Productivity growth in outpatient child and adolescent mental health services: the impact of case-mix adjustment.
The performance of health service providers may be monitored by measuring productivity. However, the policy value of such measures may depend crucially on the accuracy of input and output measures. In particular, an important question is how to adjust adequately for case-mix in the production of health care. In this study, we assess productivity growth in Norwegian outpatient child and adolescent mental health service units (CAMHS) over a period characterized by governmental utilization of simple productivity indices, a substantial increase in capacity and a concurrent change in case-mix. We analyze the sensitivity of the productivity growth estimates using different specifications of output to adjust for case-mix differences. Case-mix adjustment is achieved by distributing patients into eight groups depending on reason for referral, age and gender, as well as correcting for the number of consultations. We utilize the nonparametric Data Envelopment Analysis (DEA) method to implicitly calculate weights that maximize each unit's efficiency. Malmquist indices of technical productivity growth are estimated and bootstrap procedures are performed to calculate confidence intervals and to test alternative specifications of outputs. The dataset consist of an unbalanced panel of 48-60 CAMHS in the period 1998-2006. The mean productivity growth estimate from a simple unadjusted patient model (one single output) is 35%; adjusting for case-mix (eight outputs) reduces the growth estimate to 15%. Adding consultations increases the estimate to 28%. The latter reflects an increase in number of consultations per patient. We find that the governmental productivity indices strongly tend to overestimate productivity growth. Case-mix adjustment is of major importance and governmental utilization of performance indicators necessitates careful considerations of output specifications.


Widespread contribution of Gdf7 lineage to cerebellar cell types and implications for hedgehog-driven medulloblastoma formation.
The roof plate is a specialized embryonic midline tissue of the central nervous system that functions as a signaling center regulating dorsal neural patterning. In the developing hindbrain, roof plate cells express Gdf7 and previous genetic fate mapping studies showed that these cells contribute mostly to non-neural choroid plexus epithelium. We demonstrate here that constitutive activation of the Sonic hedgehog signaling pathway in the Gdf7 lineage invariably leads to medulloblastoma. Lineage tracing analysis reveals that Gdf7-lineage cells not only are a source of choroid plexus epithelial cells, but are also present in the cerebellar rhombic lip and contribute to a subset of cerebellar granule neuron precursors, the presumed cell-of-origin for Sonic hedgehog-driven medulloblastoma. We further show that Gdf7-lineage cells also contribute to multiple neuronal and glial cell types in the cerebellum, including glutamatergic granule neurons, unipolar brush cells, Purkinje neurons, GABAergic interneurons, Bergmann glial cells, and white matter astrocytes. These findings establish hindbrain roof plate as a novel source of diverse neural cell types in the cerebellum that is also susceptible to oncogenic transformation by deregulated Sonic hedgehog signaling.


Including all voices in international data-sharing governance.
Governments, funding bodies, institutions, and publishers have developed a number of strategies to encourage researchers to facilitate access to datasets. The rationale behind this approach is that this will bring a number of benefits and enable advances in healthcare and medicine by allowing the maximum returns from the investment in research, as well as reducing waste and promoting transparency. As this approach gains momentum, these data-sharing practices have implications for many kinds of research as they become standard practice across the world. The governance frameworks that have been developed to support biomedical research are not well equipped to deal with the complexities of international data sharing. This system is nationally based and is dependent upon expert committees for oversight and compliance, which has often led to piece-meal decision-making. This system tends to perpetuate inequalities by obscuring the contributions and the important role of different data providers along the data stream, whether they be low- or middle-income country researchers, patients, research participants, groups, or communities. As research and data-sharing activities are largely publicly funded, there is a strong moral argument for including the people who provide the data in decision-making and to develop governance systems for their continued participation. We recommend that governance of science becomes more transparent, representative, and responsive to the voices of many constituencies by conducting public consultations about data-sharing addressing issues of access and use; including all data providers in decision-making about the use and sharing of data along the whole of the data stream; and using digital technologies to encourage accessibility, transparency, and accountability. We anticipate that this approach could enhance the legitimacy of the research process, generate insights that may otherwise be overlooked or ignored, and help to bring valuable perspectives into the decision-making around international data sharing.


Methods for measuring tau pathology in transgenic mouse models.
In Alzheimer's disease (AD) and tauopathies, tau becomes hyperphosphorylated, undergoes a conformational change, and becomes aggregated and insoluble. There are three methods commonly used to study the insoluble tau fraction, two that utilize detergents (Sarkosyl and RIPA) and another that does not (insoluble). However, these methods require large amounts of homogenate for a relatively low yield of the insoluble fraction, which can be problematic when dealing with small tissue samples. Furthermore, the most common way of analyzing this material is through densitometry of immunoblots, offering only semiquantitative measurements. We provide a comparison of the three methods commonly used (Sarksoyl, RIPA, and insoluble) through immunoblot and ELISA analyses. Finally, we tested a new method to determine aggregated tau levels, utilizing a monoantibody tau ELISA. The insoluble fractions of four different mouse models (P301 L, htau, wild type, and knockout) as well as human AD and control brains were examined. There were significant correlations between the three insoluble methods for both total tau and pS396/404 tau measured by immunoblot or ELISA analyses. Additionally, the results from the ELISA method correlated significantly with those from immunoblot analyses. Finally, the monoantibody assay on the lysate significantly correlated with the total tau ELISAs performed on the three insoluble preparations. Taken together, these results suggest that all three insoluble preparation methods offer similar results for measuring insoluble tau in either mouse or human brains. In addition the new monoantibody ELISA offers a simple quantitative method to measure the amount of aggregated tau in both human and mouse brains.


Differential cellular immune responses against Orientia tsutsugamushi Karp and Gilliam strains following acute infection in mice.
Scrub typhus is a leading cause of febrile illness in endemic countries due to infection with Orientia tsutsugamushi (Ot), a seriously understudied intracellular bacterium. Pulmonary involvement associated with vascular parasitism in patients is common and can develop into life threatening interstitial pneumonia. The diverse antigenicity of Ot genotypes and inter-strain differences in genome content are connected to varied virulence and clinical outcomes; however, detailed studies of strain-related pulmonary immune responses in human patients or small animal models of infection are lacking. In this study, we have used two clinically prevalent bacterial strains (Karp and Gilliam) to reveal cellular immune responses in inflamed lungs and potential biomarkers of disease severity. The results demonstrate that outbred CD-1 mice are highly susceptible to both Karp and Gilliam strains; however, C57BL/6 (B6) mice were susceptible to Karp, but resistant to Gilliam (with self-limiting infection), corresponding to their tissue bacterial burdens and lung pathological changes. Multicolor flow cytometric analyses of perfused B6 mouse lungs revealed robust and sustained influx and activation of innate immune cells (macrophages, neutrophils, and NK cells), followed by CD4+ and CD8+ T cells, during Karp infection, but such responses were greatly attenuated during Gilliam infection. The robust cellular responses in Karp-infected B6 mice positively correlated with significantly early and high levels of serum cytokine/chemokine protein levels (CXCL1, CCL2/3/5, and G-CSF), as well as pulmonary gene expression (Cxcl1/2, Ccl2/3/4, and Ifng). In vitro infection of B6 mouse-derived primary macrophages also revealed bacterial strain-dependent immune gene expression profiles. This study provided the lines of evidence that highlighted differential tissue cellular responses against Karp vs. Gilliam infection, offering a framework for future investigation of Ot strain-related mechanisms of disease pathogenesis vs. infection control.


The efficacy and safety of the melatonin agonist beta-methyl-6-chloromelatonin in primary insomnia: a randomized, placebo-controlled, crossover clinical trial.
While melatonin agonists are known to regulate circadian sleep rhythms, it is not clear whether melatonin agonists have a direct soporific effect. It has been suggested that melatonin's soporific effect is secondary to its ability to induce hypothermia. beta-Methyl-6-chloromelatonin is a high-affinity melatonin receptor agonist that is not associated with hypothermia. The purpose of the present study was to determine if the melatonin agonist beta-methyl-6-chloromelatonin has a direct soporific effect in subjects with primary insomnia. A double-blind, placebo-controlled, crossover safety and efficacy study of 20 mg, 50 mg, and 100 mg of beta-methyl-6-chloromelatonin and placebo was conducted in subjects with DSM-IV-TR primary insomnia. Of 84 subjects screened, 40 progressed to randomly receive each of 3 beta-methyl-6-chloromelatonin doses or placebo on each of 2 consecutive nights with 5-day washout periods between treatments. The effect of treatment on both polysomnographic and subjectively measured sleep parameters, next-morning psychomotor performance, and safety measures was determined. The primary outcome measure was latency to persistent sleep measured by polysomnography. A significant effect of beta-methyl-6-chloromelatonin on the primary efficacy variable, latency to persistent sleep, was observed (p = .0003). The 20-mg dose resulted in a significant 31% improvement in sleep latency compared with placebo, while significant 32% and 41% improvements were observed at the 50-mg and 100-mg doses, respectively (20 mg, p = .0082; 50 mg, p = .0062; 100 mg, p < .0001). Similarly, a significant effect of beta-methyl-6-chloromelatonin on subjective measures of time to fall asleep occurred (p = .0050), with significant improvement observed at both the 50-mg and 100-mg doses (p = .0350 and .0198, respectively) and a trend toward improvement observed at the 20-mg dose (p = .0582). Adverse events were mild to moderate in severity and did not differ in frequency between beta-methyl-6-chloromelatonin and placebo treatments. beta-Methyl-6-chloromelatonin significantly decreases both objective and subjective measures of sleep latency in subjects with primary insomnia. Thus, these data suggest that mel-atonin agonists may exert a direct soporific effect, as previous research indicates that beta-methyl-6-chloromelatonin is not associated with changes in body temperature, heart rate, or blood pressure.


Reliability and Validity of the Diagnostic Criteria for Temporomandibular Disorders Axis I in Clinical and Research Settings: A Critical Appraisal.
The recently published Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) Axis I, which is recommended for use in clinical and research settings, has provided an update of the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). The authors of the DC/TMD based their publication on the results of a Validation Project (2001-2008) and consecutive workgroup sessions held between 2008 and 2013. The DC/TMD represents a major change in both content and procedures; nonetheless, earlier concerns and new insights have only partly been followed up when drafting the new recommendations. Moreover, the emphasis on immediate implementation in clinical and research settings is not in line with the provided external evidence on which the DC/TMD is based. This Focus Article describes these concerns with regard to several aspects of the DC/TMD: the additional classification categories; the high dependency on pressure-pain results from use of the recommended palpation technique; the TMD pain screening instrument; the test population characteristics; the utility of additional subgroups; the use of a reference standard; the dichotomy between pain and dysfunction; and the DC/TMD algorithms. Thus, although the DC/TMD represents an improvement over the RDC/TMD, its immediate implementation in research and clinical care does not yet appear to be adequately substantiated.


