The 29,277 patients in our study had an average COCI of 0.68 (± 0.31), and 42.3% of patients had an index of 1. More than 1 in 20 patients-1641 (5.61%)-had at least 1 asthma ED visit, and the mean number of visits per user was 1.46 (± 0.99). After controlling for covariates, the groups with medium and low continuity of ambulatory asthma care had 21% (odds ratio [OR], 1.21; 95% CI, 1.06-1.39) and 38% (OR, 1.38; 95% CI, 1.21-1.58) higher asthma-related ED utilization, respectively, than the group with high COCI. However, among users, the number of ED visits was not statistically correlated to the continuity of ambulatory asthma care. High continuity of ambulatory asthma care can decrease asthma-specific ED utilization risk in children with newly diagnosed asthma in Taiwan. We suggest that providers and the government reinforce the use of follow-up care and education for high-risk groups to improve the continuity of ambulatory asthma care.


Tuberculosis incidence in HIV/AIDS patients in Israel, 1983-2010.
People living with HIV/AIDS (PLWHA) who develop tuberculosis disease are at greater mortality-risk. This study aimed to assess tuberculosis disease incidence among all PLWHA in Israel and identify populations at high-risk for developing tuberculosis. Retrospective cohort-study based on the National HIV and Tuberculosis Registries, which were cross-matched and followed for the last 28-years. PLWHA who developed tuberculosis were compared to those who did not by the Cox-proportional analysis to generate hazard-ratios, and survival-analysis was performed by Log-Rank test. Of all the 6579 PLWHA reported between 1983 and 2010, corresponding to 55737 person-years, 384 (5.8%) developed tuberculosis. Of those, 14 were Israeli-born and 370 were non-Israeli born. The overall tuberculosis incidence-density was 6.9 cases/1000 person-years (95% CI 1.8-12.0). The cumulative tuberculosis-incidence among PLWHA in 2010 was 586 times higher than in HIV-negative individuals (3400 and 5.8 cases per 100000 population, respectively). Higher hazard-ratios to developing tuberculosis were found in migrant citizens PLWHA who were males, non-Israeli born, those who were diagnosed with HIV/AIDS after 1997, those who originated in high-tuberculosis prevalence country and those who acquired HIV by heterosexual or drug-injection transmission. PLWHA who developed tuberculosis had higher odds of dying than other PLWHA (36.5% and 16.6%, respectively, p<0.001, odds ratio = 2.8, 95% confidence-interval 2.3-3.6). In survival-analysis, time to develop tuberculosis was shorter among males than females, in PLWHA who were reported with HIV after 1997, in heterosexual who originated in high-tuberculosis countries, followed by injecting drug-users, heterosexual from low-tuberculosis burden countries and men who have sex with men. Tuberculosis-incidence is higher among non-Israeli born PLWHA, with decreasing trends from 1991. Despite the moderate TB-rate disease among PLWHA, it remains an important cause for severe morbidity and mortality. Tuberculosis in PLWHA reflects mainly the tuberculosis-burden in the originating country and possibly also the mode of HIV-transmission.


The role of experience during childhood in shaping the other-race effect.
It is well known that adults' face recognition is characterized by an 'other-race effect' (ORE; see Meissner & Brigham, 2001), but few studies have investigated this ORE during the development of the face processing system. Here we examined the role of experience with other-race faces during childhood by testing a group of 6- to 14-year-old Asian children adopted between 2 and 26 months in Caucasian families living in Western Europe, as well as a group of age-matched Caucasian children. The latter group showed a strong ORE in favour of own-race faces that was stable from 6 to 14 years of age. The adopted participants did not show a significant reversal of the ORE, unlike a recently reported study (Sangrigoli et al., 2005), but rather comparable results with Asian and Caucasian faces. Their pattern of performance was neither influenced by their age of adoption, nor by the amount of experience they accumulated during childhood with other-race faces. These results indicate that the balance of performance with Asian and Caucasian faces can be modulated, but not completely reversed, in children whose exposure to own- and other-race faces changes drastically during the period of maturation of the face recognition system, depending on the length of exposure to the new face race. Overall, experience appears to be crucial during childhood to shape the face recognition system towards the most predominant morphologies of faces present in the environment.


