Fexinidazole--a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness.
Human African trypanosomiasis (HAT), also known as sleeping sickness, is a fatal parasitic disease caused by trypanosomes. Current treatment options for HAT are scarce, toxic, no longer effective, or very difficult to administer, in particular for the advanced, fatal stage of the disease (stage 2, chronic HAT). New safe, effective and easy-to-use treatments are urgently needed. Here it is shown that fexinidazole, a 2-substituted 5-nitroimidazole rediscovered by the Drugs for Neglected Diseases initiative (DNDi) after extensive compound mining efforts of more than 700 new and existing nitroheterocycles, could be a short-course, safe and effective oral treatment curing both acute and chronic HAT and that could be implemented at the primary health care level. To complete the preclinical development and meet the regulatory requirements before initiating human trials, the anti-parasitic properties and the pharmacokinetic, metabolic and toxicological profile of fexinidazole have been assessed. Standard in vitro and in vivo anti-parasitic activity assays were conducted to assess drug efficacy in experimental models for HAT. In parallel, a full range of preclinical pharmacology and safety studies, as required by international regulatory guidelines before initiating human studies, have been conducted. Fexinidazole is moderately active in vitro against African trypanosomes (IC₅₀ against laboratory strains and recent clinical isolates ranged between 0.16 and 0.93 µg/mL) and oral administration of fexinidazole at doses of 100 mg/kg/day for 4 days or 200 mg/kg/day for 5 days cured mice with acute and chronic infection respectively, the latter being a model for the advanced and fatal stage of the disease when parasites have disseminated into the brain. In laboratory animals, fexinidazole is well absorbed after oral administration and readily distributes throughout the body, including the brain. The absolute bioavailability of oral fexinidazole was 41% in mice, 30% in rats, and 10% in dogs. Furthermore, fexinidazole is rapidly metabolised in vivo to at least two biologically active metabolites (a sulfoxide and a sulfone derivative) that likely account for a significant portion of the therapeutic effect. Key pharmacokinetic parameter after oral absorption in mice for fexinidazole and its sulfoxide and sulfone metabolites are a C(max) of 500, 14171 and 13651 ng/mL respectively, and an AUC₀₋₂₄ of 424, 45031 and 96286 h.ng/mL respectively. Essentially similar PK profiles were observed in rats and dogs. Toxicology studies (including safety pharmacology and 4-weeks repeated-dose toxicokinetics in rat and dog) have shown that fexinidazole is well tolerated. The No Observed Adverse Event Levels in the 4-weeks repeated dose toxicity studies in rats and dogs was 200 mg/kg/day in both species, with no issues of concern identified for doses up to 800 mg/kg/day. While fexinidazole, like many nitroheterocycles, is mutagenic in the Ames test due to bacterial specific metabolism, it is not genotoxic to mammalian cells in vitro or in vivo as assessed in an in vitro micronucleus test on human lymphocytes, an in vivo mouse bone marrow micronucleus test, and an ex vivo unscheduled DNA synthesis test in rats. The results of the preclinical pharmacological and safety studies indicate that fexinidazole is a safe and effective oral drug candidate with no untoward effects that would preclude evaluation in man. The drug has entered first-in-human phase I studies in September 2009. Fexinidazole is the first new clinical drug candidate with the potential for treating advanced-stage sleeping sickness in thirty years.


A genomic view of the NOD-like receptor family in teleost fish: identification of a novel NLR subfamily in zebrafish.
A large multigene family of NOD-like receptor (NLR) molecules have been described in mammals and implicated in immunity and apoptosis. Little information, however, exists concerning this gene family in non-mammalian taxa. This current study, therefore, provides an in-depth investigation of this gene family in lower vertebrates including extensive phylogenetic comparison of zebrafish NLRs with orthologs in tetrapods, and analysis of their tissue-specific expression. Three distinct NLR subfamilies were identified by mining genome databases of various non-mammalian vertebrates; the first subfamily (NLR-A) resembles mammalian NODs, the second (NLR-B) resembles mammalian NALPs, while the third (NLR-C) appears to be unique to teleost fish. In zebrafish, NLR-A and NLR-B subfamilies contain five and six genes respectively. The third subfamily is large, containing several hundred NLR-C genes, many of which are predicted to encode a C-terminal B30.2 domain. This subfamily most likely evolved from a NOD3-like molecule. Gene predictions for zebrafish NLRs were verified using sequence derived from ESTs or direct sequencing of cDNA. Reverse-transcriptase (RT)-PCR analysis confirmed expression of representative genes from each subfamily in selected tissues. Our findings confirm the presence of multiple NLR gene orthologs, which form a large multigene family in teleostei. Although the functional significance of the three major NLR subfamilies is unclear, we speculate that conservation and abundance of NLR molecules in all teleostei genomes, reflects an essential role in cellular control, apoptosis or immunity throughout bony fish.


Using Participatory and Creative Methods to Research Gender-Based Violence in the Global South and With Indigenous Communities: Findings From a Scoping Review.
This review provides a synthesis of existing research on best practice recommendations for the use of participatory and creative methods to research gender-based violence in the Global South. Following a five-stage scoping review process, 44 papers, which each related to at least two of the three parts of the topic, were selected for inclusion. A frequency table was compiled to identify the elements of best practice, which were most common across the literature. Qualitative content analysis was then used to group these elements into inductive themes. An overarching theme of safety was identified, along with four broad and intersecting domains underpinning ethical research approaches in this area: contextual, reflexive, relational, and transformative. The validity of these themes was confirmed through consultation with partners, who also emphasized the importance of a survivor-centered approach. The aims, methods, barriers, evidence for practice, and research recommendations (AMBER) framework was developed for this project as an innovative tool for analyzing the data collected and drawing out the relevance for research practice. The framework draws out the aims, methods, and barriers involved in participatory research in this context and sets out best practice recommendations and directions for future research in the following areas: (1) ensuring safety of participants and researchers, (2) redressing power inequalities within the research process, (3) embedding locally responsive ethical frameworks, and (4) understanding cultural context and respecting cultural norms.


Porphyromonas gingivalis invades human trophoblasts and inhibits proliferation by inducing G1 arrest and apoptosis.
Porphyromonas gingivalis is an oral pathogen that is also associated with serious systemic conditions such as preterm delivery. Here we investigated the interaction between P. gingivalis and a cell line of extravillous trophoblasts (HTR-8) derived from the human placenta. P. gingivalis internalized within HTR-8 cells and inhibited proliferation through induction of arrest in the G1 phase of the cell cycle. G1 arrest was associated with decreased expression of cyclin D and of CDKs 2, 4 and 6. In addition, levels of CDK inhibitors p15, p16, p18 and p21 were increased following P. gingivalis infection. The amount of Rb was diminished by P. gingivalis, and transient overexpression of Rb, with concomitant upregulation of phospho-Rb, relieved P. gingivalis-induced G1 arrest. HTR-8 cells halted in the G1 phase became apoptotic, and apoptosis was accompanied by an increase in the ratio of Bax/Bcl-2 and increased activity of caspases 3, 7 and 9. HTR-8 cells infected with P. gingivalis also exhibited a sustained activation of ERK1/2, and knock-down of ERK1/2 activity with siRNA abrogated both G1 arrest and apoptosis. Thus, P. gingivalis can invade placental trophoblasts and induce G1 arrest and apoptosis through pathways involving ERK1/2 and its downstream effectors, properties that provide a mechanistic basis for pathogenicity in complications of pregnancy.


Attracting and maintaining the Y Generation in nursing: a literature review.
This paper explores the literature related to attracting the Y Generation (Y Gen: people born between 1980 and 2000) to the nursing profession and retaining them in our current workforce. A comprehensive review of the literature supported the need for further research. Three searches were conducted and all relevant literature was reviewed by each researcher. Literature included in the review was chosen based on specific search-term inclusion. Structured searches were conducted with no limitations on publication type, date or language. Search engines used included: Australian Family and Society, CINAHL, Expanded Academic, Google Scholar, Medline, ProQuest and PubMed. A critical review of the literature, particularly empirical work on the subject has informed decision making regarding the research questions that remain to be explored. The literature revealed that the Y Gen is currently contributing to the nursing workforce demographics. Much discussion exists surrounding the integration of the Y Gen into the workplace along with the other three generations of nurses. There is also an abundance of descriptions of the Y Gen characteristics and values. There is, however, limited reference relating to what attracted this generation to nursing or what might retain them in the nursing workforce. The Y Gen is the largest generation to enter our workforce since the Baby Boomers. Health services need to recognize the needs of the Y Gen nurses and develop strategies to move the profession forward by preparing the current workforce and environment for a generation that is already here. The focus should be on their strengths with development made to structure a workforce that will support the Y Gen in their professional nursing role. Understanding what attracts the Y Gen to nursing, what managers can do to retain the Y Gen in nursing and how the nursing profession can support the Y Gen to assume a role in nursing and nursing governance will ensure that the retiring generation has left the nursing profession in capable hands.