Assessment of the performance of Partin's nomogram (2007) in contemporary Indian cohort.
Partin's nomogram is an important prognostic tool to predict adverse pathological features for clinically localized prostate carcinoma. This tool is widely used by both radiation and surgical oncologists for pre-intervention counseling, treatment planning, and predicting the possible need for adjuvant treatment. However, the model is derived from a Western population with typical characteristics of prostate cancer in a prostate-specific antigen (PSA) screened population. Therefore, this study was conducted to assess the performance of the Partin's nomogram as applied to an Indian cohort by assessing the discrimination and calibration properties. A retrospective review of 282 patients treated with robotic radical prostatectomy from 2010 to 2015 was conducted. Partin tables (year 2007) were used to calculate the predicted probabilities for lymph node invasion (LNI), seminal vesicle invasion (SVI), and extraprostatic extension (EPE). The discrimination properties were assessed using the receiver operating characteristic (ROC) curves. Calibration of the model was done to show the relationship between predicted and observed values. The mean age of the patients was 64.3 years. Most (59.4%) were clinical T2 disease. Patients with PSA >10 ng/ml comprised 60% of the population. ECE, SVI, and LNI were present in 39.2%, 22%, and 11% of cases, respectively. ROC analysis revealed area under curve values for EPE, SVI, and LNI of 68%, 67.5%, and 71.2%, respectively. Calibration plot suggested that the Partin tables under-predicted the risk whenever the values of predicted risk were more than 26%, 3%, and 1% for EPE, SVI, and LNI, respectively, and over predicted when the risk was lower. Our data show that Partin's tables, despite having fair discrimination properties, do not accurately predict LNI, SVI, and ECE across the entire range of predicted values in a contemporary Indian cohort.


A function for Rac1 in the terminal differentiation and pigmentation of hair.
The small GTPase Rac1 is ubiquitously expressed in proliferating and differentiating layers of the epidermis and hair follicles. Previously, Rac1 was shown to regulate stem cell behaviour in these compartments. We have asked whether Rac1 has, in addition, a specific, stem-cell-independent function in the regulation of terminal hair follicle differentiation. To address this, we have expressed a constitutively active mutant of Rac1, L61Rac1, only in the basal epidermal layer and outer root sheath of mice possessing an epidermis-specific deletion of endogenous Rac1, which experience severe hair loss. The resulting 'rescue' mice exhibited a hair coat throughout their lives. Therefore, expression of Rac1 activity in the keratin-14-positive compartment of the skin is sufficient for the formation of hair follicles and hair in normal quantities. The quality of hair formed in rescue mice was, however, not normal. Rescue mice showed a grey, dull hair coat, whereas that of wild-type and L61Rac1-transgenic mice was black and shiny. Hair analysis in rescue mice revealed altered structures of the hair shaft and the cuticle and disturbed organization of medulla cells and pigment distribution. Disorganization of medulla cells correlates with the absence of cortical, keratin-filled spikes that normally protrude from the cortex into the medulla. The desmosomal cadherin Dsc2, which normally decorates these protrusions, was found to be reduced or absent in the hair of rescue mice. Our study demonstrates regulatory functions for Rac1 in the formation of hair structure and pigmentation and thereby identifies, for the first time, a role for Rac1 in terminal differentiation.


Vibrio cholerae O1 with Reduced Susceptibility to Ciprofloxacin and Azithromycin Isolated from a Rural Coastal Area of Bangladesh.
Cholera outbreaks occur each year in the remote coastal areas of Bangladesh and epidemiological surveillance and routine monitoring of cholera in these areas is challenging. In this study, a total of 97 Vibrio cholerae O1 isolates from Mathbaria, Bangladesh, collected during 2010 and 2014 were analyzed for phenotypic and genotypic traits, including antimicrobial susceptibility. Of the 97 isolates, 95 possessed CTX-phage mediated genes, ctxA, ace, and zot, and two lacked the cholera toxin gene, ctxA. Also both CTX+ and CTX-V. cholerae O1 isolated in this study carried rtxC, tcpAET, and hlyA. The classical cholera toxin gene, ctxB1, was detected in 87 isolates, while eight had ctxB7. Of 95 CTX+V. cholerae O1, 90 contained rstRET and 5 had rstRCL. All isolates, except two, contained SXT related integrase intSXT. Resistance to penicillin, streptomycin, nalidixic acid, sulfamethoxazole-trimethoprim, erythromycin, and tetracycline varied between the years of study period. Most importantly, 93% of the V. cholerae O1 were multidrug resistant. Six different resistance profiles were observed, with resistance to streptomycin, nalidixic acid, tetracycline, and sulfamethoxazole-trimethoprim predominant every year. Ciprofloxacin and azithromycin MIC were 0.003-0.75 and 0.19-2.00 μg/ml, respectively, indicating reduced susceptibility to these antibiotics. Sixteen of the V. cholerae O1 isolates showed higher MIC for azithromycin (≥0.5 μg/ml) and were further examined for 10 macrolide resistance genes, erm(A), erm(B), erm(C), ere(A), ere(B), mph(A), mph(B), mph(D), mef(A), and msr(A) with none testing positive for the macrolide resistance genes.


Genome-wide association study to identify common variants associated with brachial circumference: a meta-analysis of 14 cohorts.
Brachial circumference (BC), also known as upper arm or mid arm circumference, can be used as an indicator of muscle mass and fat tissue, which are distributed differently in men and women. Analysis of anthropometric measures of peripheral fat distribution such as BC could help in understanding the complex pathophysiology behind overweight and obesity. The purpose of this study is to identify genetic variants associated with BC through a large-scale genome-wide association scan (GWAS) meta-analysis. We used fixed-effects meta-analysis to synthesise summary results across 14 GWAS discovery and 4 replication cohorts comprising overall 22,376 individuals (12,031 women and 10,345 men) of European ancestry. Individual analyses were carried out for men, women, and combined across sexes using linear regression and an additive genetic model: adjusted for age and adjusted for age and BMI. We prioritised signals for follow-up in two-stages. We did not detect any signals reaching genome-wide significance. The FTO rs9939609 SNP showed nominal evidence for association (p<0.05) in the age-adjusted strata for men and across both sexes. In this first GWAS meta-analysis for BC to date, we have not identified any genome-wide significant signals and do not observe robust association of previously established obesity loci with BC. Large-scale collaborations will be necessary to achieve higher power to detect loci underlying BC.


Local redundancy governs infants' spontaneous orienting to visual-temporal sequences.
Two experiments demonstrate that 5-month-olds are sensitive to local redundancy in visual-temporal sequences. In Experiment 1, 20 infants saw 2 separate sequences of looming colored shapes that possessed the same elements but contrasting transitional probabilities. One sequence was random whereas the other was based on bigrams. Without any prior exposure, infants looked longer at the random sequence. In Experiment 2, 17 infants looked equally long at bigram- and trigram-based sequences. However, an analysis of local redundancy revealed that in both experiments disengagement from the sequences was governed by local repetitions rather than by global sequence statistics. This finding suggests that a spontaneous sensitivity to stimulus complexity helps orient infants to sequences they can learn from.


Higher brain BDNF gene expression is associated with slower cognitive decline in older adults.
We tested whether brain-derived neurotrophic factor (BDNF) gene expression levels are associated with cognitive decline in older adults. Five hundred thirty-five older participants underwent annual cognitive assessments and brain autopsy at death. BDNF gene expression was measured in the dorsolateral prefrontal cortex. Linear mixed models were used to examine whether BDNF expression was associated with cognitive decline adjusting for age, sex, and education. An interaction term was added to determine whether this association varied with clinical diagnosis proximate to death (no cognitive impairment, mild cognitive impairment, or dementia). Finally, we examined the extent to which the association of Alzheimer disease (AD) pathology with cognitive decline varied by BDNF expression. Higher brain BDNF expression was associated with slower cognitive decline (p < 0.001); cognitive decline was about 50% slower with the 90th percentile BDNF expression vs 10th. This association was strongest in individuals with dementia. The level of BDNF expression was lower in individuals with pathologic AD (p = 0.006), but was not associated with macroscopic infarcts, Lewy body disease, or hippocampal sclerosis. BDNF expression remained associated with cognitive decline in a model adjusting for age, sex, education, and neuropathologies (p < 0.001). Furthermore, the effect of AD pathology on cognitive decline varied by BDNF expression such that the effect was strongest for high levels of AD pathology (p = 0.015); thus, in individuals with high AD pathology (90th percentile), cognitive decline was about 40% slower with the 90th percentile BDNF expression vs 10th. Higher brain BDNF expression is associated with slower cognitive decline and may also reduce the deleterious effects of AD pathology on cognitive decline.


Association between measures of vitamin A and the ocular fundus findings in cerebral malaria.
To investigate the relationship between serum vitamin A levels and conjunctival impression cytology and retinal whitening present in Malawian children with cerebral malaria. Standard retinal examination and conjunctival impression cytology were performed at hospital admission on 101 consecutively admitted children with cerebral malaria. Blood samples were drawn from 56 children at 24 hours, frozen at -20 degrees C, and transported for assessment of vitamin A levels by high-performance liquid chromatography. Associations among fundus findings and vitamin A measurements were sought. The whitening of the retina that we have previously described in children with cerebral malaria was found to be associated with a mean+/-SD serum vitamin A level of 0.29+/-0.1 micromol/L, compared with a mean vitamin A level of 0.41+/-0.2 micromol/L in children without retinal whitening. Children with retinal whitening were 2.77 (95% CI, 1.06-7.3) times more likely to have abnormal conjunctival impression cytology results than those without whitening. No child had any clinical or ophthalmologic evidence of chronic vitamin A deficiency. The retinal whitening described in children with cerebral malaria is associated with low serum vitamin A levels and with abnormal conjunctival impression cytology results and may be due to acute vitamin A deficiency at the tissue level.