Severe experimental folate deficiency in a human subject - a longitudinal study of biochemical and haematological responses as megaloblastic anaemia develops.
The currently accepted theory, that the human liver store of folate is limited to about four months, is based on the findings of Victor Herbert and others of the era before folate fortification of food. A recent model, developed by Lin et al., predicts far greater liver folate storage capacity than reported by Herbert. The conflict between Herbert's and Lin's models needs to be resolved experimentally, however current research is restricted because ethical considerations prevent such risky experimentation on patients or healthy human volunteers. The objective was to provide a detailed record of the biochemical and haematological responses to the development of severe experimental folate deficiency in an initially replete human subject. This 58 year old male severely depleted himself of folate, using a folate-deficient diet, until overt megaloblastic anaemia developed. The biochemical and haematological responses were monitored by routine blood tests. Daily intake of dietary supplements prevented deficiencies of other relevant nutrients. The rate of change of all analytes was significantly slower, and the delay before any change for several analytes was significantly longer, than reported for previous experiments. The time before reporting of abnormal biochemical and haematological results was therefore very significantly longer than reported by Herbert, but was consistent with the recent model of Lin et al. Serum folate and red-cell folate became abnormally low after 219 and 413 days respectively. Macrocytic anaemia was produced after 469 days, and megaloblastic anaemia was confirmed by bone marrow biopsy on day 575. Folate starvation ceased on day 586, and recovery was complete on day 772. The currently accepted four month time scale for development of megaloblastic anaemia from folate deficiency, based on the early work of Herbert and others, is not consistent with the results from this study. The > 300 day liver folate storage time, predicted by the model of Lin et al., is supported by this experiment. Self-experimentation has produced a detailed record of the biochemical and haematological responses to severe experimental folate deficiency, whereas using patients or healthy volunteers as subjects would be unethical.


A Systematic Review of the Safety and Effect of Neurofeedback on Fatigue and Cognition.
Many cancer survivors continue to experience ongoing symptoms, such as fatigue and cognitive impairment, which are poorly managed and have few effective, evidence-based treatment options. Neurofeedback is a noninvasive, drug-free form of brain training that may alleviate long-term symptoms reported by cancer patients. The purpose of this systematic review of the literature was to describe the effectiveness and safety of neurofeedback for managing fatigue and cognitive impairment. A systematic review of the literature was conducted using Joanna Briggs Institute (JBI) methodology. A comprehensive search of 5 databases was conducted: Medline, CINAHL, AMED, PsycInfo, and Embase. Randomized and nonrandomized controlled trials, controlled before and after studies, cohort, case control studies, and descriptive studies were included in this review. Twenty-seven relevant studies were included in the critical appraisals. The quality of most studies was poor to moderate based on the JBI critical appraisal checklists. Seventeen studies were deemed of sufficient quality to be included in the review: 10 experimental studies and 7 descriptive studies. Of these, only 2 were rated as high-quality studies and the remaining were rated as moderate quality. All 17 included studies reported positive results for at least one fatigue or cognitive outcome in a variety of populations, including 1 study with breast cancer survivors. Neurofeedback interventions were well tolerated with only 3 studies reporting any side effects. Despite issues with methodological quality, the overall positive findings and few reported side effects suggest neurofeedback could be helpful in alleviating fatigue and cognitive impairment. Currently, there is insufficient evidence that neurofeedback is an effective therapy for management of these symptoms in cancer survivors, however, these promising results support the need for further research with this patient population. More information about which neurofeedback technologies, approaches, and protocols could be successfully used with cancer survivors and with minimal side effects is needed. This research will have significance to nurses and physicians in oncology and primary care settings who provide follow-up care and counseling to cancer survivors experiencing debilitating symptoms in order to provide information and education related to evidence-based therapy options.


Measurement of cylindrical particles with phase Doppler anemometry.
Light scattering from cylindrical particles has been described with geometric optics. The feasibility of determining the particle diameter with a planar phase Doppler anemometer has been examined by simulations and experiments. In particular, the influence of particle orientation on measurability and measurement accuracy has been investigated. Some recommendations for realizing a practical-measurement instrument have been presented.