Temporal Genetic Dynamics of an Experimental, Biparental Field Population of Phytophthora capsici.
Defining the contributions of dispersal, reproductive mode, and mating system to the population structure of a pathogenic organism is essential to estimating its evolutionary potential. After introduction of the devastating plant pathogen, Phytophthora capsici, into a grower's field, a lack of aerial spore dispersal restricts migration. Once established, coexistence of both mating types results in formation of overwintering recombinant oospores, engendering persistent pathogen populations. To mimic these conditions, in 2008, we inoculated a field with two P. capsici isolates of opposite mating type. We analyzed pathogenic isolates collected in 2009-2013 from this experimental population, using genome-wide single-nucleotide polymorphism markers. By tracking heterozygosity across years, we show that the population underwent a generational shift; transitioning from exclusively F1 in 2009-2010, to multi-generational in 2011, and ultimately all inbred in 2012-2013. Survival of F1 oospores, characterized by heterozygosity excess, coupled with a low rate of selfing, delayed declines in heterozygosity due to inbreeding and attainment of equilibrium genotypic frequencies. Large allele and haplotype frequency changes in specific genomic regions accompanied the generational shift, representing putative signatures of selection. Finally, we identified an approximately 1.6 Mb region associated with mating type determination, constituting the first detailed genomic analysis of a mating type region (MTR) in Phytophthora. Segregation patterns in the MTR exhibited tropes of sex-linkage, where maintenance of allele frequency differences between isolates of opposite mating type was associated with elevated heterozygosity despite inbreeding. Characterizing the trajectory of this experimental system provides key insights into the processes driving persistent, sexual pathogen populations.


Different stages in drug development for muscle-invasive bladder cancer.
Muscle-invasive bladder cancer (MIBC) is a highly aggressive disease. Despite optimal therapy, half of the patients will succumb to disease. This prognosis could not be improved over the last three decades. Therefore, MIBC is left behind from other cancers such as prostate, where novel treatment options were discovered and improve patient outcomes. While being aware of the recent emerging evidence of checkpoint inhibition in MIBC, we aim to describe different stages of drug development in MIBC by using three specific targets. On the example of Her2 targeting, we aimed to indicate, that either a target is ineffective in MIBC or that the patient selection is insufficient. The first clinical trials using a pan fibroblast growth factor receptor (panFGFR) inhibitor to target the FGFR pathway showed promising results. Data of further trials are to be awaited before implementing these drugs into daily clinical practice. A large variety of novel agents are investigated in vitro and in vivo. On the example of a malaria protein, we aimed to discuss a treatment paradigm that is not dependent on pathway signaling and the genomic landscape of MIBC. The ultimate question still remains to be answered: How do we select the optimal treatment for the right patient?


A new species of Comephoronema (Nematoda: Cystidicolidae) from the squirrelfish Holocentrus adscensionis (Beryciformes: Holocentridae) off Brazil.
A new nematode species, Comephoronema multipapillatum sp. n. (Cystidicolidae), is described from the anterior intestine and caecum of the squirrelfish Holocentrus adscensionis (Osbeck) (Beryciformes: Holocentridae) collected in Angra dos Reis, State of Rio de Janeiro, offshore Brazil. The new species was placed in Comephoronema Layman, 1933 by having an oval oral aperture, four submedian labia, four bilobed submedian sublabia, two narrow lateral pseudolabia and four single cephalic papillae, but mainly by numerous precloacal papillae in males (more than six pairs), in which it differs from species of the otherwise morphologically similar genus Ascarophis van Beneden, 1871. Comephoronema multipapillatum sp. n. can be easily distinguished from other congeners based on the high number of precloacal papillae in males (18 pairs + one unpaired) and also by the bidentate plate structure on the inner margin of pseudolabia, mature eggs with two long filaments on a single pole, body length of male (9.4-11.5 mm) and female (10.2-19.9 mm), left spicule size (222-278 microm) and length ratio of spicules (1 : 2.2-2.8). This is the fifth nominal species of Comephoronema, the first nematode registered parasitizing H. adscensionis and the first species of the genus in the Neotropical part of the Atlantic Ocean.


Outcomes and predictors of very stable INR control during chronic anticoagulation therapy.
For patients on warfarin therapy, an international normalized ratio (INR) recall interval not exceeding 4 weeks has traditionally been recommended. Less frequent INR monitoring may be feasible in stable patients. We sought to identify patients with stable INRs (defined as having INR values exclusively within the INR range) and comparator patients (defined as at least one INR outside the INR range) in a retrospective, longitudinal cohort study. Occurrences of thromboembolism, bleeding, and death were compared between groups. Multivariate logistic regression models were used to identify independent predictors of stable INR control. There were 2504 stable and 3569 comparator patients. The combined rates of bleeding and thromboembolism were significantly lower in stable patients. Independent predictors of stable INR control were age older than 70 years and the absence of comorbid heart failure and diabetes. Stable patients were significantly less likely to have target INR of 3.0 or higher or chronic diseases. We hypothesize that many patients demonstrating stable INR control could be safely treated with INR recall intervals greater than the traditional 4 weeks.


Cervical laminoforaminotomy for the treatment of cervical degenerative radiculopathy.
The objective of this systematic review was to use evidence-based medicine to examine the efficacy of posterior laminoforaminotomy in the treatment of cervical radiculopathy. The National Library of Medicine and Cochrane Database were queried using MeSH headings and key words relevant to posterior laminoforaminotomy and cervical radiculopathy. Abstracts were reviewed, and studies meeting inclusion criteria were selected. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Classes I-III). Disagreements regarding the level of evidence were resolved through an expert consensus conference. The group formulated recommendations which contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer review by the Joint Guidelines Committee of the American Association of Neurological Surgeons/Congress of Neurological Surgeons. Posterior laminoforaminotomy improves clinical outcome in the treatment of cervical radiculopathy resulting from soft lateral cervical disc displacement or cervical spondylosis with resulting narrowing of the lateral recess. All studies were Class III. The most frequent design flaw involved the lack of utilization of validated outcomes measures. In addition, few historical studies included a detailed preoperative analysis of the patients. As such, the vast majority of studies that included both pre- and postoperative assessments with legitimate outcomes measures have been performed since 1990. Posterior laminoforaminotomy is an effective treatment for cervical radiculopathy.


Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: systematic review and meta-analysis of observational studies.
To systematically review associations between intake of saturated fat and trans unsaturated fat and all cause mortality, cardiovascular disease (CVD) and associated mortality, coronary heart disease (CHD) and associated mortality, ischemic stroke, and type 2 diabetes. Systematic review and meta-analysis. Medline, Embase, Cochrane Central Registry of Controlled Trials, Evidence-Based Medicine Reviews, and CINAHL from inception to 1 May 2015, supplemented by bibliographies of retrieved articles and previous reviews. Observational studies reporting associations of saturated fat and/or trans unsaturated fat (total, industrially manufactured, or from ruminant animals) with all cause mortality, CHD/CVD mortality, total CHD, ischemic stroke, or type 2 diabetes. Two reviewers independently extracted data and assessed study risks of bias. Multivariable relative risks were pooled. Heterogeneity was assessed and quantified. Potential publication bias was assessed and subgroup analyses were undertaken. The GRADE approach was used to evaluate quality of evidence and certainty of conclusions. For saturated fat, three to 12 prospective cohort studies for each association were pooled (five to 17 comparisons with 90,501-339,090 participants). Saturated fat intake was not associated with all cause mortality (relative risk 0.99, 95% confidence interval 0.91 to 1.09), CVD mortality (0.97, 0.84 to 1.12), total CHD (1.06, 0.95 to 1.17), ischemic stroke (1.02, 0.90 to 1.15), or type 2 diabetes (0.95, 0.88 to 1.03). There was no convincing lack of association between saturated fat and CHD mortality (1.15, 0.97 to 1.36; P=0.10). For trans fats, one to six prospective cohort studies for each association were pooled (two to seven comparisons with 12,942-230,135 participants). Total trans fat intake was associated with all cause mortality (1.34, 1.16 to 1.56), CHD mortality (1.28, 1.09 to 1.50), and total CHD (1.21, 1.10 to 1.33) but not ischemic stroke (1.07, 0.88 to 1.28) or type 2 diabetes (1.10, 0.95 to 1.27). Industrial, but not ruminant, trans fats were associated with CHD mortality (1.18 (1.04 to 1.33) v 1.01 (0.71 to 1.43)) and CHD (1.42 (1.05 to 1.92) v 0.93 (0.73 to 1.18)). Ruminant trans-palmitoleic acid was inversely associated with type 2 diabetes (0.58, 0.46 to 0.74). The certainty of associations between saturated fat and all outcomes was "very low." The certainty of associations of trans fat with CHD outcomes was "moderate" and "very low" to "low" for other associations. Saturated fats are not associated with all cause mortality, CVD, CHD, ischemic stroke, or type 2 diabetes, but the evidence is heterogeneous with methodological limitations. Trans fats are associated with all cause mortality, total CHD, and CHD mortality, probably because of higher levels of intake of industrial trans fats than ruminant trans fats. Dietary guidelines must carefully consider the health effects of recommendations for alternative macronutrients to replace trans fats and saturated fats.


Human tumour-associated macrophages are capable of bone resorption.
Cellular mechanisms of bone resorption associated with skeletal metastasis are poorly understood. Human tumour-associated macrophages (TAMs) isolated from primary lung carcinomas were incubated on bone slices where they formed resorption lacunae after 14 days co-culture with a mouse marrow-derived stromal cell line (ST2) with added 1 alpha, 25-dihydroxy Vitamin D3 and dexamethasone. These co-cultures were associated with the formation of increased numbers of tartrate resistant acid phosphatase positive mononuclear and multinucleated cells. Similar cocultures of ST2 cells with normal alveolar macrophages did not result in lacunar resorption. Both in the presence and absence of ST2 cells, TAMs and normal alveolar macrophages produced roughening of the bone surface with exposure of mineralised collagen fibres. TAMs are capable of both low-grade surface resorption and high-grade lacunar resorption of bone, and a specific interaction with stromal cells is necessary for the latter to occur. TAMs may thus directly contribute to the bone resorption associated with skeletal metastasis.