The negative event scale: measuring frequency and intensity of adult hassles.
This study examined the structure, concurrent validity, and reliability of a hassle measure for middle-aged adults in both event frequency and intensity recordings. The measure included a range of interpersonal day-to-day events and re-examined aspects of the primary appraisal confounding debate between Lazarus and colleagues (Lazarus, Delongis, Folkman, & Gruen, 1985) and Dohrenwend and Shrout (1985). Of the 373 participants, 73% were female, 72% were in paid work, 69% were in permanent relationships and 62% had children. Principal component analyses of separate hassle frequency and intensity scores highlighted components consistent with previous research. There were seven interpersonal and four non-interpersonal subscales associated with negative events with family and friends, work, health, money, and household. The subscales had very good reliability and concurrent validity and there were generally strong correlations (i.e. up .84) between frequency and intensity scores for each subscale. Given some important sampling limitations (e.g. female overrepresentation) the findings show a psychometrically sound hassle scale for adults.


The international standard ISO/TS 21872-1 to study the occurence of total and pathogenic Vibrio parahaemolyticus and Vibrio cholerae in seafood: ITS improvement by use of a chromogenic medium and PCR.
During two surveys conducted in 2008 and 2009, the culture method described in the international standard ISO/TS 21872-1 was applied to the detection of Vibrio parahaemolyticus and Vibrio cholerae in 112 living bivalve mollusc samples, with a chromogenic medium used in addition to the TCBS agar, as second selective isolation medium and for enumeration of V. parahaemolyticus and V. cholerae by surface inoculation. A PCR method for detection of these 2 Vibrio species and the hemolysin genes tdh and trh, was applied in parallel. In 2009, the survey was extended to finfish fillets and crustaceans. PCR was also used for species confirmation of characteristic colonies. The identity of the PCR products, specifically targeting V. parahaemolyticus, was checked by sequencing. Occurrence of V. parahaemolyticus and V. cholerae isolates in living bivalve molluscs ranged from 30.4% to 32.6% and from 1.4% to 4.7% respectively. In frozen crustaceans (2009 survey) V. parahaemolyticus and V. cholerae isolates were respectively found in 45% and 10% of the samples. No V. parahaemolyticus or V. cholerae was detected in frozen fish fillets, neither by the ISO method nor by PCR. In 2009, enteropathogenic V. parahaemolyticus (trh+) was isolated from 4 out of 43 oyster samples while the trh gene was present in V. alginolyticus strains and in samples where V. parahaemolyticus was not detected (9 over 112 samples). The ISO method failed to isolate V. parahaemolyticus in 44% to 53% of the living bivalve molluscs where PCR detected the toxR gene specific of V. parahaemolyticus (Vp-toxR). Our results highlighted the need for a revision of the ISO/TS 21872-1 standard, at least, for analysis of living bivalve molluscs, and confirmed the increasing concern of enteropathogenic V. parahaemolyticus in French bivalve molluscs. Enrichment at 41.5°C was questioned and some reliable solutions for the improvement of the ISO/TS 21872-1 method, such as the PCR method for screening of positive samples and confirmation of colonies, were pointed out.


Effects of ethanol on immune response in the brain: region-specific changes in adolescent versus adult mice.
Alcohol use occurs across the life span beginning in adolescence and continuing through adulthood. Ethanol (EtOH)-induced pathology varies with age and includes changes in neurogenesis, neurodegeneration, and glial cell activation. EtOH-induced changes in glial activation and immune activity are believed to contribute to EtOH-induced neuropathology. Recent studies indicate an emerging role of glial-derived neuroimmune molecules in alcohol abuse and addiction. Adolescent and adult C57BL/6 mice were treated via gavage with 6 g/kg EtOH for 10 days, and tissue was harvested 1 day post treatment. We compared the effects of EtOH on chemokine and cytokine expression and astrocyte glial fibrillary acidic protein (GFAP) immunostaining and morphology in the hippocampus, cerebellum, and cerebral cortex. EtOH increased mRNA levels of the chemokine CCL2/MCP-1 in all 3 regions of adult mice relative to controls. The cytokine interleukin-6 (IL-6) was selectively increased only in the adult cerebellum. EtOH did not affect mRNA levels of the cytokine tumor necrosis factor-alpha (TNF-α) in any of these brain regions in adult animals. Interestingly, CCL2, IL-6, and TNF-α mRNA levels were not increased in the hippocampus, cerebellum, or cortex of adolescent mice. EtOH treatment of adult and adolescent mice resulted in increased GFAP immunostaining. Collectively, these data indicate an age- and region-specific susceptibility to EtOH regulation of neuroinflammatory and addiction-related molecules as well as astrocyte phenotype. These studies may have important implications concerning differential alcohol-induced neuropathology and alcohol addiction across the life span.


Treatment adherence in schizophrenia: a patient-level meta-analysis of combined CATIE and EUFEST studies.
The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) obtained a sample of 1493 chronic schizophrenia patients. The European First Episode Schizophrenia Trial (EUFEST) studied a sample of 498 patients. We have combined these two samples to study the predictors and correlates of adherence to treatment. Here we report on adherence to pharmacological treatment at the six and twelve month assessments of these trials with a combined subsample of 1154 schizophrenia patients. Individual patients׳ data were used for analyses. We used logistic regression to examine the effects of substance use, akathisia, parkinsonism, dyskinesia, hostility, and insight on pharmacological adherence. The results showed that reduced adherence to pharmacological treatment was associated with substance use (p=0.0003), higher levels of hostility (p=0.0002), and impaired insight (p<0.0001). Furthermore, poor adherence to study medication was associated with earlier discontinuation in the combined data. The clinical implications of the results point to the importance of routine assessments and interventions to address patients׳ insight and comorbid substance use and the establishment of therapeutic alliance.


Tuberculosis detection in nonhuman primates is enhanced by use of testing algorithms that include an interferon-γ release assay.
To develop a testing algorithm that incorporates multiple assays to evaluate host cellular and humoral immunity and antigen detection concerning Mycobacterium tuberculosis complex (MTBC) infection in captive nonhuman primates. Cohorts of captive-bred and wild-caught macaques from 5 different geographic regions. Macaques were tested for MTBC infection by use of a γ interferon tuberculosis (GIFT) assay, an interferon-γ release assay, and other assays. In the first 2 cohorts (n = 15 and 181), initial validation of the GIFT assay was performed by use of experimentally infected and unexposed control macaques. In the next 3 cohorts (n = 59, 42, and 11), results were obtained for opportunistically collected samples from macaques exposed during spontaneous outbreaks. Sensitivity and specificity of the GIFT assay in the control cohorts were 100% and 97%, respectively, and were variable but enhanced by incorporating results from multiple assays in spontaneous outbreaks. The detection and management of MTBC infection in captive nonhuman primate populations is an ongoing challenge, especially with animal imports and transfers. Despite standardized practices of initial quarantine with regular intradermal tuberculin skin testing, spontaneous outbreaks continue to be reported. Since infection encompasses a range of disease manifestations over time, a testing algorithm that incorporates multiple assays, such as the GIFT assay, to evaluate host cellular and humoral immunity in addition to agent detection is needed. Testing a combination of samples from controlled studies and spontaneous outbreaks of MTBC infection in nonhuman primates would advance the development and validation of a functional algorithm that incorporates promising tools such as the GIFT assay.


Delayed gastric emptying following pancreatoduodenectomy: a Roux-en-Y gastrojejunostomy vs Billroth II gastrojejunostomy randomized study.
delayed gastric emptying (DGE) is the most common complication after pancreaticoduodenectomy (PD) and it occurs in 50% of cases. the endpoint was to determine if there were any differences in the incidence of DGE between Roux-en-Y gastrojejunostomy (ReY) and Billroth II gastrojejunostomy (BII) in PD with pancreaticogastrostomy (PG). this was a case-control prospective randomized study of all PD cases between 2013 and 2016. Sixty-four patients were included, 32 in each group. An intention-to-treat statistical analysis was performed. no significant differences were found with regard to morbidity and mortality or hospital stay. DGE was present in 25% of the patients in the BII group in comparison to 15.6% in the ReY group, which was not statistically significant (p = 0.35). There was a higher percentage of patients with primary DGE in the BII group, 12.5% versus 6.2%, but this was not statistically significant (p = 0.53). No difference in DGE severity was observed. Male gender (OR 8.38 [1.1; 129]), abdominal complications (OR 15 [1.7; 396.9]), pre-operative malnutrition (OR 99.7 [3.3, 11,126]) and hemorrhage (OR 9.4 [1.37, 107.94]) were the main risk factors for DGE according to the multivariate analysis. there were no significant differences in the incidence or severity of DGE between BII or ReY after PD with PG.


Rhesus macaques (Macaca mulatta) are natural hosts of specific Staphylococcus aureus lineages.
Currently, there is no animal model known that mimics natural nasal colonization by Staphylococcus aureus in humans. We investigated whether rhesus macaques are natural nasal carriers of S. aureus. Nasal swabs were taken from 731 macaques. S. aureus isolates were typed by pulsed-field gel electrophoresis (PFGE), spa repeat sequencing and multi-locus sequence typing (MLST), and compared with human strains. Furthermore, the isolates were characterized by several PCRs. Thirty-nine percent of 731 macaques were positive for S. aureus. In general, the macaque S. aureus isolates differed from human strains as they formed separate PFGE clusters, 50% of the isolates were untypeable by agr genotyping, 17 new spa types were identified, which all belonged to new sequence types (STs). Furthermore, 66% of macaque isolates were negative for all superantigen genes. To determine S. aureus nasal colonization, three nasal swabs from 48 duo-housed macaques were taken during a 5 month period. In addition, sera were analyzed for immunoglobulin G and A levels directed against 40 staphylococcal proteins using a bead-based flow cytometry technique. Nineteen percent of the animals were negative for S. aureus, and 17% were three times positive. S. aureus strains were easily exchanged between macaques. The antibody response was less pronounced in macaques compared to humans, and nasal carrier status was not associated with differences in serum anti-staphylococcal antibody levels. In conclusion, rhesus macaques are natural hosts of S. aureus, carrying host-specific lineages. Our data indicate that rhesus macaques are useful as an autologous model for studying S. aureus nasal colonization and infection prevention.


