Artificial Neural Network Analysis of Pharmacokinetic and Toxicity Properties of Lead Molecules for Dengue Fever, Tuberculosis and Malaria.
Poor pharmacokinetic and toxicity profiles are major reasons for the low rate of advancing lead drug candidates into efficacy studies. The In-silico prediction of primary pharmacokinetic and toxicity properties in the drug discovery and development process can be used as guidance in the design of candidates. In-silico parameters can also be used to choose suitable compounds for in-vivo testing thereby reducing the number of animals used in experiments. At the Novartis Institute for Tropical Diseases, a data set has been curated from in-house measurements in the disease areas of Dengue, Tuberculosis and Malaria. Volume of distribution, half-life, total in-vivo clearance, in-vitro human plasma protein binding and in-vivo oral bioavailability have been measured for molecules in the lead optimization stage in each of these three disease areas. Data for the inhibition of the hERG channel using the radio ligand binding dofetilide assay was determined for a set of 300 molecules in these therapeutic areas. Based on this data, Artificial Neural Networks were used to construct In-silico models for each of the properties listed above that can be used to prioritize candidates for lead optimization and to assist in selecting promising molecules for in-vivo pharmacokinetic studies.


Validation of quality of life questionnaire for patients with cancer--Indian scenario.
Quality of Life (QOL) is an important health outcome measure in oncology. Given the underlying pressure of individual geo-political entities, a universal solution may not be applicable and hence there is a need to develop a regional tool and standardize the same to address the linguistic and socio-cultural factors. To standardize a tool to assess the QOL of patients with cancer to suit the Indian scenario. The samples were collected from the Cancer Institute (WIA), Chennai. Samples comprise of 400 patients with all sites and stages of cancer. January 2001 to January 2002. Patients were in the age range of 41-60 years. Thirty-eight items were pooled from existing tools, reviews, and the field trial, by which face and factorial validity were established. Reliability of the tool was also tested. Correlation analysis was done to find out the relation between the domains of QOL. STATISTICS USED: Principal component method with varimax rotation was used. Spearmen product moment correlation and Cronbach alpha coefficient were used for reliability analysis. Ten factors emerged with Eigen values ranging from 8.55 to 1.10 and accounted for 62.6% of variance. The first factor contributed maximally, 22% of variance. The remaining nine factors contributed totally to 40% of the variance on QOL. The ten factors that emerged were psychological well being, self-adequacy, physical well being, confidence in self-ability, external support, pain, mobility, optimism and belief, interpersonal relationship and self-sufficiency and independence. The internal consistency using Cronbach alpha test was 0.90 and split-half reliability was 0.74. The tool was found to be highly reliable and valid. It was feasible to administer it at clinical settings.


Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. An overview of 61 randomized trials among 28,896 women.
We sought information worldwide on mortality according to assigned treatment in all randomized trials that began before 1985 of adjuvant tamoxifen or cytotoxic therapy for early breast cancer (with or without regional lymph-node involvement). Coverage was reasonably complete for most countries. In 28 trials of tamoxifen nearly 4000 of 16,513 women had died, and in 40 chemotherapy trials slightly more than 4000 of 13,442 women had died. The 8106 deaths were approximately evenly distributed over years 1, 2, 3, 4, and 5+ of follow-up, with little useful information beyond year 5. Systematic overviews of the results of these trials demonstrated reductions in mortality due to treatment that were significant when tamoxifen was compared with no tamoxifen (P less than 0.0001), any chemotherapy with no chemotherapy (P = 0.003), and polychemotherapy with single-agent chemotherapy (P = 0.001). In tamoxifen trials, there was a clear reduction in mortality only among women 50 or older, for whom assignment to tamoxifen reduced the annual odds of death during the first five years by about one fifth. In chemotherapy trials there was a clear reduction only among women under 50, for whom assignment to polychemotherapy reduced the annual odds of death during the first five years by about one quarter. Direct comparisons showed that combination chemotherapy was significantly more effective than single-agent therapy, but suggested that administration of chemotherapy for 8 to 24 months may offer no survival advantage over administration of the same chemotherapy for 4 to 6 months. Because it involved several thousand women, this overview was able to demonstrate particularly clearly that both tamoxifen and cytotoxic therapy can reduce five-year mortality.


Tissue inhibitors of metalloproteinases: evolution, structure and function.
The matrix metalloproteinases (MMPs) play a key role in the normal physiology of connective tissue during development, morphogenesis and wound healing, but their unregulated activity has been implicated in numerous disease processes including arthritis, tumor cell metastasis and atherosclerosis. An important mechanism for the regulation of the activity of MMPs is via binding to a family of homologous proteins referred to as the tissue inhibitors of metalloproteinases (TIMP-1 to TIMP-4). The two-domain TIMPs are of relatively small size, yet have been found to exhibit several biochemical and physiological/biological functions, including inhibition of active MMPs, proMMP activation, cell growth promotion, matrix binding, inhibition of angiogenesis and the induction of apoptosis. Mutations in TIMP-3 are the cause of Sorsby's fundus dystrophy in humans, a disease that results in early onset macular degeneration. This review highlights the evolution of TIMPs, the recently elucidated high-resolution structures of TIMPs and their complexes with metalloproteinases, and the results of mutational and other studies of structure-function relationships that have enhanced our understanding of the mechanism and specificity of the inhibition of MMPs by TIMPs. Several intriguing questions, such as the basis of the multiple biological functions of TIMPs, the kinetics of TIMP-MMP interactions and the differences in binding in some TIMP-metalloproteinase pairs are discussed which, though not fully resolved, serve to illustrate the kind of issues that are important for a full understanding of the interactions between families of molecules.


Hopping hotspots: global shifts in marine biodiversity.
Hotspots of high species diversity are a prominent feature of modern global biodiversity patterns. Fossil and molecular evidence is starting to reveal the history of these hotspots. There have been at least three marine biodiversity hotspots during the past 50 million years. They have moved across almost half the globe, with their timing and locations coinciding with major tectonic events. The birth and death of successive hotspots highlights the link between environmental change and biodiversity patterns. The antiquity of the taxa in the modern Indo-Australian Archipelago hotspot emphasizes the role of pre-Pleistocene events in shaping modern diversity patterns.


Effect of treatment with geraniol on ovalbumin-induced allergic asthma in mice.
Asthma, a complex highly prevalent airway disease, is a major public health problem for which current treatment options are inadequate. To evaluate the antiasthma activity of geraniol and investigate its underlying molecular mechanisms. In a standard experimental asthma model, Balb/c mice were sensitized with ovalbumin, treated with geraniol (100 or 200 mg/kg) or a vehicle control, during ovalbumin challenge. Treatment of ovalbumin-sensitized/challenged mice with geraniol significantly decreased airway hyperresponsiveness to inhaled methacholine. Geraniol treatment reduced eotaxin levels in bronchoalveolar lavage fluid and attenuated infiltration of eosinophils induced by ovalbumin. Geraniol treatment reduced TH2 cytokines (including interleukins 4, 5, and 13), increased TH1 cytokine interferon γ in bronchoalveolar lavage fluid, and reduced ovalbumin-specific IgE in serum. In addition, treatment of ovalbumin-sensitized/challenged mice with geraniol enhanced T-bet (TH1 response) messenger RNA expression and reduced GATA-3 (TH2 response) messenger RNA expression in lungs. Furthermore, treatment of ovalbumin -sensitized/challenged mice with geraniol further enhanced Nrf2 protein expression and activated Nrf2-directed antioxidant pathways, such as glutamate-cysteine ligase, superoxide dismutase, and glutathione S-transferase, and enhanced formation of reduced glutathione and reduced formation of malondialdehyde in lungs. Geraniol attenuated important features of allergic asthma in mice, possibly through the modulation of TH1/TH2 balance and activation the of Nrf2/antioxidant response element pathway.


Cattle density and Shiga toxin-producing Escherichia coli infection in Germany: increased risk for most but not all serogroups.
Shiga toxin-producing Escherichia coli (STEC) cause severe gastroenteritis and life-threatening hemolytic-uremic syndrome. For STEC of serogroup O157, association between disease incidence and cattle contact has been established in some countries. For other (non-O157) serogroups, however, accounting for approximately 80% of notified STEC gastroenteritis in Germany, the role of cattle in human infection is less clear. For example, an association of non-O157 STEC infection and cattle density has not been investigated. The aim of this study was thus to investigate a potential association between STEC incidence and cattle density in Germany, with special attention to the non-O157 serogroups. We modeled district-level incidence of notified human STEC cases in relation to cattle density, utilizing German notification data from 2001 through 2003. Cattle numbers came from the national "Proof of Origin and Information Database for Animals." A Bayesian Poisson regression model was used, incorporating independent, as well as spatially correlated, district-level random effects into the analysis. We analyzed 3216 German STEC cases. Cattle density was positively associated with overall STEC incidence. The risk for STEC infection increased by 68% per 100 additional cattle/km(2). The magnitude of the risk estimates differed by serogroup and was greatest for O111. A positive association was found for all major disease-causing serogroups (O26, O103, O111, O128, O145, O157) except O91. The association with serogroup O26 (lowest median age of patients) was only borderline significant. Residual variation indicates that additional factors not under study may also be of importance, and that they may be serogroup- and region-specific, too. In conclusion, this study suggests that living in a cattle-raising region appears to imply risk not only for STEC O157, but also for most non-O157 serogroups. Furthermore, the varying magnitude of this risk and the residual variation found for different serogroups indicate that risk profiles for human STEC infection may be serogroup-specific. This needs to be taken into account in risk factor studies for non-O157 STEC, ideally by reporting risks separately by serogroup.