Carbonyl emissions from a novel heated tobacco product (IQOS): comparison with an e-cigarette and a tobacco cigarette.
To measure carbonyl emissions from a heated tobacco product (IQOS) in comparison with an e-cigarette (Nautilus Mini) and a commercial tobacco cigarette (Marlboro Red). Regular and menthol variants of the heated tobacco product were tested. A tank-type atomizer was tested with a tobacco-flavoured liquid at 10 and 14 W. Aerosol and smoke were collected in impingers containing 2,4-dinitrophenylhydrazine. Health Canada Intense and two more intense puffing regimens were used. Analytical laboratory in Greece. Carbonyl levels in the aerosol and smoke. At the Health Canada Intense regimen, heated tobacco products emitted 5.0-6.4 μg/stick formaldehyde, 144.1-176.7 μg/stick acetaldehyde, 10.4-10.8 μg/stick acrolein, 11.0-12.8 μg/stick propionaldehyde and 1.9-2.0 μg/stick crotonaldehyde. Compared with the tobacco cigarette, levels were on average 91.6% lower for formaldehyde, 84.9% lower for acetaldehyde, 90.6% lower for acrolein, 89.0% lower for propionaldehyde and 95.3% lower for crotonaldehyde. The e-cigarette emitted 0.5-1.0 μg/12 puffs formaldehyde, 0.8-1.5 μg/12 puffs acetaldehyde and 0.3-0.4 μg/12 puffs acrolein, but no propionaldehyde and crotonaldehyde. At more intense puffing regimens, formaldehyde was increased in heated tobacco products, but levels were three-fourfold lower compared with the tobacco cigarette. Based on the findings from Health Canada Intense puffing regimen, use of 20 heated tobacco sticks would result in approximately 85% to 95% reduced carbonyl exposure compared with smoking 20 tobacco cigarettes; the respective reduction in exposure from use of 5 g e-cigarette liquid would be 97% to > 99%. The IQOS heated tobacco product emits substantially lower levels of carbonyls than a commercial tobacco cigarette (Marlboro Red) but higher levels than a Nautilus Mini e-cigarette.


Unraveling Vascular Inflammation: From Immunology to Imaging.
Inflammation is a critical factor in early atherosclerosis and its progression to myocardial infarction. The search for valid surrogate markers of arterial vascular inflammation led to the increasing use of positron emission tomography/computed tomography. Indeed, vascular inflammation is associated with future risk for myocardial infarction and can be modulated with short-term therapies, such as statins, that mitigate cardiovascular risk. However, to better understand vascular inflammation and its mechanisms, a panel was recently convened of world experts in immunology, human translational research, and positron emission tomographic vascular imaging. This contemporary review first strives to understand the diverse roles of immune cells implicated in atherogenesis. Next, the authors describe human chronic inflammatory disease models that can help elucidate the pathophysiology of vascular inflammation. Finally, the authors review positron emission tomography-based imaging techniques to characterize the vessel wall in vivo.


Pollen diversity matters: revealing the neglected effect of pollen diversity on fitness in fragmented landscapes.
Few studies have documented the impacts of habitat fragmentation on plant mating patterns together with fitness. Yet, these processes require urgent attention to better understand the impact of contemporary landscape change on biodiversity and for guiding native plant genetic resource management. We examined these relationships using the predominantly insect-pollinated Eucalyptus socialis. Progeny were collected from trees located in three increasingly disturbed landscapes in southern Australia and were planted out in common garden experiments. We show that individual mating patterns were increasingly impacted by lower conspecific density caused by habitat fragmentation. We determined that reduced pollen diversity probably has effects over and above those of inbreeding on progeny fitness. This provides an alternative mechanistic explanation for the indirect density dependence often inferred between conspecific density and offspring fitness.


Subversion of Cell-Autonomous Immunity and Cell Migration by Legionella pneumophila Effectors.
Bacteria trigger host defense and inflammatory processes, such as cytokine production, pyroptosis, and the chemotactic migration of immune cells toward the source of infection. However, a number of pathogens interfere with these immune functions by producing specific so-called "effector" proteins, which are delivered to host cells via dedicated secretion systems. Air-borne Legionella pneumophila bacteria trigger an acute and potential fatal inflammation in the lung termed Legionnaires' disease. The opportunistic pathogen L. pneumophila is a natural parasite of free-living amoebae, but also replicates in alveolar macrophages and accidentally infects humans. The bacteria employ the intracellular multiplication/defective for organelle trafficking (Icm/Dot) type IV secretion system and as many as 300 different effector proteins to govern host-cell interactions and establish in phagocytes an intracellular replication niche, the Legionella-containing vacuole. Some Icm/Dot-translocated effector proteins target cell-autonomous immunity or cell migration, i.e., they interfere with (i) endocytic, secretory, or retrograde vesicle trafficking pathways, (ii) organelle or cell motility, (iii) the inflammasome and programed cell death, or (iv) the transcription factor NF-κB. Here, we review recent mechanistic insights into the subversion of cellular immune functions by L. pneumophila.


Fermentation of animal components in strict carnivores: a comparative study with cheetah fecal inoculum.
The natural diet of felids contains highly digestible animal tissues but also fractions resistant to small intestinal digestion, which enter the large intestine where they may be fermented by the resident microbial population. Little information exists on the microbial degradability of animal tissues in the large intestine of felids consuming a natural diet. This study aimed to rank animal substrates in their microbial degradability by means of an in vitro study using captive cheetahs fed a strict carnivorous diet as fecal donors. Fresh cheetah fecal samples were collected, pooled, and incubated with various raw animal substrates (chicken cartilage, collagen, glucosamine-chondroitin, glucosamine, rabbit bone, rabbit hair, and rabbit skin; 4 replicates per substrate) for cumulative gas production measurement in a batch culture technique. Negative (cellulose) and positive (casein and fructo-oligosaccharides; FOS) controls were incorporated in the study. Additionally, after 72 h of incubation, short-chain fatty acids (SCFA), including branched-chain fatty acids (BCFA), and ammonia concentrations were determined for each substrate. Glucosamine and glucosamine-chondroitin yielded the greatest organic matter cumulative gas volume (OMCV) among animal substrates (P < 0.05), whereas total SCFA production was greatest for collagen (P < 0.05). Collagen induced an acetate production comparable with FOS and a markedly high acetate-to-propionate ratio (8.41:1) compared with all other substrates (1.67:1 to 2.97:1). Chicken cartilage was rapidly fermentable, indicated by a greater maximal rate of gas production (R(max)) compared with all other substrates (P < 0.05). In general, animal substrates showed an earlier occurrence for maximal gas production rate compared with FOS. Rabbit hair, skin, and bone were poorly fermentable substrates, indicated by the least amount of OMCV and total SCFA among animal substrates (P < 0.05). The greatest amount of ammonia production among animal substrates was measured after incubation of collagen and rabbit bone (P < 0.05). This study provides the first insight into the potential of animal tissues to influence large intestinal fermentation in a strict carnivore, and indicates that animal tissues have potentially similar functions as soluble or insoluble plant fibers in vitro. Further research is warranted to assess the impact of fermentation of each type of animal tissue on gastro-intestinal function and health in the cheetah and other felid species.


Reliability, validity, and responsiveness of the Western Ontario and McMaster Universities Osteoarthritis Index for elderly patients with a femoral neck fracture.
The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) has been extensively evaluated in groups of patients with osteoarthritis, yet not in patients with a femoral neck fracture. This study aimed to determine the reliability, construct validity, and responsiveness of the WOMAC compared with the Short Form-12 (SF-12) and the EuroQol 5D (EQ-5D) questionnaires for the assessment of elderly patients with a femoral neck fracture. Reliability was tested by assessing the Cronbach alpha. Construct validity was determined with the Pearson correlation coefficient. Change scores were calculated from ten weeks to twelve months of follow-up. Standardized response means and floor and ceiling effects were determined. Analyses were performed to compare the results for patients less than eighty years old with those for patients eighty years of age or older. The mean WOMAC total score was 89 points before the fracture in the younger patients and increased from 70 points at ten weeks to 81 points at two years postoperatively. In the older age group, these scores were 86, 75, and 78 points. The mean WOMAC pain scores before the fracture and at ten weeks and two years postoperatively were 92, 76, and 87 points, respectively, in the younger age group and 92, 84, and 93 points in the older age group. Function scores were 89, 68, and 79 points for the younger age group and 84, 71, and 73 points for the older age group. The Cronbach alpha for pain, stiffness, function, and the total scale ranged from 0.83 to 0.98 for the younger age group and from 0.79 to 0.97 for the older age group. Construct validity was good, with 82% and 79% of predefined hypotheses confirmed in the younger and older age groups, respectively. Responsiveness was moderate. No floor effects were found. Moderate to large ceiling effects were found for pain and stiffness scales at ten weeks and twelve months in younger patients (18% to 36%) and in the older age group (38% to 53%). The WOMAC showed good reliability, construct validity, and responsiveness in both age groups of elderly patients with a femoral neck fracture who had been physically and mentally fit before the fracture. The instrument is suitable for use in future clinical studies in these populations. The results are based on two clinical trials. The questionnaires used concern pure, clinically relevant issues (ability to walk, climb stairs, etc.). Moreover, the results can be used for future research comparing clinical outcomes (or treatments) for populations with a femoral neck fracture.