Chinese herbal medicine for menopausal symptoms.
Chinese herbal medicine (CHM) usage is expected to increase as women suffering from menopausal symptoms are seeking alternative therapy due to concerns from the adverse effects (AEs) associated with hormone therapy (HT). Scientific evidence for their effectiveness and safety is needed. To evaluate the effectiveness and safety of CHM in the treatment of menopausal symptoms. We searched the Gynaecology and Fertility Group's Specialised Register of controlled trials, Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 3), MEDLINE, Embase, CINAHL, AMED, and PsycINFO (from inception to March 2015). Others included Current Control Trials, Citation Indexes, conference abstracts in the ISI Web of Knowledge, LILACS database, PubMed, OpenSIGLE database, and China National Knowledge Infrastructure database (CNKI, 1999 to 2015). Other resources included reference lists of articles as well as direct contact with authors. Randomised controlled trials (RCTs) comparing the effectiveness of CHM with placebo, HT, pharmaceutical drugs, acupuncture, or another CHM formula in women over 18 years of age, and suffering from menopausal symptoms. Two review authors independently assessed 864 studies for eligibility. Data extractions were performed by them with disagreements resolved through group discussion and clarification of data or direct contact with the study authors. Data analyses were performed in accordance with Cochrane Collaboration guidelines. We included 22 RCTs (2902 women). Participants were from different ethnic backgrounds with the majority of Chinese origin.When CHM was compared with placebo (eight RCTs), there was little or no evidence of a difference between the groups for the following pooled outcomes: hot flushes per day (MD 0.00, 95% CI -0.88 to 0.89; 2 trials, 199 women; moderate quality evidence); hot flushes per day assessed by an overall hot flush score in which a difference of one point equates to one mild hot flush per day (MD -0.81 points, 95% CI -2.08 to 0.45; 3 RCTs, 263 women; low quality evidence); and overall vasomotor symptoms per month measured by the Menopause-Specific Quality of Life questionnaire (MENQOL, scale 0 to 6) (MD -0.42 points; 95% CI -1.52 to 0.68; 3 RCTs, 256 women; low quality evidence).In addition, results from individual studies suggested there was no evidence of a difference between the groups for daily hot flushes assessed by severity (MD -0.70 points, 95% CI -1.00, -0.40; 1 RCT, 108 women; moderate quality evidence); or overall monthly hot flushes scores (MD -2.80 points, 95% CI -8.93 to 3.33; 1 RCT, 84 women; very low quality evidence); or overall daily night sweats scores (MD 0.07 points, 95% CI -0.19 to 0.33, 1 RCT, 64 women; low quality evidence); or overall monthly night sweats scores (MD 1.30 points, 95% CI -1.76 to 4.36, 1 RCT, 84 women; very low quality evidence). However one study using the Kupperman Index reported that overall monthly vasomotor symptom scores were lower in the CHM group (MD -4.79 points, 95% CI -5.52 to -4.06; 1 RCT, 69 women; low quality evidence).When CHM was compared with hormone therapy (HT) (10 RCTs), only two RCTs reported monthly vasomotor symptoms using MENQOL. It was uncertain whether CHM reduces vasomotor symptoms (MD 0.47 points, 95% CI -0.50 to 1.44; 2 RCTs, 127 women; very low quality evidence).Adverse effects were not fully reported in the included studies. Adverse events reported by women taking CHM included mild diarrhoea, breast tenderness, gastric discomfort and an unpleasant taste. Effects were inconclusive because of imprecise estimates of effects: CHM versus placebo (RR 1.51; 95% CI 0.69 to 3.33; 7 trials, 705 women; I² = 40%); CHM versus HT (RR 0.96; 95% CI 0.66 to 1.39; 2 RCTs, 864 women; I² = 0%); and CHM versus specific conventional medications (such as Fluoxetine and Estazolam) (RR 0.20; 95% CI 0.03 to 1.17; 2 RCTs, 139 women; I² = 61%). We found insufficient evidence that Chinese herbal medicines were any more or less effective than placebo or HT for the relief of vasomotor symptoms. Effects on safety were inconclusive. The quality of the evidence ranged from very low to moderate; there is a need for well-designed randomised controlled studies.


Behavior and abundance of Anopheles darlingi in communities living in the Colombian Amazon riverside.
In the past few years, relative frequencies of malaria parasite species in communities living in the Colombian Amazon riverside have changed, being Plasmodium vivax (61.4%) and Plasmodium malariae (43.8%) the most frequent. Given this epidemiological scenario, it is important to determine the species of anophelines involved in these parasites' transmission. This study was carried out in June 2016 in two indigenous communities living close to the tributaries of the Amazon River using protected human bait. The results of this study showed a total abundance of 1,085 mosquitos, of which 99.2% corresponded to Anopheles darlingi. Additionally, only two anopheline species were found, showing low diversity in the study areas. Molecular confirmation of some individuals was then followed by evolutionary analysis by using the COI gene. Nested PCR was used for identifying the three Plasmodium species circulating in the study areas. Of the two species collected in this study, 21.0% of the An. darlingi mosquitoes were infected with P. malariae, 21.9% with P. vivax and 10.3% with Plasmodium falciparum. It exhibited exophilic and exophagic behavior in both study areas, having marked differences regarding its abundance in each community (Tipisca first sampling 49.4%, Tipisca second sampling 39.6% and Doce de Octubre 10.9%). Interestingly, An. mattogrossensis infected by P. vivax was found for the first time in Colombia (in 50% of the four females collected). Analysis of An. darlingi COI gene diversity indicated a single population maintaining a high gene flow between the study areas. The An. darlingi behavior pattern found in both communities represents a risk factor for the region's inhabitants living/working near these sites. This highlights the need for vector control efforts such as the use of personal repellents and insecticides for use on cattle, which must be made available in order to reduce this Anopheline's abundance.


Synthesis and structure determination of the hierarchical meso-microporous zeolite ITQ-43.
The formation of mesopores in microporous zeolites is generally performed by postsynthesis acid, basic, and steam treatments. The hierarchical pore systems thus formed allow better adsorption, diffusion, and reactivity of these materials. By combining organic and inorganic structure-directing agents and high-throughput methodologies, we were able to synthesize a zeolite with a hierarchical system of micropores and mesopores, with channel openings delimited by 28 tetrahedral atoms. Its complex crystalline structure was solved with the use of automated diffraction tomography.


Reconfigurable optical differential phase-shift-keying pattern recognition based on incoherent photonic processing.
We propose and experimentally demonstrate asynchronous optical differential phase-shift-keying (DPSK) pattern recognition using a fully reconfigurable technique. The proposed method uses optical phase-to-bipolar intensity conversion through all-optical differentiation in conjunction with an incoherent time-spectrum convolution system where the pattern to be recognized is implemented directly in the spectral domain through optical amplitude-only linear filtering. Full reconfigurability in terms of bit rate, pattern sequence, and pattern length is achieved using electronically programmable optical filters. We demonstrate dynamically switching recognition of different 64 bit patterns in a continuous 12 Gb/s DPSK pseudorandom optical bit stream with contrast ratio up to 3.8 dB.


Anthropometric definitions of dysmorphic facial signs.
A photoanthropometric method is presented, which enables an objective definition of facial structures. It may support the clinical description of patients with dysmorphic syndromes. Eighteen parameters were studied. The measuring points were elected on the base of anthropological criteria. The measurements were related to reference values in the same face. The obtained indices were compared to an age related control group of 100 normal children between 0 and 12 years. Values below the 3rd and above the 97th percentile were considered as dysmorphisms. The results give information on the frequency and age dependency of different dysmorphic signs.


Social determinants in the sexual health of adolescent Aboriginal Australians: a systematic review.
While research indicates that Aboriginal and Torres Strait Islander adolescents may be at increased risk of some sexually transmitted infections, there is limited information about factors that may place these young people at more risk of adverse sexual health than their non-Indigenous counterparts. Current research has tended to focus on surveillance-type data, but there is an increasing need to understand social determinants of sexual health risk. This systematic review assessed the evidence of social determinants impacting on Aboriginal and Torres Strait Islander adolescents' sexual health in Australia. Published, English-language literature was searched across key databases from 2003 to 2015. Fourteen studies were included in the qualitative synthesis. Findings suggest that social determinants such as access to healthcare, poverty, substance use, educational disadvantage, sociocultural context, gender inequalities, status and identity, and social disadvantage impacted on Indigenous adolescents' sexual behaviours and sexual health risk. Evidence from the literature included in the review suggests that peer education may be an acceptable and appropriate approach for addressing such issues. There remains a need for programmes and services to be community-developed and community-led, thus ensuring cultural appropriateness and relevance. However, there is also a significant need for such programmes to be effectively and rigorously evaluated with data that goes beyond surveillance, and seeks to unpack how sexual norms are experienced by Indigenous adolescents, particularly outside of remote Australia - and how these experiences act as either risk or protective factors to good sexual health and positive social and emotional well-being.


Internet-Based Intervention for Tinnitus: Outcome of a Single-Group Open Trial.
Managing chronic tinnitus is challenging, and innovative ways to address the resulting health-care burden are required. Internet-based cognitive behavioral therapy (iCBT) for tinnitus shows promise as a cost-effective treatment option. The feasibility and effectiveness of iCBT in the United Kingdom are yet to be explored. Furthermore, it is not known if iCBT can be supported by an audiologist rather than a psychologist. This study aimed to determine the feasibility of guided iCBT using audiological support on tinnitus distress and tinnitus-related comorbidities. Furthermore, it aimed to establish the feasibility of iCBT for tinnitus distress in the United Kingdom, by determining recruitment, attrition, and compliance rates. Finally, it aimed to identify which aspects of the protocol require refinement for subsequent clinical trials. A single-group open trial design was implemented. This study would serve as a prerequisite study, to identify barriers, before undertaking effectiveness trials. Participants consisted of 37 adults (18 males, 19 females), with an age range of between 50 and 59 yr. The mean preintervention tinnitus severity rating was 56.15 (standard deviation = 18.35), which is categorized as "severe tinnitus" as measured by the Tinnitus Functional Index (TFI). Five participants withdrew during the study, and 29 of the remaining participants completed the postintervention questionnaire. The guided iCBT intervention ran over an eight-week period and consisted of 16 obligatory modules and five optional modules. The intervention was designed to be interactive, interesting, and stimulating. A key element was the provision of support from an audiologist throughout the program. Online questionnaires were used throughout the study. These were administered at baseline and postintervention to determine attrition and compliance rates and to facilitate sample size estimates for further clinical trials. Outcome measures for tinnitus severity, hearing handicap, insomnia, cognitive functioning, hyperacusis, anxiety, depression, and life satisfaction were used to investigate the effects of iCBT with audiological support. In addition, a weekly questionnaire was incorporated to monitor change in tinnitus distress while undertaking the intervention. Feasibility was established using an audiologist to support this guided iCBT intervention, as a significant change postintervention was found for tinnitus severity, as measured by the TFI and the Tinnitus Handicap Inventory, Screening version. The attrition rate was 22% and compliance was variable. Although these results were based on a small sample, they provide encouraging evidence for the feasibility of delivering iCBT treatment for tinnitus symptoms with audiology support in the United Kingdom. An Internet-based intervention of tinnitus appears to be feasible in the United Kingdom when using audiological support. Randomized controlled trials to further investigate the effectiveness of iCBT for tinnitus in the United Kingdom are required.