Diagnostic accuracy of the Xpert CT/NG and OSOM Trichomonas Rapid assays for point-of-care STI testing among young women in South Africa: a cross-sectional study.
Syndromic management of sexually transmitted infections (STIs) omits asymptomatic infections, particularly among women. Accurate point-of-care assays may improve STI care in low- and middle-income countries (LMICs). We aimed to evaluate the diagnostic performance of the Xpert Chlamydia trachomatis/Neisseria gonorrhoeae (CT/NG) and OSOM Trichomonas vaginalis (TV) Test as part of a STI care model for young women in South Africa. Diagnostic evaluation conducted as part of a prospective cohort study (CAPRISA 083) between May 2016 and January 2017. One large public healthcare facility in central Durban, KwaZulu-Natal, South Africa PARTICIPANTS: 247 women, aged 18-40 years, attending for sexual and reproductive services to the clinic. Pregnant and HIV-positive women were excluded. Diagnostic performance of the Xpert CT/NG and OSOM TV assays against the laboratory-based Anyplex II STI-7 Detection. All discordant results were further tested on the Fast Track Diagnostics (FTD) STD9 assay. We obtained vaginal swabs from 247 women and found 96.8% (239/247) concordance between Xpert and Anyplex for CT and 100% (247/247) for NG. All eight discrepant CT results were positive on Xpert, but negative on Anyplex. FTD STD9 confirmed three positive and five negative results, giving a confirmed prevalence of CT 15.0% (95% CI 10.5 to 19.4), NG 4.9% (2.2-7.5) and TV 3.2% (1.0-5.4). Sensitivity and specificity of Xpert CT/NG were 100% (100-100) and 97.6% (95.6-99.7) for CT and 100% (100-100) and 100% (100-100) for NG. The sensitivity and specificity of OSOM TV were 75.0% (45.0-100) and 100% (100-100). The Xpert CT/NG showed high accuracy among young South African women and combined with the OSOM TV proved a useful tool in this high HIV/STI burden setting. Further implementation and cost-effectiveness studies are needed to assess the potential role of this assay for diagnostic STI testing in LMICs. NCT03407586; Pre-results.


Climate change and the permafrost carbon feedback.
Large quantities of organic carbon are stored in frozen soils (permafrost) within Arctic and sub-Arctic regions. A warming climate can induce environmental changes that accelerate the microbial breakdown of organic carbon and the release of the greenhouse gases carbon dioxide and methane. This feedback can accelerate climate change, but the magnitude and timing of greenhouse gas emission from these regions and their impact on climate change remain uncertain. Here we find that current evidence suggests a gradual and prolonged release of greenhouse gas emissions in a warming climate and present a research strategy with which to target poorly understood aspects of permafrost carbon dynamics.


Photoelectrochemical bioanalysis: the state of the art.
The evolution of photoelectrochemical (PEC) bioanalysis has resulted in substantial progress in its analytical performance and biodetection applications. The aim of this review is to provide a panoramic snapshot of the state of the art in this dynamically developing field, with special emphasis on PEC DNA analysis, immunoassay, enzymatic biosensing and cell-related detection. The future prospects in this area are also evaluated and discussed. This work will serve as a useful source to inform the interested audience of the latest developments and applications in the field of PEC bioanalysis.


Polychromatic solitons and symmetry breaking in curved waveguide arrays.
We theoretically and experimentally study the nonlinear propagation of polychromatic light in curved waveguide arrays. We show that at moderate light powers the nonlinear self-action breaks the left-right symmetry of the polychromatic beam, resulting in the separation of different spectral components owing to the wavelength-dependent spatial shift. At high light powers a diffraction-managed polychromatic soliton is formed. These results demonstrate new possibilities for tunable demultiplexing and spatial filtering of supercontinuum light.


A gene expression signature from peripheral whole blood for stage I lung adenocarcinoma.
Affordable early screening in subjects with high risk of lung cancer has great potential to improve survival from this deadly disease. We measured gene expression from lung tissue and peripheral whole blood (PWB) from adenocarcinoma cases and controls to identify dysregulated lung cancer genes that could be tested in blood to improve identification of at-risk patients in the future. Genome-wide mRNA expression analysis was conducted in 153 subjects (73 adenocarcinoma cases, 80 controls) from the Environment And Genetics in Lung cancer Etiology study using PWB and paired snap-frozen tumor and noninvolved lung tissue samples. Analyses were conducted using unpaired t tests, linear mixed effects, and ANOVA models. The area under the receiver operating characteristic curve (AUC) was computed to assess the predictive accuracy of the identified biomarkers. We identified 50 dysregulated genes in stage I adenocarcinoma versus control PWB samples (false discovery rate ≤0.1, fold change ≥1.5 or ≤0.66). Among them, eight (TGFBR3, RUNX3, TRGC2, TRGV9, TARP, ACP1, VCAN, and TSTA3) differentiated paired tumor versus noninvolved lung tissue samples in stage I cases, suggesting a similar pattern of lung cancer-related changes in PWB and lung tissue. These results were confirmed in two independent gene expression analyses in a blood-based case-control study (n = 212) and a tumor-nontumor paired tissue study (n = 54). The eight genes discriminated patients with lung cancer from healthy controls with high accuracy (AUC = 0.81, 95% CI = 0.74-0.87). Our finding suggests the use of gene expression from PWB for the identification of early detection markers of lung cancer in the future.


Interpretation of Multivariate Association Patterns between Multicollinear Physical Activity Accelerometry Data and Cardiometabolic Health in Children-A Tutorial.
Associations between multicollinear accelerometry-derived physical activity (PA) data and cardiometabolic health in children needs to be analyzed using an approach that can handle collinearity among the explanatory variables. The aim of this paper is to provide readers a tutorial overview of interpretation of multivariate pattern analysis models using PA accelerometry data that reveals the associations to cardiometabolic health. A total of 841 children (age 10.2 ± 0.3 years) provided valid data on accelerometry (ActiGraph GT3X+) and six indices of cardiometabolic health that were used to create a composite score. We used a high-resolution PA description including 23 intensity variables covering the intensity spectrum (from 0-99 to ≥10000 counts per minute), and multivariate pattern analysis to analyze data. We report different statistical measures of the multivariate associations between PA and cardiometabolic health and use decentile groups of PA as a basis for discussing the meaning and impact of multicollinearity. We show that for high-resolution accelerometry data; considering all explanatory variables is crucial to obtain a correct interpretation of associations to cardiometabolic health; which is otherwise strongly confounded by multicollinearity in the dataset. Thus; multivariate pattern analysis challenges the traditional interpretation of findings from linear regression models assuming independent explanatory variables.


Identification of mutations that cause cell migration defects in mosaic clones.
Cell movement is an important feature of animal development, wound healing and tumor metastasis; however, the mechanisms underlying cell motility remain to be elucidated. To further our understanding, it would be useful to identify all of the proteins that are essential for a cell to migrate, yet such information is not currently available for any cell type. We have carried out a screen for mutations affecting border cell migration in Drosophila. Mutations that cause defects in mosaic clones were identified, so that genes that are also required for viability could be detected. From 6000 mutagenized lines, 20 mutations on chromosome 2R were isolated that cause defects in border cell position. One of the mutations was dominant while all of the recessive mutations appeared to be homozygous lethal. This lethality was used to place the mutations into 16 complementation groups. Many of the mutations failed to complement cytologically characterized deficiencies, allowing their rapid mapping. Mutations in three loci altered expression of a marker gene in the border cells, whereas the remaining mutations did not. One mutation, which caused production of supernumerary border cells, was found to disrupt the costal-2 locus, indicating a role for Hedgehog signaling in border cell development. This screen identified many new loci required for border cell migration and our results suggest that this is a useful approach for elucidating the mechanisms involved in cell motility.


Corticotropin-releasing factor receptor 1 in mouse spleen: expression after immune stimulation and identification of receptor-bearing cells.
A specific polyclonal Ab against the N-terminal domain of corticotropin-releasing factor (CRF) receptor, type 1 (CRF-R1), was employed to an immunohistochemical analysis of the spleen from naive mice and mice exposed to an immune challenge. Cell types stained with anti-CRF-R1 Ab were identified by their nuclear shapes and colocalization with the cell type-specific markers ER-MP58, ER-MP20, Moma-1, Moma 2, anti-CD3e mAbs, and anti-Ig Ab. Only a few clusters of CRF-R1+ cells were found in spleen sections of naive mice at sites typical for granulopoietic islands. However, a 17-fold increase in the mean number of CRF-R1+ cells was noted within hours following a challenge of acute systemic inflammation induced by i.p. administration of LPS. The majority of these cells were identified as mature neutrophils. CRF-R1 was shown to mediate suppression of the IL-1beta secretion by these cells. However, at later time points a large number of granulocyte-macrophage precursors was strongly labeled with anti-CRF-R1 Ab. Western blot analysis of splenic membranes from animals treated with LPS revealed a m.w. of approximately 70,000 for CRF-R1. Subcellular staining patterns were suggestive for the predominant localization of CRF-R1 on granule membranes. CRF-R1 mRNA was detected in spleen but not in bone marrow and peripheral blood leukocytes from naive mice. Thus, it was indicated that CRF-R1 was not produced constitutively by mature or immature neutrophils. Its production was rather triggered by inflammatory stimuli.


Monophosphoryl lipid A induces protection against LPS in medullary thick ascending limb through induction of Tollip and negative regulation of IRAK-1.
LPS inhibits HCO3- absorption in the medullary thick ascending limb (MTAL) through a Toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-extracellular signal-regulated kinase (ERK) pathway that is upregulated by sepsis. Pretreatment with the nontoxic immunomodulator monophosphoryl lipid A (MPLA) prevents inhibition by LPS through activation of a TLR4-TIR-domain-containing adaptor-inducing interferon-β (TRIF)-phosphatidylinositol 3-kinase (PI3K) pathway that prevents LPS-induced ERK activation. Here, we identified the molecular mechanisms that underlie the protective inhibitory interaction between the MPLA-PI3K and LPS-ERK pathways. Treatment of mouse MTALs with LPS in vitro increased phosphorylation of IL-1 receptor-associated kinase (IRAK)-1, a critical mediator of LPS signaling downstream of TLR4-MyD88. Activation of ERK by LPS was eliminated by a selective IRAK-1 inhibitor, establishing IRAK-1 as the upstream mediator of ERK activation. Pretreatment of MTALs with MPLA in vitro prevented LPS-induced IRAK-1 activation; this effect was dependent on PI3K. Treatment of MTALs with MPLA increased expression of Toll-interacting protein (Tollip), an inducible protein that negatively regulates LPS signaling by inhibiting IRAK-1. The MPLA-induced increase in Tollip protein level was prevented by PI3K inhibitors. In coimmunoprecipitation experiments, MPLA increased the amount of Tollip stably bound to IRAK-1, an interaction that inhibits IRAK-1 activation. These results support a mechanism whereby MPLA increases Tollip expression in the MTAL through a PI3K-dependent pathway. Tollip, in turn, inhibits LPS-induced TLR4 signaling by suppressing activation of IRAK-1, thereby preventing activation of ERK that inhibits HCO3- absorption. These studies show that MPLA induces reprogramming of MTAL cells that protects against LPS stimulation and identify IRAK-1 and Tollip as new therapeutic targets to prevent renal tubule dysfunction in response to infectious and inflammatory stimuli.