Molecular evidence for the rapid propagation of mouse t haplotypes from a single, recent, ancestral chromosome.
Mouse t haplotypes are variant forms of chromosome 17 that exist at high frequencies in worldwide populations of two species of commensal mice. To determine both the relationship of t haplotypes to each other and the species within which they exist, 35 representative t haplotypes were analyzed by means of 10 independent molecular probes, including five DNA clones and five polypeptide spots identified by means of two-dimensional gel electrophoresis. All of the tested haplotypes were found to share restriction fragments and polypeptide spots that are absent in mice carrying wild-type forms of chromosome 17. This observation provides the first direct evidence that all of the known t haplotypes are descendents of a single ancestral chromosome. The absence of variation among t haplotypes could mean that this ancestral chromosome existed relatively recently, in which case it would be necessary to postulate introgressions of t haplotypes across species lines to explain their presence in both Mus domesticus and M. musculus. Alternatively, it is possible that the ancestral chromosome existed prior to the split between M. domesticus and M. musculus and that, by chance, our probes fail to detect polymorphisms that exist among the t haplotypes. A further result of our analysis is the characterization of a partial t haplotype in a wild population of Israeli mice.


Propagation of laser radiation in a medium with thermally induced birefringence and cubic nonlinearity.
A system of differential equations describing, neglecting diffraction, the propagation of laser radiation in a medium with birefringence and cubic nonlinearity is derived. It is shown that the efficiency of depolarization compensation by means of a 90 degrees polarization rotator or a Faraday mirror decreases with increasing B-integral (nonlinear phase incursion). Comparison of the effectiveness of the considered method in the case of incident linear and circular polarization showed that for the circular polarization the optimal angle of polarization rotator is different from 90 degrees and the degree of polarization is less than for the linear one.


Primary prevention of cardiovascular disease: cost-effectiveness comparison.
The aim of this study was to evaluate the cost-effectiveness of four risk-lowering interventions (smoking cessation, antihypertensives, aspirin, and statins) in primary prevention of cardiovascular disease. Using data from the Framingham Heart Study and the Framingham Offspring study, we built life tables to model the benefits of the selected interventions. Participants were classified by age and level of risk of coronary heart disease. The effects of risk reduction are obtained as numbers of death averted and life-years saved within a 10-year period. Estimates of risk reduction by the interventions were obtained from meta-analyses and costs from Dutch sources. The most cost-effective is smoking cessation therapy, representing savings in all situations. Aspirin is the second most cost-effective (euro 2,263 to euro 16,949 per year of life saved) followed by antihypertensives. Statins are the least cost-effective (euro 73,971 to euro 190,276 per year of life saved). A cost-effective strategy should offer smoking cessation for smokers and aspirin for moderate and high levels of risk among men 45 years of age and older. Statin therapy is the most expensive option in primary prevention at levels of 10-year coronary heart disease risk below 30 percent and should not constitute the first choice of treatment in these populations.


Sex- and age-related mouse toxicity and disposition of the amino acid antitumor agent, acivicin.
Studies of acivicin [(alpha S,5S)-alpha-amino-3-chloro-2-isoxazoline-5-acetic acid, AT-125] plasma levels in ICR, B6D2F1 and CD2F1 mice after single dose i.p. administration showed that total body clearance of drug by male mice was ca. twice the clearance by females of the same strain. Clearance was also greater in older (22-25 g) than in younger (15-18 g) ICR mice. Testosterone pretreatment increased the clearance of acivicin by ICR female mice to that of males. Sex- and age-related differences in pharmacokinetics were more pronounced than strain differences. Excretion studies showed that 53 to 82% of doses were recovered unchanged in the urine with no significant differences between sexes in urinary recovery. In tissue distribution studies in ICR mice, the tissue/plasma concentration ratios at each sampling time were similar for both sexes in all tissues analyzed except kidney (male range: 7-22; female range: 1.5-2.5) and muscle (male range: 5-9; female range: 0.8-1.4). Testosterone pretreatment of females increased the kidney/plasma concentration ratio of acivicin to that of males. Acivicin was also shown to be more toxic (as indicated by LD50) to female than to male mice of the B6D2F1 and CD2F1 strains, in agreement with previous studies in ICR mice. The disposition data suggest that the sex- and age-dependent toxicity of acivicin in mice is due to differences in pharmacokinetics which, in turn, may be related to renal excretion mechanisms.


Bee venom phospholipase A2 ameliorates motor dysfunction and modulates microglia activation in Parkinson's disease alpha-synuclein transgenic mice.
α-Synuclein (α-Syn) has a critical role in microglia-mediated neuroinflammation, which leads to the development of Parkinson's disease (PD). Recent studies have shown that bee venom (BV) has beneficial effects on PD symptoms in human patients or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxin-induced PD mice. This study investigated whether treatment with BV-derived phospholipase A2 (bvPLA2) would improve the motor dysfunction and pathological features of PD in human A53T α-Syn mutant transgenic (A53T Tg) mice. The motor dysfunction of A53T Tg mice was assessed using the pole test. The levels of α-Syn, microglia and the M1/M2 phenotype in the spinal cord were evaluated by immunofluorescence. bvPLA2 treatment significantly ameliorated motor dysfunction in A53T Tg mice. In addition, bvPLA2 significantly reduced the expression of α-Syn, the activation and numbers of microglia, and the ratio of M1/M2 in A53T Tg mice. These results suggest that bvPLA2 could be a promising treatment option for PD.


Country-Level Gender Equality and Adolescents' Contraceptive Use in Europe, Canada and Israel: Findings from 33 Countries.
Although an association between gender equality and contraceptive use has been confirmed among adult samples, few studies have explored this relationship among adolescents. An examination of whether adolescents' contraceptive use is more prevalent in countries with higher levels of gender equality is needed to fill this gap. Nationally representative data from 33 countries that participated in the 2013-2014 Health Behaviour in School-Aged Children study and country-level measures of gender equality-using the 2014 Global Gender Gap Index-were analyzed. Multilevel multinomial logistic regression analyses were employed to assess associations between gender equality and contraceptive use (condom only, pill only and dual methods) at last intercourse as reported by 4,071 females and 4,110 males aged 14-16. Increasing gender equality was positively associated with contraceptive use among both males and females. For every 0.1-point increase on the equality scale, the likelihood of condom use at last intercourse rose (odds ratio, 2.1 for females), as did the likelihood of pill use (6.5 and 9.6, respectively, for males and females) and dual method use (2.1 and 5.6, respectively). Associations with pill use and dual use remained significant after national wealth and income inequality were controlled for. Overall, associations were stronger for females than for males. More research is needed to identify potential causal pathways and mechanisms through which gender equality and adolescents' contraceptive use may influence one another.


[Knowledges related to self-care in health among women of Southern Brazil's rural area].
This article aimed to study self-care actions by a group of rural women from the city of Pelotas, state of Rio Grande do Sul, Brazil. This was a qualitative research in which 11 women living in the city's rural area have participated. Data collection occurred between May and June, 2010, through semi-structured interviews. A content analysis was performed on the data. The oldest informants have participated in the community group for 12 years, doing workmanship and exchanging knowledge on the use of medicinal plants. Self-care is part of the actions of these women, which are performed in many different ways, including actions in the family context, and the transmission of beliefs and habits through generations. We hope to contribute to the valorization of rural women, educating health professionals on health practices that meet real needs of the assisted community, reclaiming the culture related to self-care.


Improving sleep and learning in rehabilitation after stroke, part 2 (INSPIRES2): study protocol for a home-based randomised control trial of digital cognitive behavioural therapy (dCBT) for insomnia.
Consolidation of motor skill learning, a key component of rehabilitation post-stroke, is known to be sleep dependent. However, disrupted sleep is highly prevalent after stroke and is often associated with poor motor recovery and quality of life. Previous research has shown that digital cognitive behavioural therapy (dCBT) for insomnia can be effective at improving sleep quality after stroke. Therefore, the aim of this trial is to evaluate the potential for sleep improvement using a dCBT programme, to improve rehabilitation outcomes after stroke. We will conduct a parallel-arm randomised controlled trial of dCBT (Sleepio) versus treatment as usual among individuals following stroke affecting the upper limb. Up to 100 participants will be randomly allocated (2:1) into either the intervention (6-8 week dCBT) or control (continued treatment as usual) group. The primary outcome of the study will be change in insomnia symptoms pre to post intervention compared with treatment as usual. Secondary outcomes include improvement in overnight motor memory consolidation and sleep measures between intervention groups, correlations between changes in sleep behaviour and overnight motor memory consolidation in the dCBT group and changes in symptoms of depression and fatigue between the dCBT and control groups. Analysis of covariance models and correlations will be used to analyse data from the primary and secondary outcomes. The study has received approval from the National Research Ethics Service (22/EM/0080), Health Research Authority (HRA) and Health and Care Research Wales (HCRW), IRAS ID: 306 291. The results of this trial will be disseminated via presentations at scientific conferences, peer-reviewed publication, public engagement events, stakeholder organisations and other forms of media where appropriate. NCT05511285.


Tumor necrosis factor-alpha dependent cytotoxicity of human skin mast cells is enhanced by anti-IgE antibodies.
Mast cells dispersed from human skin and purified by density-gradient centrifugation were cytotoxic toward the mouse fibrosarcoma cell line WEHI-164. Skin mast cells were not cytotoxic toward the NK cell-sensitive cell line K562. Killing of WEHI-164 occurred over a prolonged (greater than 18 h) period of incubation with mast cells and was effectively inhibited by polyclonal antibodies and mAb against TNF-alpha suggesting that this cytokine plays an important role in mast cell-mediated cytotoxicity. Whereas lysates of rat peritoneal mast cells exhibited cytotoxicity toward WEHI-164, this was not found with lysates of unstimulated skin mast cells suggesting that TNF-alpha is not stored preformed in the latter. Killing of WEHI-164 cells by skin mast cells was enhanced by anti-IgE and there was a significant correlation between histamine release and cytotoxicity after activation with this stimulus. We conclude that human skin mast cells are a potential source of TNF-alpha and suggest that these cells, particularly after activation, might contribute to the synthesis of this multifunctional cytokine in inflammatory sites.