Increased Urge to Gamble Following Near-Miss Outcomes May Drive Purchasing Behaviour in Scratch Card Gambling.
Previous research into scratch card gambling has highlighted the effects of these games on players' arousal and affective states. Specifically, near-miss outcomes in scratch cards (uncovering 2 of 3 needed jackpot symbols) have been associated with high levels of physiological and subjective arousal and negative emotional evaluations, including increased frustration. We sought to extend this research by examining whether near-misses prompted increases in gambling urge, and the subsequent purchasing of additional scratch cards. Participants played two scratch cards with varying outcomes with half of the sample experiencing a near-miss for the jackpot prize, and the other half experiencing a regular loss. Players rated their urge to continue gambling after each game outcome, and following the initial playing phase, were then able to use their winnings to purchase additional cards. Our results indicated that near-misses increased the urge to gamble significantly more than regular losses, and urge to gamble in the near-miss group was significantly correlated with purchasing at least one additional card. Although some players in the loss group purchased another card, there was no correlation between urge to gamble and purchasing in this group. Additionally, participants in the near-miss group who purchased additional cards reported higher levels of urge than those who did not purchase more cards. This was not true for the loss group: participants who experienced solely losing outcomes reported similar levels of urge regardless of whether or not they purchased more scratch cards. Despite near-misses' objective status as monetary losses, the increased urge that follows near-miss outcomes may translate into further scratch card gambling for a subset of individuals .


An NF90/long noncoding RNA-LET/miR-548k feedback amplification loop controls esophageal squamous cell carcinoma progression.
In our previous study we have found that miR-548k has oncogenic roles in esophageal squamous cell carcinoma (ESCC) via repressing long noncoding RNA (lncRNA)-LET and further upregulating nuclear factor 90 (NF90). However, the upstream factors controlling miR-548k expression are still unknown. In this study, we found NF90 directly binds pri-miR-548k, increases the stability of pri-miR-548k, and upregulates the expression of pri-miR-548k and miR-548k. Therefore, NF90, miR-548k and lncRNA-LET forms a feedback loop. Gain-of-function and loss-of-function assays demonstrated that in accordance with the roles of miR-548k, NF90 also promotes ESCC cell proliferation and migration. Furthermore, we verified the regulatory feedback loop between NF90, miR-548k, and lncRNA-LET. We found NF90 upregulated miR-548k and downregulated lncRNA-LET. miR-548k downregulated lncRNA-LET and upregulated NF90. lncRNA-LET downregulated NF90 and miR-548k. Through the reciprocal regulations between each other, the NF90/miR-548k/lncRNA-LET feedback loop controls the expressions of NF90 targets (HIF-1α and VEGF), miR-548k targets (KLF10 and EGFR), and lncRNA-LET target (p53). Further functional assays demonstrated that activation of the NF90/miR-548k/lncRNA-LET feedback loop via simultaneously overexpressing NF90 and miR-548k and simultaneously depleting lncRNA-LET significantly promotes ESCC cell proliferation and migration in vitro and ESCC tumor growth in vivo. Targeting the NF90/miR-548k/lncRNA-LET feedback loop via simultaneously depleting NF90 and miR-548k and simultaneously overexpressing lncRNA-LET significantly inhibits ESCC cell proliferation and migration in vitro and ESCC tumor growth in vivo. In summary, our findings identified a crucial oncogenic NF90/lncRNA-LET/miR-548k feedback amplification loop, which may be promising therapeutic targets for ESCC.


Signal analysis using a multiresolution form of the singular value decomposition.
This paper proposes a multiresolution form of the singular value decomposition (SVD) and shows how it may be used for signal analysis and approximation. It is well-known that the SVD has optimal decorrelation and subrank approximation properties. The multiresolution form of SVD proposed here retains those properties, and moreover, has linear computational complexity. By using the multiresolution SVD, the following important characteristics of a signal may he measured, at each of several levels of resolution: isotropy, sphericity of principal components, self-similarity under scaling, and resolution of mean-squared error into meaningful components. Theoretical calculations are provided for simple statistical models to show what might be expected. Results are provided with real images to show the usefulness of the SVD decomposition.


The workplace health group: A case study of 20 years of multidisciplinary research.
The Workplace Health Group (WHG) was established in 1998 to conduct research on worker health and safety and organizational effectiveness. This multidisciplinary team includes researchers with backgrounds in psychology, health promotion and behavior, and intervention design, implementation, and evaluation. The article begins with a brief history of the team, its guiding principles, and stages of team formation and development. This section provides examples of the roles, team composition, structure, processes, cognition, leadership, and climate played in the various stages of team development, as well as how they influenced team effectiveness. The WHG formed with functional diversity-variety in knowledge, skills, and abilities-in mind, and the impact of this diversity is discussed throughout the article. Illustrations of how the functional diversity of the WHG has led to real-world impact are provided. The article concludes with some lessons learned and recommendations for creating and sustaining multidisciplinary teams based on the WHG's 20 years of experience and the team science literature. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Alteration of clonal profile. I. Effect of sublethal irradiation on the responses to phosphorylcholine in BALB/c mice.
BALB/c mice exhibit greater than 90% H8 clonal dominance in the immune response to phosphorylcholine. Adult mice exposed to 500 rads were initally unable to produce a humoral immune response to both phosphorylcholine and trinitrophenol antigens, and the direct plaque-forming cell response was slowly regained over several weeks. Clonotypic analysis wity antisera directed against the H8 idiotype showed that the H8 clone initially dominated the recovery of the response to phosphorycholine but that 60 days after the irradiation significant numbers of non-H8 clones could be detected. This same pattern could be seen in mice irradiated with 100 rads, a dose that does not completely abrogate the H8 response to phosphorylcholine. Sublethal irradiation of neonates before they had acquired responsiveness to phosphorylcholine could also eventually lead to the emergence of non-H8 idiotypes. Thus, a radiosensitive element regulates the expression of clonal dominance in anti-phosphorylcholine responses of BALB/c mice.


Hybrid Approach to Estimation of Underreporting of Tuberculosis Case Notification in High-Burden Settings With Weak Surveillance Infrastructure: Design and Implementation of an Inventory Study.
The greatest risk of infectious disease undernotification occurs in settings with limited capacity to detect it reliably. World Health Organization guidance on the measurement of misreporting is paradoxical, requiring robust, independent systems to assess surveillance rigor. Methods are needed to estimate undernotification in settings with incomplete, flawed, or weak surveillance systems. This study attempted to design a tuberculosis (TB) inventory study that balanced rigor with feasibility for high-need settings. This study aims to design a hybrid TB inventory study for contexts without World Health Organization preconditions. We estimated the proportion of TB cases that were not reported to the Ministry of Health in 2015. The study sought to describe TB surveillance coverage and quality at different levels of TB care provision. Finally, we aimed to identify structural-, facility-, and provider-level barriers to notification and reasons for underreporting, nonreporting, and overreporting. Retrospective partial digitalization of paper-based surveillance and facility records preceded deterministic and probabilistic record linkage; a hybrid of health facilities and laboratory census with a stratified sampling of HFs with no capacity to notify leveraged a priori knowledge. Distinct extrapolation methods were applied to the sampled health facilities to estimate bacteriologically confirmed versus clinical TB. In-depth interviews and focus groups were used to identify causal factors responsible for undernotification and test the acceptability of remedies. The hybrid approach proved viable and instructive. High-specificity verification of paper-based records in the field was efficient and had minimal errors. Limiting extrapolation to clinical cases improved precision. Probabilistic record linkage is computationally intensive, and the choice of software influences estimates. Record absence, decay, and overestimation of the private sector TB treatment behavior threaten validity, meriting mitigation. Data management demands were underestimated. Treatment success was modest in all sectors (R=37.9%-72.0%) and did not align with treatment success reported by the state (6665/8770, 75.99%). One-fifth of TB providers (36/178, 20%) were doubtful that the low volume of patients with TB treated in their facility merited mastery of the extensive TB notification forms and procedures. Subnational inventory studies can be rigorous, relevant, and efficient in countries that need them even in the absence of World Health Organization preconditions, if precautions are taken. The use of triangulation techniques, with minimal recourse to sampling and extrapolation, and the privileging of practical information needs of local decision makers yield reasonable misreporting estimates and viable policy recommendations.


Clinical performance of a combined approach for the esthetic management of fluorosed teeth: Three-year results.
The long-term clinical performance of combined therapy including enamel microabrasion and vital bleaching is debatable due to the abrasion of outer enamel surface. The aim of this longitudinal cohort study was to evaluate the 3-year clinical performance of enamel microabrasion in combination with vital tooth bleaching for the esthetic management of fluorosed teeth. Fifteen patients with 176 fluorosed incisors and canines were included in this study. All the teeth were treated with enamel microabrasion (Opalustre, Ultradent), and at-home bleaching technique (10% Opalescence PF, Ultradent). Fluorosed teeth were evaluated at baseline, after microabrasion, after combined therapy, and at 3-year follow-up in terms of esthetic criteria (esthetic appearance, brown stains, and opaque white areas), side effects, and patient satisfaction using visual analog scales. The data were statistically analyzed (α = 0.05). Fluorosed teeth revealed significantly better esthetic appearance after microabrasion and combined therapy and at 3-year follow-up compared to those at baseline (P P Conclusions: The combined therapy was effective in the esthetic management of fluorosed teeth. However, a significant relapse was observed in the esthetic appearance and brown stains of these patients after 3 years, which also reduced patient satisfaction.