Newly identified pair of proteasomal subunits regulated reciprocally by interferon gamma.
Interferon (IFN) gamma induces replacements of the proteasomal subunits X and Y by LMP7 and LMP2, respectively, resulting in an alteration of the proteolytic specificity. We found a third pair of proteasome subunits expressed reciprocally in response to IFN-gamma. Molecular cloning of a cDNA encoding one subunit designated as Z, downregulated by IFN-gamma, showed that it is a novel proteasomal subunit with high homology to MECL1, which is markedly induced by IFN-gamma. Thus, IFN-gamma induces subunit replacements of not only X and Y by LMP7 and LMP2, respectively, but also of Z by MECL1, producing proteasomes responsible for immunological processing of endogenous antigens. When processed from their precursors, three pairs of the 10 homologous, but distinct, beta-type subunits of eukaryotic proteasomes, that is, X/LMP7, Y/LMP2, and Z/MECL1, have an NH2-terminal threonine residue, assumed to be part of a catalytic center. These findings suggest that the altered molecular organization of the proteasome induced by IFN-gamma may be responsible for acquisition of its functional change.


Id1 Deficiency Protects against Tumor Formation in Apc(Min/+) Mice but Not in a Mouse Model of Colitis-Associated Colon Cancer.
Different mechanisms contribute to the development of sporadic, hereditary and colitis-associated colorectal cancer. Inhibitor of DNA binding/differentiation (Id) proteins act as dominant-negative antagonists of basic helix-loop-helix transcription factors. Id1 is a promising target for cancer therapy, but little is known about its role in the development of colon cancer. We used immunohistochemistry to demonstrate that Id1 is overexpressed in human colorectal adenomas and carcinomas, whether sporadic or syndromic. Furthermore, elevated Id1 levels were found in dysplasia and colon cancer arising in patients with inflammatory bowel disease. Because levels of PGE2 are also elevated in both colitis and colorectal neoplasia, we determined whether PGE2 could induce Id1. PGE2 via EP4 stimulated protein kinase A activity resulting in enhanced pCREB-mediated Id1 transcription in human colonocytes. To determine the role of Id1 in carcinogenesis, two mouse models were used. Consistent with the findings in humans, Id1 was overexpressed in tumors arising in both Apc(Min) (/+) mice, a model of familial adenomatous polyposis, and in experimental colitis-associated colorectal neoplasia. Id1 deficiency led to significant decrease in the number of intestinal tumors in Apc(Min) (/+) mice and prolonged survival. In contrast, Id1 deficiency did not affect the number or size of tumors in the model of colitis-associated colorectal neoplasia, likely due to exacerbation of colitis associated with Id1 loss. Collectively, these results suggest that Id1 plays a role in gastrointestinal carcinogenesis. Our findings also highlight the need for different strategies to reduce the risk of colitis-associated colorectal cancer compared with sporadic or hereditary colorectal cancer.


An α-1,6-and α-1,3-linked glucan produced by Leuconostoc citreum ABK-1 alternansucrase with nanoparticle and film-forming properties.
Alternansucrase catalyses the sequential transfer of glucose residues from sucrose onto another sucrose molecule to form a long chain polymer, known as "alternan". The alternansucrase-encoding gene from Leuconostoc citreum ABK-1 (Lcalt) was successfully cloned and expressed in Escherichia coli. Lcalt encoded LcALT of 2,057 amino acid residues; the enzyme possessed an optimum temperature and pH of 40 °C and 5.0, respectively, and its' activity was stimulated up to 2.4-fold by the presence of Mn2+. Kinetic studies of LcALT showed a high transglycosylation activity, with Km 32.2 ± 3.2 mM and kcat 290 ± 12 s-1. Alternan generated by LcALT (Lc-alternan) harbours partially alternating α-1,6 and α- 1,3 glycosidic linkages confirmed by NMR spectroscopy, methylation analysis, and partial hydrolysis of Lc-alternan products. In contrast to previously reported alternans, Lc-alternan can undergo self-assembly, forming nanoparticles with an average size of 90 nm in solution. At concentrations above 15% (w/v), Lc-alternan nanoparticles disassemble and form a high viscosity solution, while this polymer forms a transparent film once dried.