Safety evaluation of the food enzyme α-amylase from the Parageobacillus thermoglucosidasius strain DP-Gzb47.
The food enzyme α-amylase (1,4-α-d-glucan glucanohydrolase; EC 220.127.116.11) is produced with a non-genetically modified Parageobacillus thermoglucosidasius strain DP-Gzb47 by Danisco US Inc. The α-amylase food enzyme is intended to be used in brewing processes and distilled alcohol production. Since residual amounts of the food enzyme are removed by distillation, dietary exposure was only calculated for brewing processes. Based on the maximum use levels recommended for brewing processes, and individual data from the EFSA Comprehensive European Food Database, dietary exposure to the food enzyme-Total Organic Solids (TOS) was estimated to be up to 0.880 mg TOS/kg body weight (bw) per day in European populations. As the production strain of P. thermoglucosidasius meets the requirements for a Qualified Presumption of Safety (QPS) approach, no toxicological data are required. Similarity of the amino acid sequence to those of known allergens was searched for and no match was found. The Panel considered that under the intended conditions of use, other than distilled alcohol production, the risk of allergic sensitisation and elicitation reactions by dietary exposure cannot be excluded, but the likelihood for this to occur is considered to be low. Based on the data provided, the Panel concluded that this food enzyme does not give rise to safety concerns under the intended conditions of use.


Muscle protein synthesis, mTORC1/MAPK/Hippo signaling, and capillary density are altered by blocking of myostatin and activins.
Loss of muscle mass and function occurs in various diseases. Myostatin blocking can attenuate muscle loss, but downstream signaling is not well known. Therefore, to elucidate associated signaling pathways, we used the soluble activin receptor IIb (sActRIIB-Fc) to block myostatin and activins in mice. Within 2 wk, the treatment rapidly increased muscle size as expected but decreased capillary density per area. sActRIIB-Fc increased muscle protein synthesis 1-2 days after the treatment correlating with enhanced mTORC1 signaling (phosphorylated rpS6 and S6K1, r = 0.8). Concurrently, increased REDD1 and eIF2Bε protein contents and phosphorylation of 4E-BP1 and AMPK was observed. In contrast, proangiogenic MAPK signaling and VEGF-A protein decreased. Hippo signaling has been characterized recently as a regulator of organ size and an important regulator of myogenesis in vitro. The phosphorylation of YAP (Yes-associated protein), a readout of activated Hippo signaling, increased after short- and longer-term myostatin and activin blocking and in exercised muscle. Moreover, dystrophic mdx mice had elevated phosphorylated and especially total YAP protein content. These results show that the blocking of myostatin and activins induce rapid skeletal muscle growth. This is associated with increased protein synthesis and mTORC1 signaling but decreased capillary density and proangiogenic signaling. It is also shown for the first time that Hippo signaling is activated in skeletal muscle after myostatin blocking and exercise and also in dystrophic muscle. This suggests that Hippo signaling may have a role in skeletal muscle in various circumstances.


Keratodermia blenorrhagica, arthritis, and polymyositis with cardiopulmonary complications.
A patient is described who had polymyositis with arthritis, keratodermia blenorrhagica, pulmonary fibrosis, and cardiac failure with a right bundle branch block. The cutaneous lesions on his palms and soles, considered to be specific for Reiter's syndrome, pointed to an overlapping of polymyositis with features of this syndrome. Findings typical of myositis were present. In addition a muscle biopsy showed sarcolemmal and endomysial deposits of IgG and IgM, and the serum level of IgM was elevated. Because skin lesions appeared at the height of symptoms in other organs, the possibility is raised that both might stem from a common immune process.


Impact of exercise on articular cartilage in people at risk of, or with established, knee osteoarthritis: a systematic review of randomised controlled trials.
To investigate the impact of knee joint loading exercise on articular cartilage in people at risk of, or with established, knee osteoarthritis (OA) by conducting a systematic review of randomised controlled trials (RCTs). We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. We performed a literature search with no restriction on publication year or language in MEDLINE, EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials and Web of Science up to September 2017. RCTs investigating the impact of exercise on MRI-assessed articular cartilage in people over 18 years of age. We included nine trials, including a total of 14 comparisons of cartilage morphometry, morphology and composition outcomes, of which two included participants at increased risk of knee OA and 12 included participants with knee OA. In participants at increased risk, one study comparison reported no effect on cartilage defects and one had positive effects on glycosaminoglycans (GAG). In participants with OA, six study comparisons reported no effect on cartilage thickness, volume or defects; one reported a negative effect and one no effect on GAG; two reported a positive effect and two no effect on collagen. Knee joint loading exercise seems to not be harmful for articular cartilage in people at increased risk of, or with, knee OA. However, the quality of evidence was low, including some interventions studying activities considered outside the therapeutic loading spectrum to promote cartilage health.


Cellular High-Energy Cavitation Trauma - Description of a Novel In Vitro Trauma Model in Three Different Cell Types.
The mechanisms involved in traumatic brain injury have yet to be fully characterized. One mechanism that, especially in high-energy trauma, could be of importance is cavitation. Cavitation can be described as a process of vaporization, bubble generation, and bubble implosion as a result of a decrease and subsequent increase in pressure. Cavitation as an injury mechanism is difficult to visualize and model due to its short duration and limited spatial distribution. One strategy to analyze the cellular response of cavitation is to employ suitable in vitro models. The flyer-plate model is an in vitro high-energy trauma model that includes cavitation as a trauma mechanism. A copper fragment is accelerated by means of a laser, hits the bottom of a cell culture well causing cavitation, and shock waves inside the well and cell medium. We have found the flyer-plate model to be efficient, reproducible, and easy to control. In this study, we have used the model to analyze the cellular response to microcavitation in SH-SY5Y neuroblastoma, Caco-2, and C6 glioma cell lines. Mitotic activity in neuroblastoma and glioma was investigated with BrdU staining, and cell numbers were calculated using automated time-lapse imaging. We found variations between cell types and between different zones surrounding the lesion with these methods. It was also shown that the injured cell cultures released S-100B in a dose-dependent manner. Using gene expression microarray, a number of gene families of potential interest were found to be strongly, but differently regulated in neuroblastoma and glioma at 24 h post trauma. The data from the gene expression arrays may be used to identify new candidates for biomarkers in cavitation trauma. We conclude that our model is useful for studies of trauma in vitro and that it could be applied in future treatment studies.


Frequency multiplexed raster neural networks. 1: Theory.
In the first part of this paper we present frequency multiplexed raster (FMR) optical implementation of neural networks. A hidden difficulty for hardware (optical and electronic) implementation is that the dimension of the synaptic matrix is twice that of the input and output matrices or vectors. For 2-D images, which is we believe one of the greatest potentialities of neural networks, the synaptic matrix is 4-D and cannot be directly implemented in optics. We propose FMR as a method to fold this matrix into a 2-D format. In the second part of this paper we describe the system built in our laboratory showing the feasibility of FMR optical neural networks. The system is built from an optical input module, a fixed synaptic matrix coded on a transparency, a CCD camera, and a microcomputer which performs the thresholding and feedback operations. In a later stage the fixed matrix will be replaced by a programmable matrix.


Microfluidic sorting of protein nanocrystals by size for X-ray free-electron laser diffraction.
The advent and application of the X-ray free-electron laser (XFEL) has uncovered the structures of proteins that could not previously be solved using traditional crystallography. While this new technology is powerful, optimization of the process is still needed to improve data quality and analysis efficiency. One area is sample heterogeneity, where variations in crystal size (among other factors) lead to the requirement of large data sets (and thus 10-100 mg of protein) for determining accurate structure factors. To decrease sample dispersity, we developed a high-throughput microfluidic sorter operating on the principle of dielectrophoresis, whereby polydisperse particles can be transported into various fluid streams for size fractionation. Using this microsorter, we isolated several milliliters of photosystem I nanocrystal fractions ranging from 200 to 600 nm in size as characterized by dynamic light scattering, nanoparticle tracking, and electron microscopy. Sorted nanocrystals were delivered in a liquid jet via the gas dynamic virtual nozzle into the path of the XFEL at the Linac Coherent Light Source. We obtained diffraction to ∼4 Å resolution, indicating that the small crystals were not damaged by the sorting process. We also observed the shape transforms of photosystem I nanocrystals, demonstrating that our device can optimize data collection for the shape transform-based phasing method. Using simulations, we show that narrow crystal size distributions can significantly improve merged data quality in serial crystallography. From this proof-of-concept work, we expect that the automated size-sorting of protein crystals will become an important step for sample production by reducing the amount of protein needed for a high quality final structure and the development of novel phasing methods that exploit inter-Bragg reflection intensities or use variations in beam intensity for radiation damage-induced phasing. This method will also permit an analysis of the dependence of crystal quality on crystal size.