Microarray karyotyping of commercial wine yeast strains reveals shared, as well as unique, genomic signatures.
Genetic differences between yeast strains used in wine-making may account for some of the variation seen in their fermentation properties and may also produce differing sensory characteristics in the final wine product itself. To investigate this, we have determined genomic differences among several Saccharomyces cerevisiae wine strains by using a "microarray karyotyping" (also known as "array-CGH" or "aCGH") technique. We have studied four commonly used commercial wine yeast strains, assaying three independent isolates from each strain. All four wine strains showed common differences with respect to the laboratory S. cerevisiae strain S288C, some of which may be specific to commercial wine yeasts. We observed very little intra-strain variation; i.e., the genomic karyotypes of different commercial isolates of the same strain looked very similar, although an exception to this was seen among the Montrachet isolates. A moderate amount of inter-strain genomic variation between the four wine strains was observed, mostly in the form of depletions or amplifications of single genes; these differences allowed unique identification of each strain. Many of the inter-strain differences appear to be in transporter genes, especially hexose transporters (HXT genes), metal ion sensors/transporters (CUP1, ZRT1, ENA genes), members of the major facilitator superfamily, and in genes involved in drug response (PDR3, SNQ1, QDR1, RDS1, AYT1, YAR068W). We therefore used halo assays to investigate the response of these strains to three different fungicidal drugs (cycloheximide, clotrimazole, sulfomethuron methyl). Strains with fewer copies of the CUP1 loci showed hypersensitivity to sulfomethuron methyl. Microarray karyotyping is a useful tool for analyzing the genome structures of wine yeasts. Despite only small to moderate variations in gene copy numbers between different wine yeast strains and within different isolates of a given strain, there was enough variation to allow unique identification of strains; additionally, some of the variation correlated with drug sensitivity. The relatively small number of differences seen by microarray karyotyping between the strains suggests that the differences in fermentative and organoleptic properties ascribed to these different strains may arise from a small number of genetic changes, making it possible to test whether the observed differences do indeed confer different sensory properties in the finished wine.


Pax7 is required for establishment of the xanthophore lineage in zebrafish embryos.
The pigment pattern of many animal species is a result of the arrangement of different types of pigment-producing chromatophores. The zebrafish has three different types of chromatophores: black melanophores, yellow xanthophores, and shimmering iridophores arranged in a characteristic pattern of golden and blue horizontal stripes. In the zebrafish embryo, chromatophores derive from the neural crest cells. Using pax7a and pax7b zebrafish mutants, we identified a previously unknown requirement for Pax7 in xanthophore lineage formation. The absence of Pax7 results in a severe reduction of xanthophore precursor cells and a complete depletion of differentiated xanthophores in embryos as well as in adult zebrafish. In contrast, the melanophore lineage is increased in pax7a/pax7b double-mutant embryos and larvae, whereas juvenile and adult pax7a/pax7b double-mutant zebrafish display a severe decrease in melanophores and a pigment pattern disorganization indicative of a xanthophore- deficient phenotype. In summary, we propose a novel role for Pax7 in the early specification of chromatophore precursor cells.


Maternal IgG immune complexes induce food allergen-specific tolerance in offspring.
The role of maternal immune responses in tolerance induction is poorly understood. To study whether maternal allergen sensitization affects offspring susceptibility to food allergy, we epicutaneously sensitized female mice with ovalbumin (OVA) followed by epicutaneous sensitization and oral challenge of their offspring with OVA. Maternal OVA sensitization prevented food anaphylaxis, OVA-specific IgE production, and intestinal mast cell expansion in offspring. This protection was mediated by neonatal crystallizable fragment receptor (FcRn)-dependent transfer of maternal IgG and OVA immune complexes (IgG-IC) via breast milk and induction of allergen-specific regulatory T (T reg) cells in offspring. Breastfeeding by OVA-sensitized mothers or maternal supplementation with IgG-IC was sufficient to induce neonatal tolerance. FcRn-dependent antigen presentation by CD11c+ dendritic cells (DCs) in offspring was required for oral tolerance. Human breast milk containing OVA-IgG-IC induced tolerance in humanized FcRn mice. Collectively, we demonstrate that interactions of maternal IgG-IC and offspring FcRn are critical for induction of T reg cell responses and control of food-specific tolerance in neonates.


Acute 'pathological haematoma' without significant antecedent trauma as an unusual presentation of undiagnosed malignancy.
The authors report two cases of malignancy that presented initially with acute haematomas without any history of significant trauma. The first case was a 31-year-old male who presented with a large haematoma in the anterior triangle of the neck following minor trauma during a rugby match. This was shown to be due to haemorrhage into an undiagnosed papillary thyroid tumour. The second case was a 41-year-old male who developed a spontaneous sternocleidomastoid haematoma after laying flagstones and without any history of direct trauma. This was due to haemorrhage into a nodal deposit of non-Hodgkin's lymphoma. These cases highlight that sudden onset haematomas without obvious explanation may be the result of underlying malignancy. In such instances further investigation must be considered and re examination of the patient is essential after the haematoma has resolved.


The future of cancer immunotherapy for brain tumors: a collaborative workshop.
Harnessing the effector mechanisms of the immune system to combat brain tumors with antigen specificity and memory has been in research and clinical testing for many years. Government grant mechanisms and non-profit organizations have supported many innovative projects and trials while biotech companies have invested in the development of needed tools, assays and novel clinical approaches. The National Brain Tumor Society and the Parker Institute for Cancer Immunotherapy partnered to host a workshop to share recent data, ideas and identify both hurdles and new opportunities for harnessing immunotherapy against pediatric and adult brain tumors. Adoptively transferred cell therapies have recently shown promising early clinical results. Local cell delivery to the brain, new antigen targets and innovative engineering approaches are poised for testing in a new generation of clinical trials. Although several such advances have been made, several obstacles remain for the successful application of immunotherapies for brain tumors, including the need for more representative animal models that can better foreshadow human trial outcomes. Tumor and tumor microenvironment biopsies with multiomic analysis are critical to understand mechanisms of response and patient stratification, yet brain tumors are especially challenging for such biopsy collection. These workshop proceedings and commentary shed light on the status of immunotherapy in pediatric and adult brain tumor patients, including current research as well as opportunities for improving future efforts to bring immunotherapy to the forefront in the management of brain tumors.


Early childhood stimulation benefits adult competence and reduces violent behavior.
An estimated 178 million children younger than 5 years in developing countries experience linear growth retardation and are unlikely to attain their developmental potential. We aimed to evaluate adult benefits from early childhood stimulation and/or nutritional supplementation in growth-retarded children. In Kingston, Jamaica, 129 growth-retarded children aged 9 to 24 months took part in a 2-year trial of nutritional supplementation (1 kg milk-based formula per week) and/or psychosocial stimulation (weekly play sessions to improve mother-child interaction). We assessed IQ, educational attainment, and behavior at 22 years old in 105 participants. We used multivariate regressions, weighted to adjust for loss to follow-up, to determine treatment benefits. We found no significant benefits from supplementation. Participants who received stimulation reported less involvement in fights (odds ratio: 0.36 [95% confidence interval (CI) 0.12-1.06]) and in serious violent behavior (odds ratio: 0.33 [95% CI: 0.11-0.93]) than did participants with no stimulation. They also had higher adult IQ (coefficient: 6.3 [95% CI: 2.2-10.4]), higher educational attainment (achievement, grade level attained, and secondary examinations), better general knowledge, and fewer symptoms of depression and social inhibition. Early psychosocial intervention had wide-ranging benefits in adulthood that are likely to facilitate functioning in everyday life. The reductions in violent behavior are extremely important given the high levels of violence in many developing countries. The study provides critical evidence that early intervention can lead to gains in adult functioning.


In vitro abrasivity and chemical properties of charcoal-containing dentifrices.
Charcoal-containing dentifrices are gaining popularity, but scientific information on their effect on oral health is scarce. This study investigated properties of dentifrices that may affect dentine abrasivity, as well as their ability to adsorb fluoride, their pH and the presence of harmful substances. The dentifrices NAO and COCO were subjected to the following analyses: abrasivity, expressed as mean abraded depth and relative dentin abrasivity (RDA), and surface roughness of extracted human molars (n = 30) after simulated brushing; fluoride adsorption measured as concentration change; pH measurements; detection of polycyclic aromatic hydrocarbons by gas chromatography-mass spectrometry. The products were compared to a reference dentifrice (Colgate® MaxWhite), positive controls (ISO dentifrice slurry, activated charcoal for laboratory use) and a negative control (distilled water). The mean abraded depths of NAO and COCO were not different (p > .05), but higher than the reference dentifrice and the negative control (p < .05). The RDA values of NAO, COCO and the ISO dentifrice slurry were higher than the reference dentifrice value (p < .05) by up to 10 times. The dentine surface roughness was higher after brushing with NAO, COCO and ISO dentifrice slurry compared to distilled water (p < .05). No change in mean adsorbed fluoride concentration was observed after 24 h (p > .05). Both NAO and COCO were alkaline (pH > 7). Analysis of NAO revealed the presence of naphthalene (112.8 ± 2.0 ng/mL). The charcoal-containing dentifrices were abrasive within acceptable limits set by ISO and did not adsorb fluoride. The presence of naphthalene in one product is a cause for concern.


Behavioural and metabolic risk factors for mortality from colon and rectum cancer: analysis of data from the Asia-Pacific Cohort Studies Collaboration.
Colorectal cancer has several modifiable behavioural risk factors but their relationship to the risk of colon and rectum cancer separately and between countries with high and low incidence is not clear. Data from participants in the Asia Pacific Cohort Studies Collaboration (APCSC) were used to estimate mortality from colon (International Classification of Diseases, revision 9 (ICD-9) 153, ICD-10 C18) and rectum (ICD-9 154, ICD-10 C19-20) cancers. Data on age, body mass index (BMI), serum cholesterol, height, smoking, physical activity, alcohol and diabetes mellitus were entered into Cox proportional hazards models. 600,427 adults contributed 4,281,239 person-years follow-up. The mean ages (SD) for Asian and Australia/New Zealand cohorts were 44.0 (9.5) and 53.4 (14.5) years, respectively. 455 colon and 158 rectum cancer deaths were observed. Increasing age, BMI and attained adult height were associated with increased hazards of death from colorectal cancer, and physical activity was associated with a reduced hazard. After multiple adjustment, any physical activity was associated with a 28% lower hazard of colon cancer mortality (HR 0.72, 95%CI 0.53-0.96) and lower rectum cancer mortality (HR 0.75, 95%CI 0.45-1.27). A 2cm increase in height increased colon and all colorectal cancer mortality by 7% and 6% respectively. Physical inactivity and greater BMI are modifiable risk factors for colon cancer in both Western and Asian populations. Further efforts are needed to promote physical activity and reduce obesity while biological research is needed to understand the mechanisms by which they act to cause cancer mortality.