Biomolecular recognition on well-characterized beads packed in microfluidic channels.
We describe a new approach for the analysis of biomolecular recognition in microfluidic channels. The method involves real-time detection of soluble molecules binding to receptor-bearing microspheres, sequestered in affinity column format inside a microfluidic channel. Identification and quantitation of analytes occurs via direct fluorescence measurements or fluorescence resonance energy transfer (FRET). We establish a model system that detects the FLAG epitope. The assay can potentially detect subfemtomole quantities of antibody with a high signal-to-noise ratio and a large dynamic range spanning nearly 4 orders of magnitude in analyte concentration in microliter-to-submicroliter volumes of analyte fluid. Kinetic and equilibrium constants for the reaction of this receptor-ligand pair are obtained through modeling of kinetic responses of the affinity microcolumn and are consistent with those obtained by flow cytometry. Because of the correlation between kinetic and equilibrium data obtained for the microcolumns, quantitative analysis can be done prior to the steady-state end point of the recognition reaction. This method has the promise of combining the utility of affinity chromatography with the advantage of direct, quantitative, and real-time analysis and the cost-effectiveness of microanalytical devices. The approach has the potential to be generalized to a host of bioaffinity assay methods including analysis of protein complexes and molecular assembly and microsystem-based multianalyte determinations.


African swine fever virus infection disrupts centrosome assembly and function.
African swine fever virus (ASFV) is a large, enveloped DNA virus that assembles in perinuclear sites located close to the centrosome. It is reported here that the microtubule network becomes disorganized soon after the onset of viral DNA replication and formation of assembly sites. ASFV infection resulted in loss of gamma-tubulin and pericentrin at the centrosome; this was due to protein relocalization, but not degradation. ASFV infection also inhibited the ability of the centrosome to nucleate microtubules. The reorganization of microtubules seen in ASFV-infected cells may therefore be mediated by gamma-tubulin and pericentrin redistribution, and consequent disruption of centrosome assembly and function.


Pharmacokinetics of amodiaquine and desethylamodiaquine in pregnant and postpartum women with Plasmodium vivax malaria.
In order to study the pharmacokinetic properties of amodiaquine and desethylamodiaquine during pregnancy, 24 pregnant women in the second and third trimesters of pregnancy and with Plasmodium vivax malaria were treated with amodiaquine (10 mg/kg of body weight/day) for 3 days. The same women were studied again at 3 months postpartum. Plasma was analyzed for amodiaquine and desethylamodiaquine by use of a liquid chromatography-tandem mass spectrometry method. Individual concentration-time data were evaluated using noncompartmental analysis. There were no clinically relevant differences in the pharmacokinetics of amodiaquine and desethylamodiaquine between pregnant (n = 24) and postpartum (n = 18) women. The results suggest that the current amodiaquine dosing regimen is adequate for the treatment of P. vivax infections during pregnancy.


Metabonomic and microbiological analysis of the dynamic effect of vancomycin-induced gut microbiota modification in the mouse.
The effects of the antibiotic vancomycin (2 x 100 mg/kg/day) on the gut microbiota of female mice (outbred NMRI strain) were studied, in order to assess the relative contribution of the gut microbiome to host metabolism. The host's metabolic phenotype was characterized using (1)H NMR spectroscopy of urine and fecal extract samples. Time-course changes in the gut microbiotal community after administration of vancomycin were monitored using 16S rRNA gene PCR and denaturing gradient gel electrophoresis (PCR-DGGE) analysis and showed a strong effect on several species, mostly within the Firmicutes. Vancomycin treatment was associated with fecal excretion of uracil, amino acids and short chain fatty acids (SCFAs), highlighting the contribution of the gut microbiota to the production and metabolism of these dietary compounds. Clear differences in gut microbial communities between control and antibiotic-treated mice were observed in the current study. Reduced urinary excretion of gut microbial co-metabolites phenylacetylglycine and hippurate was also observed. Regression of urinary hippurate and phenylacetylglycine concentrations against the fecal metabolite profile showed a strong association between these urinary metabolites and a wide range of fecal metabolites, including amino acids and SCFAs. Fecal choline was inversely correlated with urinary hippurate. Metabolic profiling, coupled with the metagenomic study of this antibiotic model, illustrates the close inter-relationship between the host and microbial "metabotypes", and will provide a basis for further experiments probing the understanding of the microbial-mammalian metabolic axis.