Consumption of a high β-glucan barley flour improves glucose control and fatty liver and increases muscle acylcarnitines in the Zucker diabetic fatty rat.
The soluble fiber β-glucan, a natural component of barley, has been shown to lower the postprandial glucose response and is thought to improve insulin resistance. This study examined the effect of chronic consumption of the high β-glucan barley flour on glucose control, liver lipids and markers of muscle fatty acid oxidation in the Zucker diabetic fatty (ZDF) rat. Two groups of ZDF rats were fed diets containing either 6% β-glucan in the form of barley flour or cellulose as a control for 6 weeks. A group of Zucker lean rats served as a negative control. The barley flour group had an increased small intestinal contents viscosity compared to the obese control group. After 6 weeks, the barley flour group had reduced glycated hemoglobin, lower relative kidney weights and a reduced area under the curve during a glucose tolerance test, indicating improved glucose control. Fasting plasma adiponectin levels increased in the barley flour group and were not different than the lean control group. ZDF rats on the barley flour diet had lower relative epididymal fat pad weights than the obese control and a greater food efficiency ratio. The barley flour group also had reduced liver weights and a decreased concentration of liver lipids. The barley flour group had significantly higher concentrations of muscle acylcarnitines, a metabolite generated during fatty acid oxidation. These results show that chronic consumption of β-glucans can improve glucose control and decrease fatty liver in a model of diabetes with obesity.


Chemical Probes for Understudied Kinases: Challenges and Opportunities.
Over 20 years after the approval of the first-in-class protein kinase inhibitor imatinib, the biological function of a significant fraction of the human kinome remains poorly understood while most research continues to be focused on few well-validated targets. Given the strong genetic evidence for involvement of many kinases in health and disease, the understudied fraction of the kinome holds a large and unexplored potential for future therapies. Specific chemical probes are indispensable tools to interrogate biology enabling proper preclinical validation of novel kinase targets. In this Perspective, we highlight recent case studies illustrating the development of high-quality chemical probes for less-studied kinases and their application in target validation. We spotlight emerging techniques and approaches employed in the generation of chemical probes for protein kinases and beyond and discuss the associated challenges and opportunities.


Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States.
Newborn screening for severe combined immunodeficiency (SCID) using assays to detect T-cell receptor excision circles (TRECs) began in Wisconsin in 2008, and SCID was added to the national recommended uniform panel for newborn screened disorders in 2010. Currently 23 states, the District of Columbia, and the Navajo Nation conduct population-wide newborn screening for SCID. The incidence of SCID is estimated at 1 in 100,000 births. To present data from a spectrum of SCID newborn screening programs, establish population-based incidence for SCID and other conditions with T-cell lymphopenia, and document early institution of effective treatments. Epidemiological and retrospective observational study. Representatives in states conducting SCID newborn screening were invited to submit their SCID screening algorithms, test performance data, and deidentified clinical and laboratory information regarding infants screened and cases with nonnormal results. Infants born from the start of each participating program from January 2008 through the most recent evaluable date prior to July 2013 were included. Representatives from 10 states plus the Navajo Area Indian Health Service contributed data from 3,030,083 newborns screened with a TREC test. Infants with SCID and other diagnoses of T-cell lymphopenia were classified. Incidence and, where possible, etiologies were determined. Interventions and survival were tracked. Screening detected 52 cases of typical SCID, leaky SCID, and Omenn syndrome, affecting 1 in 58,000 infants (95% CI, 1/46,000-1/80,000). Survival of SCID-affected infants through their diagnosis and immune reconstitution was 87% (45/52), 92% (45/49) for infants who received transplantation, enzyme replacement, and/or gene therapy. Additional interventions for SCID and non-SCID T-cell lymphopenia included immunoglobulin infusions, preventive antibiotics, and avoidance of live vaccines. Variations in definitions and follow-up practices influenced the rates of detection of non-SCID T-cell lymphopenia. Newborn screening in 11 programs in the United States identified SCID in 1 in 58,000 infants, with high survival. The usefulness of detection of non-SCID T-cell lymphopenias by the same screening remains to be determined.


Association Between Socio-Demographic and Health Functioning Variables Among Patients with Opioid Use Disorder Introduced by Prescription: A Prospective Cohort Study.
Prescription opioid misuse in Canada has become a serious public health concern and has contributed to Canada's opioid crisis. There are thousands of Canadians who are currently receiving treatment for opioid use disorder, which is a chronic relapsing disorder with enormous impact on individuals and society. The aim of this study was to compare the clinical and demographic differences between cohorts of patients who were introduced to opioids through a prescription and those introduced to opioids for non-medical purposes. This was an observational, prospective cohort study. The study took place in 19 Canadian Addiction Treatment Centres across Ontario. We included a total of 976 participants who were diagnosed with Opioid Use Disorder and currently receiving methadone maintenance treatment. We excluded participants who were on any other type of prescription opioid or who were missing their 6-month follow-up urine screens. We measured the participants' initial source of introduction to opioids along with other variables using the Maudsley Addiction Profile. We also measured illicit opioid use using urine screens at baseline and at 6-months follow-up. Almost half the sample (n = 469) were initiated to opioids via prescription. Women were more likely to be initiated to opioids via a prescription (OR = 1.385, 95% CI 1.027-1.866, P = .033). Those initiated via prescription were also more likely to have post-secondary education, older age of onset of opioid use, less likely to have hepatitis C and less likely to have use cannabis. Chronic pain was significantly associated with initiation to opioids through prescription (OR = 2.720, 95% CI 1.998-3.722, P < .0001). Analyses by gender revealed that men initiated by prescription were less likely to have liver disease and less likely to use cannabis, while women initiated by prescription had a higher methadone dose. This project was limited by its study design being observational in nature; no causal relationships can be inferred. Also, the data did not allow determination of the role that the prescribed opioids played in developing opioid use disorder. Our results have revealed that almost half of this methadone maintenance treatment (MMT) population has been introduced to opioids through a prescription. Given that the increasing prescribing rates of opioids has an impact on this at-risk population, alternative treatments for pain should be considered to help decrease this opioid epidemic in Canada. Opioid use disorder, chronic pain relief, methadone maintenance treatment, prescriptions, male, female.


The effects of transcription factor competition on gene regulation.
Transcription factor (TF) molecules translocate by facilitated diffusion (a combination of 3D diffusion around and 1D random walk on the DNA). Despite the attention this mechanism received in the last 40 years, only a few studies investigated the influence of the cellular environment on the facilitated diffusion mechanism and, in particular, the influence of "other" DNA binding proteins competing with the TF molecules for DNA space. Molecular crowding on the DNA is likely to influence the association rate of TFs to their target site and the steady state occupancy of those sites, but it is still not clear how it influences the search in a genome-wide context, when the model includes biologically relevant parameters (such as: TF abundance, TF affinity for DNA and TF dynamics on the DNA). We performed stochastic simulations of TFs performing the facilitated diffusion mechanism, and considered various abundances of cognate and non-cognate TFs. We show that, for both obstacles that move on the DNA and obstacles that are fixed on the DNA, changes in search time are not statistically significant in case of biologically relevant crowding levels on the DNA. In the case of non-cognate proteins that slide on the DNA, molecular crowding on the DNA always leads to statistically significant lower levels of occupancy, which may confer a general mechanism to control gene activity levels globally. When the "other" molecules are immobile on the DNA, we found a completely different behavior, namely: the occupancy of the target site is always increased by higher molecular crowding on the DNA. Finally, we show that crowding on the DNA may increase transcriptional noise through increased variability of the occupancy time of the target sites.


Biodistribution and metabolism of the anti-influenza drug [11C]oseltamivir and its active metabolite [11C]Ro 64-0802 in mice.
Oseltamivir phosphate (Tamiflu) is an orally active anti-influenza drug, which is hydrolyzed by esterase to its carboxylate metabolite Ro 64-0802 with potent activity to inhibit the influenza virus. The abnormal behavior and death associated with the use of oseltamivir have developed into a major problem in Japan where Tamiflu is often prescribed for seasonal influenza. It is critical to determine the amount of oseltamivir and Ro 64-0802 in the human brain and to elucidate the relationship between their amounts and neuropsychiatric side effects. The aim of this study was to evaluate [(11)C]oseltamivir and [(11)C]Ro 64-0802 in mice as promising positron emission tomography (PET) ligands for measuring their amounts in living brains. Whole-body biodistribution of [(11)C]oseltamivir and [(11)C]Ro 64-0802 was determined in mice using the dissection method and micro-PET. In vitro and in vivo metabolite assay was performed in the plasma and brain of mice. Between 1 and 60 min after injection of [(11)C]oseltamivir and [(11)C]Ro 64-0802, 0.20-0.06% and 0.39-0.03% ID/g were detected in the mouse brains, respectively (dissection method). Radioactivity concentrations in the living brains between 0 and 90 min after injection were measured at standardized uptake values of 0.25-0.05 for [(11)C]oseltamivir and 0.38-0.02 for [(11)C]Ro 64-0802 (micro-PET). In vivo metabolite assay demonstrated the presence of [(11)C]oseltamivir and [(11)C]Ro 64-0802 in the brains after [(11)C]oseltamivir injection. This study determined the distribution and metabolism of [(11)C]oseltamivir and [(11)C]Ro 64-0802 in mice. PET could be used to measure their amounts in the living brain and to elucidate the relationship between the amounts in the brain and the side effects of Tamiflu in the central nervous system.