Environmental Impacts and Policy Responses to Covid-19: A View from Latin America.
COVID-19 is currently having major short run effects with possible serious long run implications for the environment and the management of natural resources in Latin America. We discuss the possible effects of the pandemic on air pollution, deforestation and other relevant environmental dimensions across the region. With contributions from environmental economists from eight countries, we give an overview of the initial and expected environmental effects of this health crisis. We discuss potential effects on environmental regulations, possible policy interventions, and an agenda for future research for those interested in the design and evaluation of environmental policies relevant for the Latin American context.


Vaccination with cyclin-dependent kinase tick antigen confers protection against Ixodes infestation.
Among arthropods, ticks lead as vectors of animal diseases and rank second to mosquitoes in transmitting human pathogens. Cyclin-dependent kinases (CDK) participate in cell cycle control in eukaryotes. CDKs are serine/threonine protein kinases and these catalytic subunits are activated or inactivated at specific stages of the cell cycle. To determine the potential of using CDKs as anti-tick vaccine antigens, hamsters were immunized with recombinant Ixodes persulcatus CDK10, followed by a homologous tick challenge. Though it was not exactly unexpected, IpCDK10 vaccination significantly impaired tick blood feeding and fecundity, which manifested as low engorgement weights, poor oviposition, and a reduction in 80% of hatching rates. These findings may underpin the development of more efficacious anti-tick vaccines based on the targeting of cell cycle control proteins.


Exploring emergency physicians' professional identities: a Q-method study.
Professional identities research in medical education has made significant contributions to the field. However, what comprises professional identities is rarely interrogated. This research tackles this relatively understudied component of professional identities research by understanding emergency medicine physicians' perspectives on the important elements that comprise their professional identities. Q-methodology was used to identify different clusters of viewpoints on professional identities; by extension, the core components that comprise emergency medicine physicians' professional identities are disclosed. Thirty-three emergency medicine physicians were recruited, through purposive sampling, from five hospitals across Taiwan. R software was used to analyse the Q-sorts, determine loadings on each viewpoint and formulate the viewpoint array. Analysis of interview data enhanced our understanding of these viewpoints. In total, twenty-five emergency medicine physicians loaded onto four distinct viewpoints, reflecting dominant perspectives of emergency medicine physicians' understanding of their professional identities. These distinct viewpoints demonstrated what emergency medicine physicians deemed significant in how they understood themselves. The viewpoints comprised: skills acquisition, capabilities and practical wisdom; coping ability and resilience; professional recognition and self-esteem; and wellbeing and quality of life. All viewpoints stressed the importance of trust between colleagues. These findings demonstrate the multitude of ways in which seemingly unified professional identities diverge across groups of individuals. An enhanced understanding of speciality work culture is gained. By understanding facets of professional identities, the development of future educational interventions and departmental initiatives, which might support key components of professional identities, can be explored.


Intrapsychic and interpersonal guilt: a critical review of the recent literature.
Various authors hold that some emotions (i.e., moral emotions) have the function of orienting people toward ethical actions. In addition to embarrassment, shame and pride, the moral emotion of guilt is believed to affect humans' behavior when they carry out transgressions that violate social and cultural standards. Over the past century, many studies (including controversial ones) have been conducted on guilt. In this study, we analyzed and summarized mainly the most recent literature on this emotion. On one side, the destructiveness of guilt is emphasized. It inflicts punishment and pain on individuals for their errors and can lead to psychopathology (e.g., depression). On the other side, it is described as a "friendly" emotion that motivates behavior adapted to social and cultural rules. How can this asymmetry be explained? Different existing views on guilt are presented and discussed, together with recent proposals, supported by research data. Finally, we discussed some systematic models that try to incorporate these different views in a single framework that could facilitate future researches.


Plant DELLAs restrain growth and promote survival of adversity by reducing the levels of reactive oxygen species.
Plant growth is adaptively modulated in response to environmental change. The phytohormone gibberellin (GA) promotes growth by stimulating destruction of the nuclear growth-repressing DELLA proteins [1-7], thus providing a mechanism for environmentally responsive growth regulation [8, 9]. Furthermore, DELLAs promote survival of adverse environments [8]. However, the relationship between these survival and growth-regulatory mechanisms was previously unknown. Here, we show that both mechanisms are dependent upon control of the accumulation of reactive oxygen species (ROS). ROS are small molecules generated during development and in response to stress that play diverse roles as eukaryotic intracellular second messengers [10]. We show that Arabidopsis DELLAs cause ROS levels to remain low after either biotic or abiotic stress, thus delaying cell death and promoting tolerance. In essence, stress-induced DELLA accumulation elevates the expression of genes encoding ROS-detoxification enzymes, thus reducing ROS levels. In accord with recent demonstrations that ROS control root cell expansion [11, 12], we also show that DELLAs regulate root-hair growth via a ROS-dependent mechanism. We therefore propose that environmental variability regulates DELLA activity [8] and that DELLAs in turn couple the downstream regulation of plant growth and stress tolerance through modulation of ROS levels.


Effect of anthocyanins contained in a blackberry extract on the circulatory failure and multiple organ dysfunction caused by endotoxin in the rat.
Anthocyanins are a group of naturally occurring phenolic compounds related to the colouring of plants, flowers and fruits. These pigments are important as quality indicators, chemotaxonomic markers and for their antioxidant activities. Here we have investigated the therapeutic efficacy of anthocyanins contained in a blackberry extract on (i) circulatory failure, (ii), multiple organ dysfunction and (iii) activity of the inducible isoforms of nitric oxide (NO) synthase (iNOS) and cyclooxygenase (COX-2) in anaesthetised rats with endotoxic shock. In a model of endotoxic shock induced by lipopolysaccharide (LPS, E. coli, 10 mg/kg, i.v.) in the rat, pretreatment with anthocyanins present in the blackberry extract (5 mg/kg, i. v. 30 min before LPS) prevented the hypotension induced by LPS. Endotoxaemia also caused rises in the serum levels of (i) glutamyl oxaloacetic transaminase (GOT), glutamyl pyruvic transaminase (GPT), alkaline phosphates and bilirubin (hepatic dysfunction) (ii) creatinine (renal dysfunction), (iii) amylase and lipase (pancreatic injury), (iii) NOx and 6-keto-PGF1 alpha. Anthocyanins attenuated the hepatic and pancreatic injury, the renal dysfunction and decreased NOx and 6-keto-PGF1 alpha levels. Endotoxaemia for 6 h resulted in a substantial increase in iNOS and COX activity in rat lung, which was attenuated in rats pretreated with anthocyanins. Moreover, anthocyanins (0.02 - 0.32 mg/mL) inhibited in vitro iNOS and COX activity from lung of LPS-treated rats. Polymorphonuclear (PMN) infiltration (myeloperoxidase activity), lipid peroxidation (malondialdehyde levels), as well as tissue injury (histological examination) induced by LPS in rat lung and ileum was reduced by anthocyanins (5 mg/kg, i. v. 30 min before LPS). Furthermore, endotoxaemia induced the formation of nitrotyrosine and poly(ADP-ribose) synthetase (PARS) activation as determined by immunohistochemical analysis of lung and ileum tissues. The degree of staining was lowered by anthocyanin treatment. These results indicate that the anthocyanins contained in the blackberry extract exert multiple protective effects in endotoxic shock.


Production of quasi-crystal template patterns using a dual beam multiple exposure technique.
We present a dual beam multiple exposure technique that can generate complex 2-D quasi-crystal template structures. The optical system is based on the interference of two laser beams producing a family of high intensity planes. Controlled reorientation of a photosensitive sample between exposures results in an exposure dose, when developed, returns a quasi-crystal pattern. Results are shown in which quasi-crystal patterns with 8, 10, and 12-fold rotation symmetry are produced in photoresist. The results of several test runs are shown in which the quasi-crystal patterns developed in photoresist are subsequently etched into silicon. Based on an extended application of the dual beam multiple exposure optical system, a potential technique for producing 3-D quasi-crystal patterns is presented.


Effect of melatonin on maturation capacity and fertilization of Nili-Ravi buffalo (Bubalus bubalis) oocytes.
This study evaluated the effect of melatonin supplementation of in vitro maturation media on in vitro maturation (IVM) and in vitro fertilization (IVF) rate of buffalo oocytes. Cumulus oocytes complexes (COCs) were aspirated from follicles of 2-8 mm diameter. In experiment I, COCs were matured in IVM medium supplemented with 0 (control), 250, 500, and 1000 μM melatonin for 22-24 hours in CO2 incubator at 38.5°C with 5% CO2 and at 95% relative humidity. The maturation rate did not differ in media supplemented with melatonin at 250 μM, 500 μM, 1000 μM and control (0 μM). In experiment II, the matured oocytes were fertilized in 50 μl droplets of Tyrode's Albumin Lactate Pyruvate (TALP) medium having 10 ug/ml heparin for sperm (2 million/ml) capacitation. The fertilization droplets were then kept for incubation at 5% CO2, 39°C and at 95% relative humidity for 18 hours. The fertilization rate was assessed by sperm penetration and pronuclear formation. Fertilization rate was improved when maturation medium was supplemented with 250 μM melatonin compared to control. In conclusion, melatonin supplementation to serum free maturation media at 250 μM improved the fertilization rate of buffalo oocytes.