Association of Childhood Exposure to Nitrogen Dioxide and Polygenic Risk Score for Schizophrenia With the Risk of Developing Schizophrenia.
Schizophrenia is a highly heritable psychiatric disorder, and recent studies have suggested that exposure to nitrogen dioxide (NO2) during childhood is associated with an elevated risk of subsequently developing schizophrenia. However, it is not known whether the increased risk associated with NO2 exposure is owing to a greater genetic liability among those exposed to highest NO2 levels. To examine the associations between childhood NO2 exposure and genetic liability for schizophrenia (as measured by a polygenic risk score), and risk of developing schizophrenia. Population-based cohort study including individuals with schizophrenia (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code F20) and a randomly selected subcohort. Using national registry data, all individuals born in Denmark between May 1, 1981, and December 31, 2002, were followed up from their 10th birthday until the first occurrence of schizophrenia, emigration, death, or December 31, 2012, whichever came first. Statistical analyses were conducted between October 24, 2018, and June 17, 2019. Individual exposure to NO2 during childhood estimated as mean daily exposure to NO2 at residential addresses from birth to the 10th birthday. Polygenic risk scores were calculated as the weighted sum of risk alleles at selected single-nucleotide polymorphisms based on genetic material obtained from dried blood spot samples from the Danish Newborn Screening Biobank and on the Psychiatric Genomics Consortium genome-wide association study summary statistics file. The main outcome was schizophrenia. Weighted Cox proportional hazards regression models were fitted to estimate adjusted hazard ratios (AHRs) for schizophrenia with 95% CIs according to the exposures. Of a total of 23 355 individuals, 11 976 (51.3%) were male and all had Danish-born parents. During the period of the study, 3531 were diagnosed with schizophrenia. Higher polygenic risk scores were correlated with higher childhood NO2 exposure (ρ = 0.0782; 95% CI, 0.065-0.091; P < .001). A 10-μg/m3 increase in childhood daily NO2 exposure (AHR, 1.23; 95% CI, 1.15-1.32) and a 1-SD increase in polygenic risk score (AHR, 1.29; 95% CI, 1.23-1.35) were independently associated with increased schizophrenia risk. These findings suggest that the apparent association between NO2 exposure and schizophrenia is only slightly confounded by a higher polygenic risk score for schizophrenia among individuals living in areas with greater NO2. The findings demonstrate the utility of including polygenic risk scores in epidemiologic studies.


Nursing job satisfaction, certification and healthcare-associated infections in critical care.
The purpose of this study was to examine the relationship between nursing job satisfaction and healthcare-associated infections (HAIs) in adult critical care. Multilevel modelling was used to examine the relationship between nursing job satisfaction and two HAIs, ventilator-associated pneumonia (VAP) and central-line associated bloodstream infections (CLABSI). Units with nurses that reported satisfaction with organisational policies were associated with a 6.08 decrease in VAP (p=0.013) and units with nurses reporting favourable perception of task requirements were associated with a 7.02 decrease in VAP (.014). Positive perception of organisational policies was associated with lower rates of CLABSI (p=0.002). Unexpected findings include a positive relationship between perception of pay and autonomy and CLABSI as well as perception of interactions and VAP. Units with a higher proportion of Critical Care Registered Nurse (CCRN) certified nurses were associated with lower rates of both CLABSI (p<0.001) and VAP (p=0.037). This study provides preliminary evidence to support the relationship between nursing job satisfaction and HAIs in critical care, although some relationships were counterintuitive. A secondary finding included significant relationships between CCRN certified nurses and HAIs.


Thyroidal and peripheral production of thyroid hormones. Review of recent findings and their clinical implications.
There are two biologically active thyroid hormones, thyroxine (T4) and triiodothyronine (T3). Most T3 is produced extrathyroidally, so that alterations in circulating thyroid hormone concentrations may occur as a result of both thyroidal and extrathyroidal abnormalities. Extrathyroidal T4 conversion to T3 is decreased in patients with different acute and chronic illnesses. When T4 conversion to T3 is impaired and serum T3 concentrations decline, serum concentrations of biologically inactive 3,3',5'-triiodothyronine (reverse T3) increase. In this review, we present current information on thyroidal and extrathyroidal T4 and T3 production in normal subjects and patients with various thyroid diseases and other illnesses, consider the physiologic significance of these changes, and discuss the value and interpretation of various iodothyronine measurements.


Simulated physician learning intervention to improve safety and quality of diabetes care: a randomized trial.
To assess two physician learning interventions designed to improve safety and quality of diabetes care delivered by primary care physicians (PCPs). This group randomized clinical trial included 57 consenting PCPs and their 2,020 eligible adult patients with diabetes. Physicians were randomized to no intervention (group A), a simulated case-based physician learning intervention (group B), or the same simulated case-based learning intervention with physician opinion leader feedback (group C). Dependent variables included A1C values, LDL cholesterol values, pharmacotherapy intensification rates in patients not at clinical goals, and risky prescribing events. Groups B and C had substantial reductions in risky prescribing of metformin in patients with renal impairment (P = 0.03). Compared with groups A and C, physicians in group B achieved slightly better glycemic control (P = 0.04), but physician intensification of oral glucose-lowering medications was not affected by interventions (P = 0.41). Lipid management improved over time (P < 0.001) but did not differ across study groups (P = 0.67). A simulated, case-based learning intervention for physicians significantly reduced risky prescribing events and marginally improved glycemic control in actual patients. The addition of opinion leader feedback did not improve the learning intervention. Refinement and further development of this approach is warranted.


Refraction correction in holographic interferometry and tomography of transparent objects.
In this paper we review and extend the state of the art in the algorithms that have been developed to tomographically reconstruct 1-D and 2-D refractive-index fields in the presence of significant refraction. A perturbation approach and two iterative procedures were tested and compared in numerical simulation of holographic interferometry experiments. Due to the nonlinearity of the problem, it is very difficult to draw general conclusions with respect to the behavior of the iterative algorithms, which is divergent in the examples presented here. In contrast, the perturbation technique, which is the easiest one to implement and the fastest to run, is shown to be very powerful in reducing refraction errors.


A novel N-terminal isoform of the neuron-specific K-Cl cotransporter KCC2.
The neuronal K-Cl cotransporter KCC2 maintains the low intracellular chloride concentration required for the hyperpolarizing actions of inhibitory neurotransmitters gamma-aminobutyric acid and glycine in the central nervous system. This study shows that the mammalian KCC2 gene (alias Slc12a5) generates two neuron-specific isoforms by using alternative promoters and first exons. The novel KCC2a isoform differs from the only previously known KCC2 isoform (now termed KCC2b) by 40 unique N-terminal amino acid residues, including a putative Ste20-related proline alanine-rich kinase-binding site. Ribonuclease protection and quantitative PCR assays indicated that KCC2a contributes 20-50% of total KCC2 mRNA expression in the neonatal mouse brain stem and spinal cord. In contrast to the marked increase in KCC2b mRNA levels in the cortex during postnatal development, the overall expression of KCC2a remains relatively constant and makes up only 5-10% of total KCC2 mRNA in the mature cortex. A rubidium uptake assay in human embryonic kidney 293 cells showed that the KCC2a isoform mediates furosemide-sensitive ion transport activity comparable with that of KCC2b. Mice that lack both KCC2 isoforms die at birth due to severe motor defects, including disrupted respiratory rhythm, whereas mice with a targeted disruption of the first exon of KCC2b survive for up to 2 weeks but eventually die due to spontaneous seizures. We show that these mice lack KCC2b but retain KCC2a mRNA. Thus, distinct populations of neurons show a differential dependence on the expression of the two isoforms: KCC2a expression in the absence of KCC2b is presumably sufficient to support vital neuronal functions in the brain stem and spinal cord but not in the cortex.


Motor innervation of dorsoventrally reversed wings in chick/quail chimeric embryos.
In the limb plexus, motor axons destined for limb muscles diverge along separate pathways to innervate muscles derived from either the dorsal or ventral premuscle masses. We have examined the axonal guidance cues involved in this initial, specific pathway choice at the plexus by making dorsoventral (D/V) limb bud reversals prior to innervation. Chick/quail chimeras were used to determine the proximodistal level of the reversal in tissue sections. The specificity of the projections to dorsal or ventral nerve trunks was assessed by retrograde HRP labeling at ages prior to motoneuron death. Axons corrected for the reversal when the level of the graft was proximal to the plexus, and when the reversed limb and its gross nerve pattern were normal. If all of these conditions were not satisfied, aberrant innervation patterns were observed. Axonal trajectories were analyzed within the host tissue, at the host-graft border, and within rotated tissue to determine where along the pathway guidance cues might be located. Special attention was given to cases in which axons compensated for the reversal to project in accord with the positions of their soma in the lateral motor column. In these correcting cases, after normal D/V sorting in the spinal nerves of the host, motor axons altered their trajectories upon entering rotated graft tissue as they approached and traversed the plexus. Because corrections were within rotated tissue and not proximal to it, the D/V pathway cues are unlikely to be long-range target-derived signals, but rather appear to be closely associated with positional information in the plexus region and also more proximally in the tissue surrounding the distal spinal nerves.


Cancer in the offspring of female radiation workers: a record linkage study.
This study uses record linkage between the National Registry of Childhood Tumours (NRCT) and the National Registry for Radiation Workers to re-assess our earlier finding that the offspring of women radiation workers exposed to ionising radiation before the child's conception may be at an increased risk of childhood cancer. An additional 16,964 childhood cancer patients taken from the NRCT, together with the same number of matched controls, are included. Pooled analyses, based on the new and original datasets, include 52,612 cases and their matched controls. Relative risks (RRs) for maternal employment as a radiation worker, maternal exposure or not during the relevant pregnancy and pattern of employment relative to conception and diagnosis dates were calculated.The new data provide no evidence of an increased risk of childhood cancer associated with maternal preconception radiation work and thus do not support our earlier finding of a raised risk in the offspring of female radiation workers. Considering the pooled data, a weak association was found between maternal radiation work during pregnancy and childhood cancer in offspring although the evidence is limited by the small numbers of linked cases and controls.


Decrease of dynamin 2 levels in late-onset Alzheimer's disease alters Abeta metabolism.
Late-onset Alzheimer's disease (LOAD) is significantly associated with a single nucleotide polymorphism located in the dynamin (DNM) 2 gene, especially in non-carriers of the apolipoprotein E-epsilon4 allele. In this study we used real-time PCR to show that DNM2 mRNA is significantly reduced in the cortex of AD brains and in the peripheral blood of dementia patients. Neuroblastoma cells transfected with a dominant negative DNM2 had increased amyloid beta protein (Abeta) secretion and most of the amyloid precursor protein (APP) in these cells was localized to the plasma membrane. In addition, these cells were rich in flotillin, which is a component of lipid rafts. These data suggest that DNM2 expression is reduced in LOAD, which results in the accumulation of APP in lipid raft-rich plasma membranes. Consequently, Abeta secretion may increase in LOAD neurons.