First Record of Colletotrichum anthrisci Causing Anthracnose on Avocado Fruits in Chile.
Anthracnose caused by Colletotrichum species is one of the most frequent and damaging fungal diseases affecting avocado fruits (Persea americana Mill.) worldwide. In Chile, the disease incidence has increased over the last decades due to the establishment of commercial groves in more humid areas. Since 2018, unusual symptoms of anthracnose have been observed on Hass avocado fruits, with lesions developing a white to gray sporulation. Morphological features and multi-locus phylogenetic analyses using six DNA barcodes (act, chs-1, gapdh, his3, ITS, and tub2) allowed the identification of the causal agent as Colletotrichum anthrisci, a member of the dematium species complex. Pathogenicity was confirmed by inoculating healthy Hass avocado fruits with representative isolates, reproducing the same symptoms initially observed, and successfully reisolating the same isolates from the margin of the necrotic pulp. Previously, several Colletotrichum species belonging to other species complexes have been associated with avocado anthracnose in other countries. To our knowledge, this is the first record of C. anthrisci and of a species of the dematium species complex causing anthracnose on avocado fruits in Chile and worldwide.


Unmanaged care: towards moral fairness in health care coverage.
Health insurers are generally guided by the principle of "actuarial fairness," according to which they distinguish among various risks on the basis of cost-related factors. Thus, insurers often limit or deny coverage for vision care, hearing aids, mental health care, and even AIDS treatment based on actuarial justifications. Furthermore, approximately forty-two million Americans have no health insurance at all, because most of these individuals cannot afford the cost of insurance. This Article argues that Americans have come to demand more than actuarial fairness from health insurers and are increasingly concerned by what I call "moral fairness." This is evidenced by the hundreds of laws that have been passed to constrain insurers' discretion with respect to particular coverage decisions. Legislative mandates are frequent, but seemingly haphazard, following no systematic methodology. This Article suggests an analytical framework that can be utilized to determine which interventions are appropriate and evaluates a variety of means by which moral fairness could be promoted in the arena of health care coverage.


Optimal interferometer designs for optical coherence tomography.
We introduce a family of power-conserving fiber-optic interferometer designs for low-coherence reflectometry that use optical circulators, unbalanced couplers, and (or) balanced heterodyne detection. Simple design equations for optimization of the signal-to-noise ratio of the interferometers are expressed in terms of relevant signal and noise sources and measurable system parameters. We use the equations to evaluate the expected performance of the new configurations compared with that of the standard Michelson interferometer that is commonly used in optical coherence tomography (OCT) systems. The analysis indicates that improved sensitivity is expected for all the new interferometer designs, compared with the sensitivity of the standard OCT interferometer, under high-speed imaging conditions.


Three Novel Players: PTK2B, SYK, and TNFRSF21 Were Identified to Be Involved in the Regulation of Bovine Mastitis Susceptibility via GWAS and Post-transcriptional Analysis.
Bovine mastitis is a common inflammatory disease caused by multiple factors in early lactation or dry period. Genome wide association studies (GWAS) can provide a convenient and effective strategy for understanding the biological basis of mastitis and better prevention. 2b-RADseq is a high-throughput sequencing technique that offers a powerful method for genome-wide genetic marker development and genotyping. In this study, single nucleotide polymorphisms (SNPs) of the immune-regulated gene correlative with mastitis were screened and identified by two stage association analysis via GWAS-2b-RADseq in Chinese Holstein cows. We have screened 10,058 high quality SNPs from 7,957,920 tags and calculated their allele frequencies. Twenty-seven significant SNPs were co-labeled in two GWAS analysis models [Bayesian (P < 0.001) and Logistic regression (P < 0.01)], and only three SNPs (rs75762330, C > T, PIC = 0.2999; rs88640083, A > G, PIC = 0.1676; rs20438858, G > A, PIC = 0.3366) were annotated to immune-regulated genes (PTK2B, SYK, and TNFRSF21). Identified three SNPs are located in non-coding regions with low or moderate genetic polymorphisms. However, independent sample population validation (Case-control study) data showed that three important SNPs (rs75762330, P < 0.025, OR > 1; rs88640083, P < 0.005, OR > 1; rs20438858, P < 0.001, OR < 1) were significantly associated with clinical mastitis trait. Importantly, PTK2B and SYK expression was down-regulated in both peripheral blood leukocytes (PBLs) of clinical mastitis cows and in vitro LPS (E. coli)-stimulated bovine mammary epithelial cells, while TNFRSF21 was up-regulated. Under the same conditions, expression of Toll-like receptor 4 (TLR4), AKT1, and pro-inflammatory factors (IL-1β and IL-8) were also up-regulated. Interestingly, network analysis indicated that PTK2B and SYK are co-expressed in innate immune signaling pathway of Chinese Holstein. Taken together, these results provided strong evidence for the study of SNPs in bovine mastitis, and revealed the role of SYK, PTK2B, and TNFRSF21 in bovine mastitis susceptibility/tolerance.


E2FB Interacts with RETINOBLASTOMA RELATED and Regulates Cell Proliferation during Leaf Development.
Cell cycle entry and quiescence are regulated by the E2F transcription factors in association with RETINOBLASTOMA-RELATED (RBR). E2FB is considered to be a transcriptional activator of cell cycle genes, but its function during development remains poorly understood. Here, by studying E2FB-RBR interaction, E2F target gene expression, and epidermal cell number and shape in e2fb mutant and overexpression lines during leaf development in Arabidopsis (Arabidopsis thaliana), we show that E2FB in association with RBR plays a role in the inhibition of cell proliferation to establish quiescence. In young leaves, both RBR and E2FB are abundant and form a repressor complex that is reinforced by an autoregulatory loop. Increased E2FB levels, either by expression driven by its own promoter or ectopically together with DIMERIZATION PARTNER A, further elevate the amount of this repressor complex, leading to reduced leaf cell number. Cell overproliferation in e2fb mutants and in plants overexpressing a truncated form of E2FB lacking the RBR binding domain strongly suggested that RBR repression specifically acts through E2FB. The increased number of small cells below the guard cells and of fully developed stomata indicated that meristemoids preferentially hyperproliferate. As leaf development progresses and cells differentiate, the amount of RBR and E2FB gradually declined. At this stage, elevation of E2FB level can overcome RBR repression, leading to reactivation of cell division in pavement cells. In summary, E2FB in association with RBR is central to regulating cell proliferation during organ development to determine final leaf cell number.


HIV testing and antiretroviral therapy in government and mission hospitals in Malawi: 2002-2007.
HIV testing and antiretroviral therapy (ART) has scaled up tremendously in Malawi in the last 5 years. We analyzed trends of HIV testing uptake in the course of ART scale-up in 25 government and mission hospitals, which were selected because they do not receive support from non-governmental organizations. Data on numbers of clients HIV tested and on cumulative ART registrations were collected from annual country-wide situational analyses and from quarterly ART supervisory visits from 2002 to 2007. In the period before ART scale up, the quarterly number of clients HIV tested increased from 2609 in 2002 to 8197 in 2004, equivalent to an average quarterly increase of 559 tests. During ART scale up, the quarterly number of clients HIV tested increased from 17977 in early 2005 to 35344 in the second quarter of 2007, equivalent to an average quarterly increase of 2171 tests. During this time, the cumulative number of patients started on ART increased from 2441 to 29756. There has been a rapid acceleration of HIV testing uptake and ART in government and mission hospitals. ART may facilitate the decision of clients to have an HIV test and therefore contribute in this way to HIV prevention efforts.


Bare skin, blood and the evolution of primate colour vision.
We investigate the hypothesis that colour vision in primates was selected for discriminating the spectral modulations on the skin of conspecifics, presumably for the purpose of discriminating emotional states, socio-sexual signals and threat displays. Here we show that, consistent with this hypothesis, there are two dimensions of skin spectral modulations, and trichromats but not dichromats are sensitive to each. Furthermore, the M and L cone maximum sensitivities for routine trichromats are optimized for discriminating variations in blood oxygen saturation, one of the two blood-related dimensions determining skin reflectance. We also show that, consistent with the hypothesis, trichromat primates tend to be bare faced.


Environmental exposure, obesity, and Parkinson's disease: lessons from fat and old worms.
A common link has been exposed, namely, that metal exposure plays a role in obesity and in Parkinson's disease (PD). This link may help to elucidate mechanisms of neurotoxicity. We reviewed the utility of the nematode, Caenorhabditis elegans, as a model organism to study neurodegeneration in obesity and Parkinson's disease (PD), with an emphasis on the neurotransmitter, dopamine (DA). A PubMed literature search was performed using the terms "obesity" and any of the following: "C. elegans," "central nervous system," "neurodegeneration," "heavy metals," "dopamine" or "Parkinson's disease." We reviewed the identified studies, including others cited therein, to summarize the current evidence of neurodegeneration in obesity and PD, with an emphasis on studies carried out in C. elegans and environmental toxins in the etiology of both diseases. Heavy metals and DA have both been linked to diet-induced obesity, which has led to the notion that the mechanism of environmentally induced neurodegeneration in PD may also apply to obesity. C. elegans has been instrumental in expanding our mechanism-based knowledge of PD, and this species is emerging as a good model of obesity. With well-established toxicity and neurogenetic assays, it is now feasible to explore the putative link between metal- and chemical-induced neurodegeneration. One side effect of an aging population is an increase in the prevalence of obesity, metabolic disorders, and neurodegenerative orders, diseases that are likely to co-occur. Environmental toxins, especially heavy metals, may prove to be a previously neglected part of the puzzle.


A preliminary investigation of the organic chemical emissions from green sand pyrolysis.
Condensable effluents from the thermal decomposition of a typical green sand foundry mold were investigated for the presence of emissions that could present health hazards in a foundry atmosphere. The benzene-soluble fraction extracted from the condensate was analyzed by gas chromatography/mass spectrometry. Over 200 compounds were observed on the chromatograms and benzo(a)pyrene, benzo(e)pyrene and perylene were identified. The concentrations of these materials were not determined, but their presence in foundry atmospheres represents in area of potential concern for health welfare.


Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Microcolony B. burgdorferi Persisters Which Are Sterilized by Daptomycin/ Doxycycline/Cefuroxime without Pulse Dosing.
Although the majority of Lyme disease patients can be cured, at least 10-20% of the patients continue to suffer from persisting symptoms such as fatigue, muscular and joint pain, and neurologic impairment after standard 2-4 week antibiotic treatment. While the causes for this post-treatment Lyme disease symptoms are unclear, one possibility is due to Borrelia burgdorferi persisters that are not effectively killed by current antibiotics such as doxycycline or amoxicillin used to treat Lyme disease. A previous study showed that four rounds of ceftriaxone pulse dosing treatment eradicated B. burgdorferi persisters in vitro using a relatively young late log phase culture (5 day old). In this study, we investigated if ceftriaxone pulse dosing could also eradicate B. burgdorferi persisters in older stationary phase cultures (10 day old) enriched with more resistant microcolony form of persisters. We found that ceftriaxone pulse dosing could only eradicate planktonic log phase B. burgdorferi spirochetal forms and round body forms but not more resistant aggregated biofilm-like microcolony persisters enriched in stationary phase cultures. Moreover, we found that not all drugs are suitable for pulse dosing, with bactericidal drugs ceftriaxone and cefuroxime being more appropriate for pulse dosing than bacteriostatic drug doxycycline and persister drug daptomycin. We also showed that drug combination pulse dosing treatment was more effective than single drug pulse dosing. Importantly, we demonstrate that pulse dosing treatment impaired the activity of the persister drug daptomycin and its drug combination against B. burgdorferi persisters and that the most effective way to kill the more resistant biofilm-like microcolonies is the daptomycin/doxycycline/ceftriaxone triple drug combination without pulse dosing. Our findings indicate pulse dosing may not always work as a general principle but rather depends on the specific drugs used, with cidal drugs being more appropriate for pulse dosing than static or persister drugs, and that drug combination approach with persister drugs is more effective at killing the more resistant microcolony form of persisters than pulse dosing. These observations may have implications for more effective treatment of Lyme disease. Future studies are required to validate these findings in animal models of B. burgdorferi persistence.


Non-associative learning and serotonin induce similar bi-directional changes in excitability of a neuron critical for learning in the medicinal leech.
In studies of the cellular basis of learning, much attention has focused on plasticity in synaptic transmission in terms of transmitter release and the number or responsiveness of neurotransmitter receptors. However, changes in postsynaptic excitability independent of receptors may also play an important role. Changes in excitability of a single interneuron in the leech, the S-cell, were measured during non-associative learning of the whole-body shortening reflex. This interneuron was chosen because it is known to be necessary for sensitization and full dishabituation of the shortening response. During sensitization, S-cell excitability increased, and this enhancement corresponded to facilitation of the shortening reflex and increased S-cell activity during the elicited response. During habituation training, there was a decrement in both the shortening reflex and the elicited S-cell activity, along with decreased S-cell excitability. Conversely, dishabituation facilitated both the shortening response and S-cell activity during shortening, with an accompanying increase in S-cell excitability. Bath application of 1-10 micrometer serotonin (5HT), a modulatory neurotransmitter that is critical for sensitization, for full dishabituation, and for associative learning, increased S-cell excitability. S-cell excitability also increased after stimulation of the serotonergic Retzius cells. However, focal application of serotonin onto the S-cell soma hyperpolarized the interneuron, and bath application of a lower dose of serotonin (0.1 micrometer) decreased excitability. The observed changes in postsynaptic excitability appear to contribute to non-associative learning, and modulatory neurotransmitters, such as serotonin, evidently help regulate excitability. Such changes in S-cell excitability may also be relevant for more complex, associative forms of learning.


Analysis of differential gene regulation in adequate versus inadequate secretory-phase endometrial complementary deoxyribonucleic acid populations from the rhesus monkey.
The ability to create artificial menstrual cycles in the rhesus monkey provides a model for studies on the regulation of genes and gene networks by estradiol or progesterone (P) in the primate endometrium. This model allowed us to create both a normal level of secretory phase P or an inadequate level of secretory phase P, i.e. endometria that cannot support implantation. The objective of our present study focused on PCR analyses of genes for several factors that are believed to be important in the proper maturation of the endometrium. Complementary DNA (cDNA) populations were prepared from endometria harvested on day 13 (peak E level), days 21-23 of an adequate secretory phase (PcDNA) and days 21-23 of an inadequate secretory phase (IcDNA). Although placental protein 14, leukemia inhibitory factor and 17-beta hydroxysteroid dehydrogenase displayed highly upregulated levels in PcDNA (P-activated genes), there was little or no up-regulation in IcDNA. Transforming growth factor-beta 2 and its receptor and insulin growth factor-I and its receptor were up-regulated in PcDNA, whereas little or no expression was observed in IcDNA. Regulators of the cell cycle and transcription, such as retinoblastoma, c-fos, and c-jun genes, were also greatly underexpressed in IcDNA compared with PcDNA. Interestingly, one gene that we studied, keratinocyte growth factor, that was up-regulated by P (peak E levels vs. PcDNA) was more highly expressed in IcDNA. This latter result suggests that low levels of circulating P are sufficient for expression of this gene, whereas high sustained P levels result in an autologous down-regulation. These data show that the regulation of genes that may play pivotal roles in endometrial maturation are differentially expressed in IcDNA vs. PcDNA and may, in part, characterize improper endometrial maturation.


Evaluating 21-day doxycycline and azithromycin treatments for experimental Chlamydophila psittaci infection in cockatiels (Nymphicus hollandicus).
To determine the efficacy of 21-day therapy with azithromycin and doxycycline in the treatment of experimental infection with Chlamydophila psittaci in cockatiels (Nymphicus hollandicus), 30 birds randomly assigned to 3 treatment groups and 1 control group were inoculated with C psittaci by combined intranasal and ocular routes. Morbidity, mortality, and results of polymerase chain reaction testing confirmed that infection was successful. Birds in group 1 (n = 8) received azithromycin at 40 mg/kg PO q48h for 21 days; in group 2 (n = 8), doxycycline at 35 mg/kg PO q24h for 21 days; in group 3 (n = 8), doxycycline at 35 mg/kg PO q24h for 45 days; and, in group 4 (controls; n = 6), no treatment. Six birds died either before or within 2 days of initiating treatment: 4 in the 3 treatment groups and 2 in the control group. Clinical signs resolved and mortality ceased 2-6 days after treatment was initiated in all treatment groups, whereas birds in the control group exhibited clinical signs for the duration of the study. Plasma doxycycline concentrations were measured during the treatment period and exceeded 1 microg/mL at all time points. The absence of clinical signs and mortality in the treatment groups, even after inducing an immunocompromised state with dexamethasone (3 mg/kg IM q24h for 5 days), starting on day 70 postinoculation, suggested that treatment resulted in elimination of the pathogen. After euthanasia of the remaining 24 birds, 23 of the carcasses were submitted for necropsy. Spleen and liver samples from the birds in all treatment and control groups were polymerase chain reaction negative for C psittaci nucleic acid, and organisms were not detected by Gimenez stain. No gross or histologic differences were observed in the livers and spleens of treated and untreated infected birds. Lesions consistent with avian chlamydiosis (hystiocytosis) were seen in all birds and were considered residual. In this study, a 21-day course of either doxycycline or azithromycin was effective in eliminating C psittaci infection in experimentally inoculated cockatiels. Additional studies are necessary to evaluate the efficacy of these treatments in naturally infected cockatiels as well as other species of birds.


Reduction of Family Violence in Aboriginal Communities: A Systematic Review of Interventions and Approaches.
Many efforts to reduce family violence are documented in the published literature. We conducted a systematic review of interventions intended to prevent family violence in Aboriginal communities. We retrieved studies published up to October 2009; 506 papers included one systematic review, two randomized controlled trials, and fourteen nonrandomized studies or reviews. Two reviews discussed interventions relevant to primary prevention (reducing the risk factors for family violence), including parenting, role modelling, and active participation. More studies addressed secondary prevention (where risk factors exist, reducing outbreaks of violence) such as restriction on the trading hours for take away alcohol and home visiting programs for high risk families. Examples of tertiary prevention (preventing recurrence) include traditional healing circles and group counselling. Most studies contributed a low level of evidence.


Temporal changes in species interactions in simple aquatic bacterial communities.
Organisms modify their environment and in doing so change the quantity and possibly the quality of available resources. Due to the two-way relationship between organisms and their resource environment, and the complexity it brings to biological communities, measuring species interactions reliably in any biological system is a challenging task. As the resource environment changes, the intensity and even the sign of interactions may vary in time. We used Serratia marcescens and Novosphingobium capsulatum bacteria to study how the interaction between resource environment and organisms influence the growth of the bacterial species during circa 200 generations. We used a sterile-filtering method to measure how changes in resource environment are reflected in growth rates of the two species. Changes in the resource environment caused complex time and species composition-dependent effects on bacterial growth performance. Variation in the quality of the growth medium indicated existence of temporally fluctuating within-species facilitation and inhibition, and between-species asymmetric facilitation. The interactions between the community members could not be fully predicted based only on the knowledge of the growth performance of each member in isolation. Growth dynamics in sterile-filtered samples of the conditioned growth medium can reveal both biologically meaningful changes in resource availability and temporally changing facilitative resource-mediated interactions between study species. This is the first study we are aware of where the filter-sterilization - growth assay method is applied to study the effect of long-term changes in the environment on species interactions.


Neo-Marxian social class inequalities in the mental well-being of employed men and women: the role of European welfare regimes.
The relation between "neo-Marxian" social class (NMSC) and health in the working population has received considerable attention in public health research. However, less is known about the distribution of mental well-being according to NMSC in a European context. The objectives of this study are (i) to analyse the association of mental well-being and NMSC among employees in Europe (using a welfare regime typology), (ii) to investigate whether the relation between NMSC and mental well-being is the same in women compared to men within each welfare regime, and (iii) to examine within each welfare regime the role of the gender division of labour and job quality as potential mediating factors in explaining this association. Data from the European Social Survey Round 5 (2010) were analysed. Mental well-being was assessed by the WHO Well-being Index. Social class was measured through E.O. Wright's social class scheme. Models separated by sex were generated using Poisson regression with a robust error variance. The associations were presented as prevalence ratios with 95% confidence intervals. Women reported NMSC differences in mental well-being in State corporatist/family support and Southern welfare regimes. Men reported NMSC differences in mental well-being in all but the Basic security/market-oriented welfare regimes. Gender inequalities were more marked and widespread in Basic security/market-oriented welfare regimes. In all welfare regimes job quality (partly) explained NMSC inequalities in mental well-being for men, the role of the gender division of labour was unclear. This study showed that the relationship between NMSC and mental well-being among employees differs by gender and welfare regimes. It confirms the importance of NMSC and welfare regimes to explain gender and social class inequalities in mental well-being.