Silencing leaf sorbitol synthesis alters long-distance partitioning and apple fruit quality.
Sorbitol and sucrose are major products of photosynthesis distributed in apple trees (Malus domestica Borkh. cv. "Greensleeves") that affect quality in fruit. Transgenic apple plants were silenced or up-regulated for sorbitol-6-phosphate dehydrogenase by using the CaMV35S promoter to define the role of sorbitol distribution in fruit development. Transgenic plants with suppressed sorbitol-6-phosphate dehydrogenase compensated by accumulating sucrose and starch in leaves, and morning and midday net carbon assimilation rates were significantly lower. The sorbitol to sucrose ratio in leaves was reduced by approximately 90% and in phloem exudates by approximately 75%. The fruit accumulated more glucose and less fructose, starch, and malic acid, with no overall differences in weight and firmness. Sorbitol dehydrogenase activity was reduced in silenced fruit, but activities of neutral invertase, vacuolar invertase, cell wall-bound invertase, fructose kinase, and hexokinase were unaffected. Analyses of transcript levels and activity of enzymes involved in carbohydrate metabolism throughout fruit development revealed significant differences in pathways related to sorbitol transport and breakdown. Together, these results suggest that sorbitol distribution plays a key role in fruit carbon metabolism and affects quality attributes such as sugar-acid balance and starch accumulation.


Receptor-based antidote for diphtheria.
Although equine diphtheria antitoxin may be an effective therapy for human diphtheria, its use often induces serum sickness. We describe here a strategy for developing an alternative treatment based on the human diphtheria toxin (DT) receptor/heparin-binding epidermal growth factor-like growth factor (HB-EGF) precursor. Recombinant mature human HB-EGF acts as a soluble receptor analog, binding radioiodinated DT and preventing its binding to the cellular DT receptor/HB-EGF precursor. However, the possibility existed that radioiodinated DT-HB-EGF complexes associate with cells due to the binding of the heparin-binding domain of recombinant HB-EGF to cell surface heparan sulfate proteoglycans. This possibility was confirmed by performing DT binding studies in the presence of heparin. A recombinant truncated HB-EGF (residues 106 to 149), which lacks most of the heparin-binding domain, showed an essentially heparin-independent binding of radioiodinated DT to cells. Furthermore, it was a more effective inhibitor of DT binding than was recombinant mature HB-EGF. Since mature HB-EGF is a known ligand for the EGF receptor and is thus highly mitogenic (tumorigenic), we then changed amino acid residues in the EGF-like domain of the recombinant truncated HB-EGF and demonstrated that this DT receptor analog (I117A/L148A) displayed a low mitogenic effect. The truncated (I117A/L148A) HB-EGF protein retained high DT binding affinity, as confirmed by using surface plasmon resonance. Our results suggest that the truncated (I117A/L148A) HB-EGF protein could be an effective, safe antidote for human diphtheria.


Reinforcement selection acting on the European house mouse hybrid zone.
Behavioural isolation may lead to complete speciation when partial postzygotic isolation acts in the presence of divergent-specific mate-recognition systems. These conditions exist where Mus musculus musculus and M. m. domesticus come into contact and hybridize. We studied two mate-recognition signal systems, based on urinary and salivary proteins, across a Central European portion of the mouse hybrid zone. Introgression of the genomic regions responsible for these signals: the major urinary proteins (MUPs) and androgen binding proteins (ABPs), respectively, was compared to introgression at loci assumed to be nearly neutral and those under selection against hybridization. The preference of individuals taken from across the zone regarding these signals was measured in Y mazes, and we develop a model for the analysis of the transition of such traits under reinforcement selection. The strongest assortative preferences were found in males for urine and females for ABP. Clinal analyses confirm nearly neutral introgression of an Abp locus and two loci closely linked to the Abp gene cluster, whereas two markers flanking the Mup gene region reveal unexpected introgression. Geographic change in the preference traits matches our reinforcement selection model significantly better than standard cline models. Our study confirms that behavioural barriers are important components of reproductive isolation between the house mouse subspecies.


Context-sensitive trace inlining for Java.
Method inlining is one of the most important optimizations in method-based just-in-time (JIT) compilers. It widens the compilation scope and therefore allows optimizing multiple methods as a whole, which increases the performance. However, if method inlining is used too frequently, the compilation time increases and too much machine code is generated. This has negative effects on the performance. Trace-based JIT compilers only compile frequently executed paths, so-called traces, instead of whole methods. This may result in faster compilation, less generated machine code, and better optimized machine code. In the previous work, we implemented a trace recording infrastructure and a trace-based compiler for [Formula: see text], by modifying the Java HotSpot VM. Based on this work, we evaluate the effect of trace inlining on the performance and the amount of generated machine code. Trace inlining has several major advantages when compared to method inlining. First, trace inlining is more selective than method inlining, because only frequently executed paths are inlined. Second, the recorded traces may capture information about virtual calls, which simplify inlining. A third advantage is that trace information is context sensitive so that different method parts can be inlined depending on the specific call site. These advantages allow more aggressive inlining while the amount of generated machine code is still reasonable. We evaluate several inlining heuristics on the benchmark suites DaCapo 9.12 Bach, SPECjbb2005, and SPECjvm2008 and show that our trace-based compiler achieves an up to 51% higher peak performance than the method-based Java HotSpot client compiler. Furthermore, we show that the large compilation scope of our trace-based compiler has a positive effect on other compiler optimizations such as constant folding or null check elimination.


Personalized diagnostics and biosensors: a review of the biology and technology needed for personalized medicine.
Exploiting the burgeoning fields of genomics, proteomics and metabolomics improves understanding of human physiology and, critically, the mutations that signal disease susceptibility. Through these emerging fields, rational design approaches to diagnosis, drug development and ultimately personalized medicine are possible. Personalized medicine and point-of-care testing techniques must fulfill a host of constraints for real-world applicability. Point-of-care devices (POCDs) must ultimately provide a cost-effective alternative to expensive and time-consuming laboratory tests in order to assist health care personnel with disease diagnosis and treatment decisions. Sensor technologies are also expanding beyond the more traditional classes of biomarkers--nucleic acids and proteins--to metabolites and direct detection of pathogens, ultimately increasing the palette of available techniques for the use of personalized medicine. The technologies needed to perform such diagnostics have also been rapidly evolving, with each generation being increasingly sensitive and selective while being more resource conscious. Ultimately, the final hurdle for all such technologies is to be able to drive consumer adoption and achieve a meaningful medical outcome for the patient.


ALVIS: interactive non-aggregative visualization and explorative analysis of multiple sequence alignments.
Sequence Logos and its variants are the most commonly used method for visualization of multiple sequence alignments (MSAs) and sequence motifs. They provide consensus-based summaries of the sequences in the alignment. Consequently, individual sequences cannot be identified in the visualization and covariant sites are not easily discernible. We recently proposed Sequence Bundles, a motif visualization technique that maintains a one-to-one relationship between sequences and their graphical representation and visualizes covariant sites. We here present Alvis, an open-source platform for the joint explorative analysis of MSAs and phylogenetic trees, employing Sequence Bundles as its main visualization method. Alvis combines the power of the visualization method with an interactive toolkit allowing detection of covariant sites, annotation of trees with synapomorphies and homoplasies, and motif detection. It also offers numerical analysis functionality, such as dimension reduction and classification. Alvis is user-friendly, highly customizable and can export results in publication-quality figures. It is available as a full-featured standalone version (http://www.bitbucket.org/rfs/alvis) and its Sequence Bundles visualization module is further available as a web application (http://science-practice.com/projects/sequence-bundles).


beta-Glucan Synthetases of Plasma Membrane and Golgi Apparatus from Onion Stem.
Biosynthesis of glucans occurred in cell-free fractions isolated from onion stem (Allium cepa L.) enriched in either dictyosomes or plasma membranes. beta-1,3- and beta-1, 4-Glucans were synthesized in differing proportions and at different rates as the concentration of uridine diphosphoglucose or the proportion of dictyosomes or plasma membrane varied. At low (1.5 mum) UDP-glucose concentrations synthesis of alkali-insoluble glucan was correlated with abundance of dicytosomes; most of the substrate utilized by plasma membrane was for glycolipid synthesis. At high (1 mm) UDP-glucose concentration, the synthesis of alkali-insoluble glucans correlated with the abundance of plasma membrane. Substrate enhancement of beta-1, 4-glucan synthesis in dictyosome fractions was less than proportional to increases in substrate concentration. In contrast, beta-1, 4-glucan synthesis by plasma membrane was more than proportionately increased. At high substrate concentrations the synthesis of beta-1, 3-glucans predominated in both dictyosome and plasma membrane fractions. The results show that the capacity to synthesize glucans resides in both Golgi apparatus and plasma membranes of onion stem, but that the plasma membrane has the greatest capacity for synthesis of alkali-insoluble glucans at high UDP-glucose concentrations.


Biologically active two-dimensional crystals of aquaporin CHIP.
Plasma membranes of several mammalian tissues are highly permeable to water due to the presence of CHIP, the 28-kDa channel-forming integral protein which is the archetypal member of the aquaporin family of water channel proteins. To define its native structure, purified red cell CHIP protein was reconstituted into lipid bilayers at a high protein-to-lipid ratio, and the resulting 3-microns diameter membrane vesicles were examined by high resolution electron microscopy. The reconstituted membranes contained highly ordered two-dimensional crystalline lattices of p422(1) symmetry in which each CHIP tetramer contained a central depression extending from the outer and inner surfaces of the membrane into the transbilayer domain of the molecule. The reconstituted membranes also exhibited extremely high osmotic water permeability, Pf = 0.472 cm/s, corresponding to the sum of activities of all incorporated CHIP molecules. These studies report the first two-dimensional crystallization of a biologically active water channel and provide direct evidence of the structure responsible for its pore-like behavior.


Assessing the threat to montane biodiversity from discordant shifts in temperature and precipitation in a changing climate.
Mountains are centres of global biodiversity, endemism and threatened species. Elevational gradients present opportunities for species currently living near their upper thermal limits to track cooler temperatures upslope in warming climates, but only if changes in precipitation are sufficiently in step with temperature. We model local population extirpation risk for a range of temperature and precipitation scenarios over the next 100 years for 16 848 vertebrate species populations distributed along 156 elevational gradients. Average population extirpation risks due to warming alone were < 5%, but increased 10-fold, on average, when changes in precipitation were also considered. Under the driest scenarios (minimum predicted precipitation), local extirpation risks increased sharply (50-60%) and were especially worrisome for hydrophilic amphibians and montane Latin America (c. 80%). Realistic assessment of risks urgently requires improved monitoring of precipitation, better regional precipitation models and more research on the effects of changes in precipitation on montane distributions.