Ovine tracheal muscle contraction in vitro: inhibition by calcium channel blockers gallopamil and verapamil.
We compared the inhibitory effects of calcium channel blockers, gallopamil and verapamil on acetylcholine (Ach)-induced contractions of ovine tracheal muscle in vitro. Adult sheep were sacrificed and tracheal strips were obtained by cutting the single tracheal rings from the mid-trachea. Tracheal strips were suspended in Krebs-Henseleit solution and isometric tension measured upon stimulation with cumulative doses of Ach (10(-7) to 10(-4) M) without and after pretreatment with gallopamil (10(-7) to 10(-6) M) or verapamil (10(-6) to 10(-5) M). In untreated tissues, the mean concentration of Ach required to produce 50% of maximal response (EC50) was 4.3 x 10(-6) M Ach. Both gallopamil and verapamil inhibited the Ach-induced contractions of ovine tracheal smooth muscle, by shifting the dose-response curves to Ach to the right. EC50 Ach for gallopamil (10(-6) M) and verapamil (10(-6) M) was 2.6 x 10(-5) and 5.2 x 10(-6) M, respectively. Dose ratio defined as postantagonist EC50 Ach/control EC50 Ach, was 7.7 for gallopamil and 2.0 for verapamil. Thus, the inhibitory effect of gallopamil was approximately 4-fold more potent than that of verapamil. Gallopamil was 17-fold more potent than verapamil in relaxing precontracted tracheal strips. The dose of calcium antagonists required to produce 25% relaxation (EC25) of tracheal strips precontracted with 10(-4) Ach was 3.7 x 10(-5) M for verapamil and 2.2 x 10(-6) M for gallopamil. These results indicate that gallopamil is effective against Ach-induced contractions of ovine trachealis muscles, and is more potent than verapamil.


EDEM1 recognition and delivery of misfolded proteins to the SEL1L-containing ERAD complex.
Terminally misfolded or unassembled secretory proteins are retained in the endoplasmic reticulum (ER) and subsequently cleared by the ER-associated degradation (ERAD) pathway. The degradation of ERAD substrates involves mannose trimming of N-linked glycans; however, the mechanisms of substrate recognition and sorting to the ERAD pathway are poorly defined. EDEM1 (ER degradation-enhancing alpha-mannosidase-like 1 protein) has been proposed to play a role in ERAD substrate signaling or recognition. We show that EDEM1 specifically binds nonnative proteins in a glycan-independent manner. Inhibition of mannosidase activity with kifunensine or disruption of the EDEM1 mannosidase-like domain by mutation had no effect on EDEM1 substrate binding but diminished its association with the ER membrane adaptor protein SEL1L. These results support a model whereby EDEM1 binds nonnative proteins and uses its mannosidase-like domain to target aberrant proteins to the ER membrane dislocation and ubiquitination complex containing SEL1L.


Addressing context to understand physical activity among Muslim university students: the role of gender, family, and culture.
Physical inactivity is a crucial risk factor for the development of chronic health issues, which have a high incidence among Arabs living in the Gulf Cooperation Council (GCC) countries. The Qatar Stepwise Survey 2012 reported that approximately 44% of young adults 18-44 years of age had insufficient levels of physical activity. Family is a powerful source of information and socialization for adolescents and has a strong influence on their attitudes, decision-making, and behaviors. The purpose of this study is to understand how university students' physical activity can be influenced by sociocultural factors, particularly family health values and Muslim Arab culture. Using the criterion sampling strategy, 20 undergraduate Muslim students (Female students =10, Male students = 10) aged from 18 to 23 years who were Qatari or born and also raised in Qatar were recruited and interviewed. Participants were asked if they consider themselves active or not, about their perception of family health values regarding physical activity and the factors shaping these values, and the influence of family values on their physical activity behavior. The interviews were transcribed verbatim, coded, and analyzed following inductive analysis. The majority of the participants were influenced by their family health values, which were shaped by Qatari culture and the culture of origin for non-Qatari and were implicitly shaped by Islam. Participants reported that their role models of physical activity were males (fathers and male siblings), a health condition will motivate their families to be physically active, and families give priority to work and academic achievement over physical activity. A few participants showed that there was explicit influence of Islam on their physical activity, because culture's influence was veiling religion's. Culture was seen as a facilitator for physical activity from the males' perspectives, which was not the case for female participants who reported the negative influence of culture on their physical activity because of the limited choices available for them. Non-Qatari students revealed that their culture of origin (such as Syria, Palestine, Egypt, Somalia, Bangladesh, Sudan, Pakistan and India) was the dominant factor in shaping their family health values. The findings address gaps in the literature about families' health values regarding physical activity in Qatar, the influence of the different ecologies surrounding these values, and the physical activity behaviors of university students. Knowledge about these factors can aid in the development of family-based interventions designed to motivate adolescents to be physically active, which should be religion- and culture-tailored.


Selection, characterisation and mapping of complex electrochemical processes at individual single-walled carbon nanotubes: the case of serotonin oxidation.
The electrochemical (EC) oxidation of the neurotransmitter, serotonin, at individual single-walled carbon nanotubes (SWNTs) is investigated at high resolution using a novel platform that combines flow-aligned SWNTs with atomic force microscopy, Raman microscopy, electronic conductance measurements, individual SWNT electrochemistry and high-resolution scanning electrochemical cell microscopy (SECCM). SECCM has been used to visualise the EC activity along side-wall sections of metallic SWNTs to assess the extent to which side-walls promote the electrochemistry of this complex multi-step process. Uniform and high EC activity is observed that is consistent with significant reaction at the side-wall, rather than electrochemistry being driven by defects alone. By scanning forward and reverse (trace and retrace) over the same region of a SWNT, it is also possible to assess any blocking of EC activity by serotonin oxidation reaction products. At a physiologically relevant concentration (5 μM), there is no detectable blocking of SWNTs, which can be attributed, at least in part, to the high diffusion rate to an individual, isolated SWNT in the SECCM format. At higher serotonin concentration (2 mM), oligomer formation from oxidation products is much more significant and major blocking of the EC process is observed from line profiles recorded as the SECCM meniscus moves over an SWNT. The SECCM line profile morphology is shown to be highly diagnostic of whether blocking occurs during EC processes. The studies herein add to a growing body of evidence that various EC processes at SWNTs, from simple outer sphere redox reactions to complex multi-step processes, occur readily at pristine SWNTs. The platform described is of general applicability to various types of nanostructures and nanowires.


Bowel obstruction secondary to mesenteric cyst formation.
A rare cause of intra-abdominal obstruction, mesenteric cysts derive from lymphatic tissue. The differential diagnosis should include mesenteric cyst when the patient presents with a history of multiple episodes of partial small-bowel obstruction or with an asymptomatic abdominal mass. A year-old girl was brought to the Family Practice Center with episodic, sharp, nonradiating, left-sided, mid-upper-abdominal pain. Examination indicated a possible diagnosis of mesenteric adenitis. Due to variation in the signs and symptoms of the condition, it appears that the use of ultrasonography is the most effective, nonoperative method of evaluation. Ultrasonography appears to be the most effective, nonoperative method of evaluation. Surgery is the only definitive diagnostic and therapeutic modality.


Effects of inflorescence stem structure and cell wall components on the mechanical strength of inflorescence stem in herbaceous peony.
Herbaceous peony (Paeonia lactiflora Pall.) is a traditional famous flower, but its poor inflorescence stem quality seriously constrains the development of the cut flower. Mechanical strength is an important characteristic of stems, which not only affects plant lodging, but also plays an important role in stem bend or break. In this paper, the mechanical strength, morphological indices and microstructure of P. lactiflora development inflorescence stems were measured and observed. The results showed that the mechanical strength of inflorescence stems gradually increased, and that the diameter of inflorescence stem was a direct indicator in estimating mechanical strength. Simultaneously, with the development of inflorescence stem, the number of vascular bundles increased, the vascular bundle was arranged more densely, the sclerenchyma cell wall thickened, and the proportion of vascular bundle and pith also increased. On this basis, cellulose and lignin contents were determined, PlCesA3, PlCesA6 and PlCCoAOMT were isolated and their expression patterns were examined including PlPAL. The results showed that cellulose was not strictly correlated with the mechanical strength of inflorescence stem, and lignin had a significant impact on it. In addition, PlCesA3 and PlCesA6 were not key members in cellulose synthesis of P. lactiflora and their functions were also different, but PlPAL and PlCCoAOMT regulated the lignin synthesis of P. lactiflora. These data indicated that PlPAL and PlCCoAOMT could be applied to improve the mechanical strength of P. lactiflora inflorescence stem in genetic engineering.