Lateral Gene Transfer Shapes the Distribution of RuBisCO among Candidate Phyla Radiation Bacteria and DPANN Archaea.
Ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) is considered to be the most abundant enzyme on Earth. Despite this, its full diversity and distribution across the domains of life remain to be determined. Here, we leverage a large set of bacterial, archaeal, and viral genomes recovered from the environment to expand our understanding of existing RuBisCO diversity and the evolutionary processes responsible for its distribution. Specifically, we report a new type of RuBisCO present in Candidate Phyla Radiation (CPR) bacteria that is related to the archaeal Form III enzyme and contains the amino acid residues necessary for carboxylase activity. Genome-level metabolic analyses supported the inference that these RuBisCO function in a CO2-incorporating pathway that consumes nucleotides. Importantly, some Gottesmanbacteria (CPR) also encode a phosphoribulokinase that may augment carbon metabolism through a partial Calvin-Benson-Bassham cycle. Based on the scattered distribution of RuBisCO and its discordant evolutionary history, we conclude that this enzyme has been extensively laterally transferred across the CPR bacteria and DPANN archaea. We also report RuBisCO-like proteins in phage genomes from diverse environments. These sequences cluster with proteins in the Beckwithbacteria (CPR), implicating phage as a possible mechanism of RuBisCO transfer. Finally, we synthesize our metabolic and evolutionary analyses to suggest that lateral gene transfer of RuBisCO may have facilitated major shifts in carbon metabolism in several important bacterial and archaeal lineages.


Environmental transmission of SARS at Amoy Gardens.
Recent investigations into the March 2003 outbreak of SARS in Hong Kong have concluded that environmental factors played an important role in the transmission of the disease. These studies have focused on a particular outbreak event, the rapid spread of SARS throughout Amoy Gardens, a large, private apartment complex. They have demonstrated that, unlike a typical viral outbreak that is spread through person-to-person contact, the SARS virus in this case was spread primarily through the air. High concentrations of viral aerosols in building plumbing were drawn into apartment bathrooms through floor drains. The initial exposures occurred in these bathrooms. The virus-laden air was then transported by prevailing winds to adjacent buildings at Amoy Gardens, where additional exposures occurred. This article reviews the results of the investigations and provides recommendations for maintenance and other measures that building owners can take to help prevent environmental transmission of SARS and other flulike viruses in their buildings.


Sibutramine-induced mania as the first manifestation of bipolar disorder.
Sibutramine, used in obesity treatment, has been associated with many neuropsychiatric side effects including hypomanic and manic episodes. Hypomanic/manic episodes related to sibutramine treatment were earlier reported in patients who had previous history of bipolar disorder, after sibutramine overdose, after over-the-counter product illegally containing very high dose of sibutramine, together with psychotic symptoms, in organic patient, or after interaction of sibutramine with other drugs. We report the first case of a patient with clear manic episode, after treatment with recommended dose of sibutramine, without previous history of mood disorders, organic changes or drug interactions, that was followed by episode of depression. Minimal recommended dose of sibutramine induced manic episode that was the first manifestation of bipolar disorder. The manic episode, associated with sibutramine treatment, was induced in a person without previous history of mood disorders. Potential risks associated with the treatment of obesity using sibutramine warn physicians to be alert not only to common and cardiovascular but also to psychiatric adverse effects. A careful assessment of patient's mental state and detailed psychiatric family history should be done before sibutramine treatment. In patients with a family history for bipolar disorder the use of even minimal dose of sibutramine should be contraindicated.


Cost-effective use of silver dressings for the treatment of hard-to-heal chronic venous leg ulcers.
To estimate the cost-effectiveness of silver dressings using a health economic model based on time-to-wound-healing in hard-to-heal chronic venous leg ulcers (VLUs). Chronic venous ulceration affects 1-3% of the adult population and typically has a protracted course of healing, resulting in considerable costs to the healthcare system. The pathogenesis of VLUs includes excessive and prolonged inflammation which is often related to critical colonisation and early infection. The use of silver dressings to control this bioburden and improve wound healing rates remains controversial. A decision tree was constructed to evaluate the cost-effectiveness of treatment with silver compared with non-silver dressings for four weeks in a primary care setting. The outcomes: 'Healed ulcer', 'Healing ulcer' or 'No improvement' were developed, reflecting the relative reduction in ulcer area from baseline to four weeks of treatment. A data set from a recent meta-analysis, based on four RCTs, was applied to the model. Treatment with silver dressings for an initial four weeks was found to give a total cost saving (£141.57) compared with treatment with non-silver dressings. In addition, patients treated with silver dressings had a faster wound closure compared with those who had been treated with non-silver dressings. The use of silver dressings improves healing time and can lead to overall cost savings. These results can be used to guide healthcare decision makers in evaluating the economic aspects of treatment with silver dressings in hard-to-heal chronic VLUs.


Combined effects of smoking, anti-EBNA antibodies, and HLA-DRB1*1501 on multiple sclerosis risk.
To examine the interplay between smoking, serum antibody titers to the Epstein-Barr virus nuclear antigens (anti-EBNA), and HLA-DR15 on multiple sclerosis (MS) risk. Individual and pooled analyses were conducted among 442 cases and 865 controls from 3 MS case-control studies-a nested case-control study in the Nurses' Health Study/Nurses' Health Study II, the Tasmanian MS Study, and a Swedish MS Study. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% CIs for the association between smoking, anti-EBNA titers, HLA-DR15, and MS risk. Study estimates were pooled using inverse variance weights to determine a combined effect and p value. Among MS cases, anti-EBNA titers were significantly higher in ever smokers compared to never smokers. The increased risk of MS associated with high anti-EBNA Ab titers was stronger among ever smokers (OR = 3.9, 95% CI = 2.7-5.7) compared to never smokers (OR = 1.8, 95% CI = 1.4-2.3; p for interaction = 0.001). The increased risk of MS associated with a history of smoking was no longer evident after adjustment for anti-EBNA Ab titers. No modification or confounding by HLA-DR15 was observed. The increased risk of MS associated with ever smoking was only observed among those who had high anti-EBNA titers (OR = 1.7, 95% CI = 1.1-2.6). Smoking appears to enhance the association between high anti-EBNA titer and increased multiple sclerosis (MS) risk. The association between HLA-DR15 and MS risk is independent of smoking. Further work is necessary to elucidate possible biologic mechanisms to explain this finding.


Out-of-pocket costs of AIDS care in China: are free antiretroviral drugs enough?
Financial access to HIV care and treatment can be difficult for many people in China, where the government provides free antiretroviral drugs but does not cover the cost of other medically necessary components, such as lab tests and drugs for opportunistic infections. This article estimates out-of-pocket costs for treatment and care that a person living with HIV/AIDS in China might face over the course of one year. Data comes from two treatment projects run by Médecins Sans Frontières in Nanning, Guangxi Province and Xiangfan, Hubei Province. Based on the national treatment guidelines, we estimated costs for seven different patient profiles ranging from WHO Clinical Stages I through IV. We found that patients face significant financial barriers to even qualify for the free ARV program. For those who do, HIV care and treatment can be a catastrophic health expenditure, with cumulative patient contributions ranging from approximately US$200-3939/year in Nanning and US$13-1179/year in Xiangfan, depending on the patient's clinical stage of HIV infection. In Nanning, these expenses translate as up to 340% of an urban resident's annual income or 1200% for rural residents; in Xiangfan, expenses rise to 116% of annual income for city dwellers and 295% in rural areas. While providing ARV drugs free of charge is an important step, the costs of other components of care constitute important financial barriers that may exclude patients from accessing appropriate care. Such barriers can also lead to undesirable outcomes in the future, such as impoverishment of AIDS-affected households, higher ARV drug-resistance rates and greater need for complex, expensive second-line antiretroviral drugs.


Tuning optical responses of metallic dipole nanoantenna using graphene.
Nanoantennas play a fundamental role in the nanotechnology due to their capabilities to confine and enhance the light through converting the localized fields to propagating ones, and vice versa. Here, we theoretically propose a novel nanoantenna with the metal-insulator-graphene configuration where a graphene sheet dynamically controls the characteristics of a metallic dipole antenna in terms of near-field distribution, resonance frequency, bandwidth, radiation pattern, etc. Our results show that by modifying dispersion relation of the graphene sheet attached to the insulator through tuning chemical potentials, we can achieve strong mode couplings between the graphene sheet and the metallic nanoantenna on the top of the insulator. Interestingly, the in-phase and out-of-phase couplings between metallic plasmonics and graphene plasmonics not only split the single resonance frequency of the conventional metallic dipole antenna but also modify the near-field and far-field responses of the metal-graphene nanoantenna. This work is of a great help to design high-performance electrically-tunable nanoantennas applicable both in nano-optics and nano-electronics fields.


Date palm sap linked to Nipah virus outbreak in Bangladesh, 2008.
We investigated a cluster of patients with encephalitis in the Manikgonj and Rajbari Districts of Bangladesh in February 2008 to determine the etiology and risk factors for disease. We classified persons as confirmed Nipah cases by the presence of immunoglobulin M antibodies against Nipah virus (NiV), or by the presence of NiV RNA or by isolation of NiV from cerebrospinal fluid or throat swabs who had onset of symptoms between February 6 and March 10, 2008. We classified persons as probable cases if they reported fever with convulsions or altered mental status, who resided in the outbreak areas during that period, and who died before serum samples were collected. For the case-control study, we compared both confirmed and probable Nipah case-patients to controls, who were free from illness during the reference period. We used motion-sensor-infrared cameras to observe bat's contact of date palm sap. We identified four confirmed and six probable case-patients, nine (90%) of whom died. The median age of the cases was 10 years; eight were males. The outbreak occurred simultaneously in two communities that were 44 km apart and separated by a river. Drinking raw date palm sap 2-12 days before illness onset was the only risk factor most strongly associated with the illness (adjusted odds ratio 25, 95% confidence intervals 3.3-∞, p<0.001). Case-patients reported no history of physical contact with bats, though community members often reported seeing bats. Infrared camera photographs showed that Pteropus bats frequently visited date palm trees in those communities where sap was collected for human consumption. This is the second Nipah outbreak in Bangladesh where date palm sap has been implicated as the vehicle of transmission. Fresh date palm sap should not be drunk, unless effective steps have been taken to prevent bat access to the sap during collection.