The transcription factors Tbx18 and Wt1 control the epicardial epithelial-mesenchymal transition through bi-directional regulation of Slug in murine primary epicardial cells.
During cardiac development, a subpopulation of epicardial cells migrates into the heart as part of the epicardial epithelial-mesenchymal transition (EMT) and differentiates into smooth muscle cells and fibroblasts. However, the roles of transcription factors in the epicardial EMT are poorly understood. Here, we show that two transcription factors expressed in the developing epicardium, T-box18 (Tbx18) and Wilms' tumor 1 homolog (Wt1), bi-directionally control the epicardial EMT through their effects on Slug expression in murine primary epicardial cells. Knockdown of Wt1 induced the epicardial EMT, which was accompanied by an increase in the migration and expression of N-cadherin and a decrease in the expression of ZO-1 as an epithelial marker. By contrast, knockdown of Tbx18 inhibited the mesenchymal transition induced by TGFβ1 treatment and Wt1 knockdown. The expression of Slug but not Snail decreased as a result of Tbx18 knockdown, but Slug expression increased following knockdown of Wt1. Knockdown of Slug also attenuated the epicardial EMT induced by TGFβ1 treatment and Wt1 knockdown. Furthermore, in normal murine mammary gland-C7 (NMuMG-C7) cells, Tbx18 acted to increase Slug expression, while Wt1 acted to decrease Slug expression. Chromatin immunoprecipitation and promoter assay revealed that Tbx18 and Wt1 directly bound to the Slug promoter region and regulated Slug expression. These results provide new insights into the regulatory mechanisms that control the epicardial EMT.


Exploring cancer support needs for older African-American men with prostate cancer.
The purpose of this study was to explore cancer support and financial issues related to cancer care experienced by African-American men with prostate cancer and to understand whom they relied on for resource issues during diagnosis and treatment. This is a descriptive qualitative study of 23 rural and urban 65 years old and older African-American prostate cancer survivors. Five focus groups were conducted containing African-American prostate cancer survivors who were recruited from community-based centers (e.g., churches, barbershops, diners, and primary care clinics) in central Virginia and Maryland. Focus group discussions were audiotaped, transcribed, and coded. Data were organized and managed using a qualitative analysis software program. Emerging themes uncovered specific problems for older rural African-American men with cancer, and focus group data were examined for potential solutions to these problems. Two common themes emerged: (1) family and physician support are important, and (2) insurance is a necessity for appropriate health care. A difference between rural and urban African-American prostate cancer survivors emerged as well: difference in spirituality during diagnosis and treatment. Rural and urban African-American prostate cancer survivors' major support resource was their wives. Health insurance played a critical role as a support source by decreasing anxiety and financial hardships. Understanding rural and urban African-American prostate cancer survivors' support needs and challenges in relation to cancer diagnosis and treatment will allow nurses and other health-care providers to tailor cancer health plans more effectively for this population.


Accounting for uncertainty in ecological analysis: the strengths and limitations of hierarchical statistical modeling.
Analyses of ecological data should account for the uncertainty in the process(es) that generated the data. However, accounting for these uncertainties is a difficult task, since ecology is known for its complexity. Measurement and/or process errors are often the only sources of uncertainty modeled when addressing complex ecological problems, yet analyses should also account for uncertainty in sampling design, in model specification, in parameters governing the specified model, and in initial and boundary conditions. Only then can we be confident in the scientific inferences and forecasts made from an analysis. Probability and statistics provide a framework that accounts for multiple sources of uncertainty. Given the complexities of ecological studies, the hierarchical statistical model is an invaluable tool. This approach is not new in ecology, and there are many examples (both Bayesian and non-Bayesian) in the literature illustrating the benefits of this approach. In this article, we provide a baseline for concepts, notation, and methods, from which discussion on hierarchical statistical modeling in ecology can proceed. We have also planted some seeds for discussion and tried to show where the practical difficulties lie. Our thesis is that hierarchical statistical modeling is a powerful way of approaching ecological analysis in the presence of inevitable but quantifiable uncertainties, even if practical issues sometimes require pragmatic compromises.