Wolf-Hirschhorn Syndrome-Associated Genes Are Enriched in Motile Neural Crest Cells and Affect Craniofacial Development in Xenopus laevis.
Wolf-Hirschhorn Syndrome (WHS) is a human developmental disorder arising from a hemizygous perturbation, typically a microdeletion, on the short arm of chromosome four. In addition to pronounced intellectual disability, seizures, and delayed growth, WHS presents with a characteristic facial dysmorphism and varying prevalence of microcephaly, micrognathia, cartilage malformation in the ear and nose, and facial asymmetries. These affected craniofacial tissues all derive from a shared embryonic precursor, the cranial neural crest (CNC), inviting the hypothesis that one or more WHS-affected genes may be critical regulators of neural crest development or migration. To explore this, we characterized expression of multiple genes within or immediately proximal to defined WHS critical regions, across the span of craniofacial development in the vertebrate model system Xenopus laevis. This subset of genes, whsc1, whsc2, letm1, and tacc3, are diverse in their currently-elucidated cellular functions; yet we find that their expression demonstrates shared tissue-specific enrichment within the anterior neural tube, migratory neural crest, and later craniofacial structures. We examine the ramifications of this by characterizing craniofacial development and neural crest migration following individual gene depletion. We observe that several WHS-associated genes significantly impact facial patterning, cartilage formation, neural crest motility in vivo and in vitro, and can separately contribute to forebrain scaling. Thus, we have determined that numerous genes within and surrounding the defined WHS critical regions potently impact craniofacial patterning, suggesting their role in WHS presentation may stem from essential functions during neural crest-derived tissue formation.


Consensus criteria for defining 'successful outcome' after ACL injury and reconstruction: a Delaware-Oslo ACL cohort investigation.
No gold standard exists for identifying successful outcomes 1 and 2 years after operative and non-operative management of anterior cruciate ligament (ACL) injury. This limits the ability of a researcher and clinicians to compare and contrast the results of interventions. To establish a consensus based on expert consensus of measures that define successful outcomes 1 and 2 years after ACL injury or reconstruction. Members of international sports medicine associations, including the American Orthopaedic Society for Sports Medicine, the European Society for Sports Traumatology, Surgery, and Knee Arthroscopy and the American Physical Therapy Association, were sent a survey via email. Blinded responses were analysed for trends with frequency counts. A summed importance percentage (SIP) was calculated and 80% SIP operationally indicated consensus. 1779 responses were obtained. Consensus was achieved for six measures in operative and non-operative management: the absence of giving way, patient return to sports, quadriceps and hamstrings' strength greater than 90% of the uninvolved limb, the patient having not more than a mild knee joint effusion and using patient-reported outcomes (PRO). No single PRO achieved consensus, but threshold scores between 85 and 90 were established for PROs concerning patient performance. The consensus identified six measures important for successful outcome after ACL injury or reconstruction. These represent all levels of the International Classification of Functioning: effusion, giving way, muscle strength (body structure and function), PRO (activity and participation) and return to sport (participation), and should be included to allow for comparison between interventions.


CD34-positive cells and their subpopulations characterized by flow cytometry analyses on the bone marrow of healthy allogenic donors.
Counting and separating hematopoietic stem cells from different sources has importance for research and clinical assays. Our aims here were to characterize and quantify hematopoietic cell populations in marrow donors and to evaluate CD34 expression and relate this to engraftment. Cross-sectional study on hematopoietic stem cell assays, using flow cytometry on donor bone marrow samples, for allogenic transplantation patients at two hospitals in São Paulo. Immunophenotyping of marrow cells was performed in accordance with positive findings of CD34FITC, CD117PE, CD38PE, CD7FITC, CD33PE, CD10FITC, CD19PE, CD14FITC, CD13PE, CD11cPE, CD15FITIC, CD22PE, CD61FITC and CD56PE monoclonal antibodies in CD45PerCP+ cells, searching for differentiation and maturation regions. CD34+ sorting cells were analyzed for CD38 and CD117. Rh-123 retention was done before and after sorting. Antigen expression and CD34+ cells were correlated with engraftment. In region R1, 0.1% to 2.8% of cells were CD34+/CD45+ and 1.1%, CD34+/CD45-. The main coexpressions of CD45+ cells were CD38, CD22, CD19 and CD56 in R2 and CD33, CD11c, CD14, CD15 and CD61 in R3 and R4. After sorting, 2.2x10(6) CD34+ cells were equivalent to 4.9% of total cells. Coexpression of CD34+/CD38+ and CD34+/CD117+ occurred in 94.9% and 82% of events, respectively. There was a positive relationship between CD34+ cells and engraftment. More than 80% of marrow cells expressed high Rh-123. CD34+ cell sorting showed that cells in regions of more differentiated lineages retained Rh-123 more intensively than in primitive lineage regions. We advocate that true stem cells are CD34+/CD45-/CD38-/low-Rh-123 accumulations.


Calibration of scattering and absorption properties of a liquid diffusive medium at NIR wavelengths. CW method.
In spite of many progresses achieved both with theories and with experiments in studying light propagation through diffusive media, a reliable method for accurate measurements of the optical properties of diffusive media at NIR wavelengths is, in our opinion, still missing. It is therefore difficult to create a diffusive medium with well known optical properties to be used as a reference. In this paper we describe a method to calibrate the reduced scattering coefficient, mu'(s) , of a liquid diffusive medium and the absorption coefficient, mu(a), of an absorbing medium with a standard error smaller than 2% both on mu'(s) and on mu(a). The method is based on multidistance measurements of fluence into an infinite medium illuminated by a CW source. The optical properties are retrieved with simple inversion procedures (linear fits) exploiting the knowledge of the absorption coefficient of the liquid into which the diffuser and the absorber are dispersed. In this study Intralipid diluted in water has been used as diffusive medium and Indian ink as absorber. For a full characterization of these media measurements of collimated transmittance have also been carried out, from which the asymmetry factor of the scattering function of Intralipid and the single scattering albedo of Indian ink have been determined.


Immunogenicity assessment of biotherapeutic products: An overview of assays and their utility.
Biotherapeutic products (BTPs) are the fastest growing medicines in the pharmaceutical market. Despite their clinical success, the immunogenicity of BTPs continues to be a major concern. Assessment of immunogenicity as well as appropriate interpretation of immunogenicity data is therefore, of critical importance for defining safety profile of these products for the purpose of their licensure and use. In the past decade, much progress has been made towards how immunogenicity should be studied. This article reflects the content of the brief presentation on principles of methods used for immunogenicity assessment and their merits and limitations given at the first World Health Organization (WHO) implementation workshop on rDNA derived biotherapeutic products held in the Republic of Korea in May 2014 to support the case studies on immunogenicity presented and discussed during the workshop. The purpose of this article is to provide an overview of the methods used for assessing immunogenicity of biotherapeutic products (BTPs) and the most important considerations in interpreting results in the context of regulatory overview of these products.


PBP1 is a component of the Bacillus subtilis cell division machinery.
Bacillus subtilis penicillin-binding protein PBP1 has been implicated in cell division. We show here that a PBP1 knockout strain is affected in the formation of the asymmetric sporulation septum and that green fluorescent protein-PBP1 localizes to the sporulation septum. Localization of PBP1 to the vegetative septum is dependent on various cell division proteins. This study proves that PBP1 forms part of the B. subtilis cell division machinery.


A questionnaire-based study of attitudes to spirituality in mental health practitioners and the relevance of the concept of spiritually competent care.
In the light of the increasing recognition of the relevance of spirituality in person-centred, holistic care, this study examines the attitudes of a convenience sample of mental health practitioners, including nurses, to the concepts of spirituality in general and in clinical practice. A series of 5-point Likert-style items assessed two key domains of spirituality in everyday life (SEDL) and spirituality in practice (SIP). The questionnaire was derived from one previously used with healthcare educators (including nurses). Each item was scored from 1 point (strongly disagree) to 5 points (strongly agree). Additional information about how far practitioners believed spirituality had been integrated in their education and how much they believed that spirituality related to religion was also ascertained. Three further items, not part of the main questionnaire, dealt with respondents' views of spirituality competent practice, in the light of a description provided as part of the questionnaire. Data were collected from 104 respondents. Standard statistical procedures, including reliability analyses, were applied to the data. Respondents who viewed spirituality to be distinct from religion, or a place of worship, were likely to place a higher value on spirituality in everyday life, while respondents who experienced the integration of spirituality within their preregistration training and/or clinical education were likely to place a higher value on the place of spirituality in practice. The possible reasons for these associations are discussed in the light of the importance of spiritual care as a part of person-centred, holistic practice.


Refactoring the nitrogen fixation gene cluster from Klebsiella oxytoca.
Bacterial genes associated with a single trait are often grouped in a contiguous unit of the genome known as a gene cluster. It is difficult to genetically manipulate many gene clusters because of complex, redundant, and integrated host regulation. We have developed a systematic approach to completely specify the genetics of a gene cluster by rebuilding it from the bottom up using only synthetic, well-characterized parts. This process removes all native regulation, including that which is undiscovered. First, all noncoding DNA, regulatory proteins, and nonessential genes are removed. The codons of essential genes are changed to create a DNA sequence as divergent as possible from the wild-type (WT) gene. Recoded genes are computationally scanned to eliminate internal regulation. They are organized into operons and placed under the control of synthetic parts (promoters, ribosome binding sites, and terminators) that are functionally separated by spacer parts. Finally, a controller consisting of genetic sensors and circuits regulates the conditions and dynamics of gene expression. We applied this approach to an agriculturally relevant gene cluster from Klebsiella oxytoca encoding the nitrogen fixation pathway for converting atmospheric N(2) to ammonia. The native gene cluster consists of 20 genes in seven operons and is encoded in 23.5 kb of DNA. We constructed a "refactored" gene cluster that shares little DNA sequence identity with WT and for which the function of every genetic part is defined. This work demonstrates the potential for synthetic biology tools to rewrite the genetics encoding complex biological functions to facilitate access, engineering, and transferability.


Isolation and culture of murine bone marrow-derived macrophages for nitric oxide and redox biology.
Macrophages are mononuclear phagocytes derived from haematopoietic progenitors that are widely distributed throughout the body. These cells participate in both innate and adaptive immune responses and lie central to the processes of inflammation, development, and homeostasis. Macrophage physiology varies depending on the environment in which they reside and they exhibit rapid functional adaption in response to external stimuli. To study macrophages in vitro, cells are typically cultured ex vivo from the peritoneum or alveoli, or differentiated from myeloid bone marrow progenitor cells to form bone marrow-derived macrophages (BMDMs). BMDMs represent an efficient and cost-effective means of studying macrophage biology. However, the inherent sensitivity of macrophages to biochemical stimuli (such as cytokines, metabolic intermediates, and RNS/ROS) makes it imperative to control experimental conditions rigorously. Therefore, the aim of this study was to establish an optimised and standardised method for the isolation and culture of BMDMs. We used classically activated macrophages isolated from WT and nitric oxide (NO)-deficient mice to develop a standardised culture method, whereby the constituents of the culture media are defined. We then methodically compared our standardised protocol to the most commonly used method of BMDM culture to establish an optimal protocol for the study of nitric oxide (NO)-redox biology and immunometabolism in vitro.


A green approach to obtain stable and hydrophilic cellulose-based electrospun nanofibrous substrates for sustained release of therapeutic molecules.
Stable and (bio)-compatible nanofibrous matrices showing effective incorporation and release of nonsteroidal anti-inflammatory drugs (NSAIDs) hold a huge potential in tissue regeneration and wound healing. Herein, a two-step, water-based and needleless electrospinning method is used to fabricate thermally cross-linked multifunctional nanofibrous substrates from a hydrophilic cellulose derivative, i.e. carboxymethyl cellulose (CMC), and polyethylene glycol (PEG) with an in situ incorporated NSAID, diclofenac (DCF). Electrospun bi-component blend nanofibers, strongly linked together by ester bonds, with different degrees of cross-linking density are achieved by varying the concentrations of butanetetracarboxylic acid (BTCA, a green polycarboxylic cross-linker) and the sodium hypophosphite (SHP) catalyst, and the temperature. The results demonstrated that not only the dimensional stability and swelling properties could be better controlled but also the morphology, fiber diameter, surface area, pore volume, pore size, and functionality of the cross-linked nanofibers. Release kinetics of DCF from the nanofibrous substrates are controlled and prolonged up to 48 h, and the overall released mass of DCF decreased linearly with increasing cross-linking degree of BTCA and SHP. Fitting of release data using various kinetic models revealed that the release of DCF follows a non-Fickian (diffusion and erosion controlled) to Fickian mechanism (only diffusion-controlled process). Cell viability testing based on crystal violet dyeing showed that the DCF-incorporating nanofibers have excellent biocompatibility and no toxic effect on human skin fibroblast cells. Overall, the reported DCF-incorporating nanofibrous substrate demonstrates high potential to be used as a smart drug delivery system in wound healing, especially due to its noninvasive characteristics.


Insights into recent aerosol trends over Asia from observations and CMIP6 simulations.
Aerosols continue to contribute the largest uncertainty in climate change. Over Asia, a global aerosol hotspot, spatial patterns of aerosol emissions are changing mainly because of changes in anthropogenic emissions, producing a dipole in atmospheric aerosol loading between East (decrease in emissions) and South Asia (increase in emissions). The resultant aerosol radiative effects are expected to be different as compared to the last decades of the 20th century because of this emerging Asian aerosol dipole. The projection and assessments of radiative and climate impacts of aerosols rely on simulating accurately the aerosol properties, thus, making it imperative that current climate models involved in climate assessments including the Intergovernmental Panel on Climate Change Assessment Reports, simulate well the magnitude and trends in changing aerosol properties. For the first time, in this study we analyze trends in aerosol properties over Asia from satellite and ground-based observations, and simulations from climate models in Coupled Model Intercomparison Project Phase 6 (CMIP6) experiment with state-of-the-art treatment of aerosol chemistry, physics and meteorology. The results reveal large inter-model differences in model estimates, and discrepancies between model simulations and observations as most models are not able to capture the recent observed magnitudes and trends in aerosol optical depth (AOD) and single scattering albedo (SSA) over Asia. The absolute and the relative (percent) trends (positive and/or negative) in AOD are significantly higher than the trends in SSA. The aerosol-induced effective radiative forcing within the atmosphere simulated with three CMIP6 models show a positive (increasing) trend over Asia. A positive trend in atmospheric heating due to aerosols in model simulations is consistent with model simulated trends in AOD (positive) and SSA (negative). These results on model-observations comparison need to be taken into account while examining the projected/expected future climate impacts due to aerosols, and potential value of various mitigation measures, in particular on regional and decadal climate change in Asia which is largely uncertain. MAIN FINDING: Our analysis of satellite and ground-based observations, and simulations from climate models in CMIP6 experiment with state-of-the-art treatment of aerosol chemistry, physics and meteorology reveal large difference in model calculations, and most models are not able to capture the recent observed trends in aerosol optical depth and single scattering albedo over Asia during 2000-2018.


Automated Algorithm Selection on Continuous Black-Box Problems by Combining Exploratory Landscape Analysis and Machine Learning.
In this article, we build upon previous work on designing informative and efficient Exploratory Landscape Analysis features for characterizing problems' landscapes and show their effectiveness in automatically constructing algorithm selection models in continuous black-box optimization problems. Focusing on algorithm performance results of the COCO platform of several years, we construct a representative set of high-performing complementary solvers and present an algorithm selection model that, compared to the portfolio's single best solver, on average requires less than half of the resources for solving a given problem. Therefore, there is a huge gain in efficiency compared to classical ensemble methods combined with an increased insight into problem characteristics and algorithm properties by using informative features. The model acts on the assumption that the function set of the Black-Box Optimization Benchmark is representative enough for practical applications. The model allows for selecting the best suited optimization algorithm within the considered set for unseen problems prior to the optimization itself based on a small sample of function evaluations. Note that such a sample can even be reused for the initial population of an evolutionary (optimization) algorithm so that even the feature costs become negligible.


Psychological theories of posttraumatic stress disorder.
We summarize recent research on the psychological processes implicated in posttraumatic stress disorder (PTSD) as an aid to evaluating theoretical models of the disorder. After describing a number of early approaches, including social-cognitive, conditioning, information-processing, and anxious apprehension models of PTSD, the article provides a comparative analysis and evaluation of three recent theories: Foa and Rothbaum's [Foa, E. B. & Rothbaum, B. O. (1998). Treating the trauma of rape: cognitive behavioral therapy for PTSD. New York: Guilford Press] emotional processing theory; Brewin, Dalgleish, and Joseph's [Psychological Review 103 (1996) 670] dual representation theory; Ehlers and Clark's [Behaviour Research and Therapy 38 (2000) 319] cognitive theory. We review empirical evidence relevant to each model and identify promising areas for further research.


Acupuncture for depression: exploring model validity and the related issue of credibility in the context of designing a pragmatic trial.
Evaluating care that is not credible to its practitioners or patients will result in a gap between evidence and practice and the potential value, or harm, of the intervention may be underestimated. Our aim was to develop a pragmatic trial that would have better model validity and credibility than trials to date in this clinical area. In-depth interviews; a nominal consensus technique and five arm pilot trial conducted in UK primary care using counseling and usual general practitioner (GP) care as comparisons for acupuncture. Patients with long standing, severe illness that had not responded, or partially responded to conventional treatments may be interested in using acupuncture and participating in a trial. Using a database method to recruit, pilot trial patients were mostly severely depressed (87.5%); chronically ill (60% with 3+ previous episodes), with high levels of comorbidity, and medication use. Acupuncture was as credible to pilot trial participants as usual GP care and more credible than counseling: most patients (62.5%) preferred to be allocated to acupuncture, rating it more highly at baseline than counseling or usual GP care as potentially able to benefit their depression (P = 0.002). Disparities were identified in the working models of acupuncturists and counselors that suggest inherent differences between interventions in terms of the process and intended potential outcomes of therapy, as well as the interaction between patients and therapists. The Medical Research Council (MRC) framework with its phased, mixed method approach has helped to develop research that has better model validity than trials to date in this field. The next phase of research will need to involve acupuncture and counseling practitioners to help researchers to develop realistic and credible care packages for a full-scale trial, where patients are likely to be severely and chronically ill.


The revolution in birth control practices of U.S. Roman Catholics.
There has been a wide and increasing defection of Roman Catholic women from the traditional teaching of their Church on the subject of birth control over the past two decades and a resulting convergence of Catholic and non-Catholic contraceptive practices. By 1970, two-thirds of all Catholic women were using methods disapproved by their Church; this figure reached three-quarters for women under age 30. Considering the fact that most of the one-quarter of young Catholic women conforming to Church teaching had never used any method, the percentage of those deviating may well reach 90 as these women grow older and the problems of fertility control become more important. Much of this increasing deviation has been among the more educated Catholics, who were formerly the most faithful adherents to Church teaching. The change between 1965 and 1970 was especially striking for Catholic women who had attended college. Perhaps the most significant finding is that the defection has been most pronounced among the women who receive Communion at least once a month. Even among this group, the majority now deviates from Church teaching on birth control; among the younger women in this group, the proportion not conforming reaches two-thirds. It seems abundantly clear that U.S. Catholics have rejected the 1968 papal encyclical's statement on birth control and that there exists a wide gulf between the behavior of most Catholic women, on the one hand, and the position of the more conservative clergy and the official stand of the Church itself, on the other. That many Catholics can continue in their other religious practices and simultaneously deviate on the issue of birth control is an interesting commentary on the process of social change. Ultimately this crisis of authority will probably be resolved by a change in official teaching, since it seems doubtful that such a major discrepancy can continue indefinitely without other repercussions. At a minimum, the cost to the Roman Catholic Church will be a loss of authority in a major area of life: that of sex and reproduction.