Domestic violence: a hidden problem for general practice.
Domestic violence is a common problem that may affect more than a quarter of women. It is a complex area in which to undertake research. Studies often focus on selected populations and exhibit a diversity of design, making comparison difficult. This review focuses on physical violence by men against women partners or ex-partners, and exemplifies important issues for general practitioners. Domestic violence frequently goes undetected. This may be the result of doctor's fears of exploring an area perceived as time-consuming, where knowledge is lacking and where they feel powerless to 'fix' the situation. Women may not reveal that they are experiencing violence, sometimes because doctors are unsympathetic or hostile. Nevertheless, women wish to be asked routinely about physical abuse and want to receive immediate advice and information about their options if necessary. Women experience a range of health and social problems in association with domestic violence, including depression, anxiety, substance abuse and pregnancy complications. However, none of these features is specific enough to be useful as an indicator of violence. Therefore, doctors should routinely ask all women direct questions about abuse. This recommendation can be incorporated into guidelines, which should be implemented widely in the UK, to improve the care of women experiencing domestic violence. In parallel with this, the educational needs of general practitioners should be addressed. Further research is needed to establish the prevalence of domestic violence in women presenting to general practice and to investigate how the problem is currently being addressed. If progress is to be made in tackling domestic violence, action within primary care is just one part of this: a fundamental change in the attitudes of men towards women is required.


Ability of the Met kinase inhibitor crizotinib and new generation EGFR inhibitors to overcome resistance to EGFR inhibitors.
Although EGF receptor tyrosine kinase inhibitors (EGFR-TKI) have shown dramatic effects against EGFR mutant lung cancer, patients ultimately develop resistance by multiple mechanisms. We therefore assessed the ability of combined treatment with the Met inhibitor crizotinib and new generation EGFR-TKIs to overcome resistance to first-generation EGFR-TKIs. Lung cancer cell lines made resistant to EGFR-TKIs by the gatekeeper EGFR-T790M mutation, Met amplification, and HGF overexpression and mice with tumors induced by these cells were treated with crizotinib and a new generation EGFR-TKI. The new generation EGFR-TKI inhibited the growth of lung cancer cells containing the gatekeeper EGFR-T790M mutation, but did not inhibit the growth of cells with Met amplification or HGF overexpression. In contrast, combined therapy with crizotinib plus afatinib or WZ4002 was effective against all three types of cells, inhibiting EGFR and Met phosphorylation and their downstream molecules. Crizotinib combined with afatinib or WZ4002 potently inhibited the growth of mouse tumors induced by these lung cancer cell lines. However, the combination of high dose crizotinib and afatinib, but not WZ4002, triggered severe adverse events. Our results suggest that the dual blockade of mutant EGFR and Met by crizotinib and a new generation EGFR-TKI may be promising for overcoming resistance to reversible EGFR-TKIs but careful assessment is warranted clinically.


Partnership and consent in MS treatment choice.
It is not only good medical practice to ensure patients are fully involved in their treatment decisions, but it also improves subsequent compliance, and may even be cost effective. However, choosing treatments in MS is becoming increasingly complex, which means that ensuring patients understand all the issues is a challenge and time consuming. Preference sensitive care (which applies to current MS immunomodulatory treatments) is particularly vulnerable to the individual doctor's opinion and there is an onus on the physician to ensure the decision made incorporates the patient's individual values. National patient decision making tools are an appropriate solution to this dilemma and may, in the future, be a legal requirement in consent to treatment.


Design principles of hair-like structures as biological machines.
Hair-like structures are prevalent throughout biology and frequently act to sense or alter interactions with an organism's environment. The overall shape of a hair is simple: a long, filamentous object that protrudes from the surface of an organism. This basic design, however, can confer a wide range of functions, owing largely to the flexibility and large surface area that it usually possesses. From this simple structural basis, small changes in geometry, such as diameter, curvature and inter-hair spacing, can have considerable effects on mechanical properties, allowing functions such as mechanosensing, attachment, movement and protection. Here, we explore how passive features of hair-like structures, both individually and within arrays, enable diverse functions across biology. Understanding the relationships between form and function can provide biologists with an appreciation for the constraints and possibilities on hair-like structures. Additionally, such structures have already been used in biomimetic engineering with applications in sensing, water capture and adhesion. By examining hairs as a functional mechanical unit, geometry and arrangement can be rationally designed to generate new engineering devices and ideas.


Genome architecture and the role of transcription.
During development or in response to environmental stimuli, eukaryotic genes change both their expression and position in 3D nuclear space. Then, is a gene transcribed because of its position, or is position determined by transcription? Are genes stochastically or deterministically engaged in transcription cycles? Recent results confirm that RNA polymerases and their transcription factors play central roles in genome organization, and that stochastic events can give rise to apparently deterministic expression. As is so often the case in biology, structure both determines function and is influenced by it.