Quantification of right ventricular volume in dogs: a comparative study between three-dimensional echocardiography and computed tomography with the reference method magnetic resonance imaging.
Right ventricular (RV) volume and function are important diagnostic and prognostic factors in dogs with primary or secondary right-sided heart failure. The complex shape of the right ventricle and its retrosternal position make the quantification of its volume difficult. For that reason, only few studies exist, which deal with the determination of RV volume parameters. In human medicine cardiac magnetic resonance imaging (CMRI) is considered to be the reference technique for RV volumetric measurement (Nat Rev Cardiol 7(10):551-563, 2010), but cardiac computed tomography (CCT) and three-dimensional echocardiography (3DE) are other non-invasive methods feasible for RV volume quantification. The purpose of this study was the comparison of 3DE and CCT with CMRI, the gold standard for RV volumetric quantification. 3DE showed significant lower and CCT significant higher right ventricular volumes than CMRI. Both techniques showed very good correlations (R > 0.8) with CMRI for the volumetric parameters end-diastolic volume (EDV) and end-systolic volume (ESV). Ejection fraction (EF) and stroke volume (SV) were not different when considering CCT and CMRI, whereas 3DE showed a significant higher EF and lower SV than CMRI. The 3DE values showed excellent intra-observer variability (<3%) and still acceptable inter-observer variability (<13%). CCT provides an accurate image quality of the right ventricle with comparable results to the reference method CMRI. CCT overestimates the RV volumes; therefore, it is not an interchangeable method, having the disadvantage as well of needing general anaesthesia. 3DE underestimated the RV-Volumes, which could be explained by the worse image resolution. The excellent correlation between the methods indicates a close relationship between 3DE and CMRI although not directly comparable. 3DE is a promising technique for RV volumetric quantification, but further studies in awake dogs and dogs with heart disease are necessary to evaluate its usefulness in veterinary cardiology.


Caspase-1 cleavage of the TLR adaptor TRIF inhibits autophagy and β-interferon production during Pseudomonas aeruginosa infection.
Bacterial infection can trigger autophagy and inflammasome activation, but the effects of inflammasome activation on autophagy are unknown. We examined this in the context of Pseudomonas aeruginosa macrophage infection, which triggers NLRC4 inflammasome activation. P. aeruginosa induced autophagy via TLR4 and its adaptor TRIF. NLRC4 and caspase-1 activation following infection attenuated autophagy. Caspase-1 directly cleaved TRIF to diminish TRIF-mediated signaling, resulting in inhibition of autophagy and in reduced type I interferon production. Expression of a caspase-1 resistant TRIF mutant enhanced autophagy and type I interferon production following infection. Preventing TRIF cleavage by caspase-1 in an in vivo model of P. aeruginosa infection resulted in enhanced bacterial autophagy, attenuated IL-1β production, and increased bacterial clearance. Additionally, TRIF cleavage by caspase-1 diminished NLRP3 inflammasome activation. Thus, caspase-1 mediated TRIF cleavage is a key event in controlling autophagy, type I interferon production, and inflammasome activation with important functional consequences.


Embedding caregiver support in community-based services for older adults: A multi-site randomized trial to test the Adult Day Service Plus Program (ADS Plus).
There are over five million people in the United States living with dementia. Most live at home and are cared for by family. These family caregivers often assume care responsibilities without education about the disease, skills training, or support, and in turn become at risk for depression, burden, and adverse health outcomes when compared to non-dementia caregivers. Despite over 200 caregiver interventions with proven benefits, many caregivers lack access to these programs. One approach to enhance access is to embed evidence-based caregiver support programs in existing community-based services for people with dementia such as adult day services (ADS). Here we describe the protocol for an embedded pragmatic trial designed to augment standard ADS known as ADS Plus. ADS Plus provides family caregivers with support via education, referrals, and problem-solving techniques over 12 months, and is delivered on-site by existing ADS staff. Embedding a program in ADS requires an understanding of outcomes and implementation processes in that specific context. Thus, we deploy a hybrid design involving a cluster randomized two-group trial to evaluate treatment effects on caregiver wellbeing, ADS utilization, as well as nursing home placement. We describe implementation practices in 30 to 50 geographically and racially/ethnically diverse participating sites. Clinical trial registration #: NCT02927821.


A Rare Case of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Glimepiride, the Unlikely Culprit.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and challenging entity which can be life threatening and is associated with many medications. Yet, Glimepiride has never been reported as offending agent. We present here the first case of Glimepiride induced DRESS syndrome. A 40-year-old male with type 2 diabetes mellitus was prescribed Glimepiride. One month later, the patient presented with diffuse rash, fever, swelling of extremities and jaundice. The leucocyte count at presentation was 22,000 cells/microL and absolute eosinophil count 5,400 cells/microL, with no atypical cells on peripheral blood smear. Skin biopsy was non-specific. Other sources of infections such as parasitic infections, HIV, viral hepatitis were ruled out. Patient improved symptomatically on discontinuation of Glimepiride and improved dramatically on steroids. DRESS syndrome as a possible complication of Glimepiride should be considered by clinicians. According to RegiSCAR, our case was categorized as definitive with score of 7. In the vast majority of reported cases, they are classified as probable cases.


Glutaredoxins catalyze the reduction of glutathione by dihydrolipoamide with high efficiency.
Glutaredoxins (Grx) are small (approximately 12kDa) proteins which catalyze thiol disulfide oxidoreductions involving glutathione (GSH) and disulfides in proteins or small molecules. Here, we present data which demonstrate the ability of glutaredoxins to catalyze the reduction of oxidized glutathione (GSSG) by dihydrolipoamide (DHL), an important biological redox catalyst and synthetic antioxidant. We have designed a new assay method to quantify the rate of reduction of GSSG and other disulfides by reduced lipoamide and have tested a set of eight recombinant Grx from human, rat, yeast, and E. coli. Lipoamide dependent activity is highest with the large atypical E. coli Grx2 (k(cat)=3.235 min(-1)) and lowest for human mitochondrial Grx2a (k(cat)=96 min(-1)) covering a wider range than k(cat) for the standard reduction of hydroxyethyldisulfide (HED) by GSH (290-2.851 min(-1)). The lipoamide/HED activity ratio was highest for yeast Grx2 (1.25) and E. coli Grx2 and lowest for E. coli Grx1 (0.13). These results suggest a new role for Grxs as ancillary proteins that could shunt reducing equivalents from main catabolic pathways to recycling of GSSG via a lipoyl group, thus serving biochemical functions which involve GSH but without NAD(P)H consumption.


Screening instruments for older adult depressive disorders: updating the evidence-based toolbox.
The prevalence of clinically significant depressive disorders in persons 65 years of age or older in the United States has been estimated to be approximately 15%, increasing the risk for functional decline, morbidity, and mortality. Utilization of a well-chosen screening instrument has been shown to improve the rates of recognition of depressive disorders in older adults. This paper presents a targeted review of the most commonly accepted tools for case-finding of depressive disorders in older adults. After a review of the benefits and shortcomings of screening tools, the strengths, weaknesses, and utility of selected depression scales in geriatric clinical settings are discussed.


Porous block copolymer separation membranes for 21st century sanitation and hygiene.
Removing hazardous particulate and macromolecular contaminants as well as viruses with sizes from a few nm up to the 100 nm-range from water and air is crucial for ensuring sufficient sanitation and hygiene for a growing world population. To this end, high-performance separation membranes are needed that combine high permeance, high selectivity and sufficient mechanical stability under operating conditions. However, design features of separation membranes enhancing permeance reduce selectivity and vice versa. Membrane configurations combining high permeance and high selectivity suffer in turn from a lack of mechanical robustness. These problems may be tackled by using block copolymers (BCPs) as a material platform for the design of separation membranes. BCPs are macromolecules that consist of two or more chemically distinct block segments, which undergo microphase separation yielding a wealth of ordered nanoscopic domain structures. Various methods allow the transformation of these nanoscopic domain structures into customized nanopore systems with pore sizes in the sub-100 nm range and with narrow pore size distributions. This tutorial review summarizes design strategies for nanoporous state-of-the-art BCP separation membranes, their preparation, their device integration and their use for water purification.


Inferring parameters of mutation, selection and demography from patterns of synonymous site evolution in Drosophila.
Selection acting on codon usage can cause patterns of synonymous evolution to deviate considerably from those expected under neutrality. To investigate the quantitative relationship between parameters of mutation, selection, and demography, and patterns of synonymous site divergence, we have developed a novel combination of population genetic models and likelihood methods of phylogenetic sequence analysis. Comparing 50 orthologous gene pairs from Drosophila melanogaster and D. virilis and 27 from D. melanogaster and D. simulans, we show considerable variation between amino acids and genes in the strength of selection acting on codon usage and find evidence for both long-term and short-term changes in the strength of selection between species. Remarkably, D. melanogaster shows no evidence of current selection on codon usage, while its sister species D. simulans experiences only half the selection pressure for codon usage of their common ancestor. We also find evidence for considerable base asymmetries in the rate of mutation, such that the average synonymous mutation rate is 20-30% higher than in noncoding regions. A Bayesian approach is adopted to investigate how accounting for selection on codon usage influences estimates of the parameters of mutation.


[Training 5th-Year Clinical Pharmacy Students to Collect and Evaluate Information from Original Articles].
Pharmacists are required to contribute to evidence-based medicine (EBM) by providing drug information, which can be collected from various sources such as books, websites, and original articles. In particular, information from original articles is needed in some situations. For example, original articles by international researchers are used to aid the management of novel in-hospital preparations on which little knowledge is available. We introduced an information evaluation program, the Okayama University Hospital EBM Model, into the clinical training of 5th-year pharmacy students. It aims to enable students to evaluate the validity of novel in-hospital preparations using original articles. This program has improved students' knowledge of EBM, and the satisfaction level of those enrolled was high. In addition, customer satisfaction analysis revealed that the overall degree of student satisfaction was related to their understanding of the necessity for EBM and the difficulty of practical training. In addition, students' achievements were evaluated using rubrics, and that method allowed the achievements of each student to be assessed appropriately. We hope to revise this program with the aim of improving students' understanding of EBM.


Health Promotion Interventions in Sports Clubs: Can We Talk About a Setting-Based Approach? A Systematic Mapping Review.
Many researchers and authorities have recognized the important role that sports clubs can play in public health. In spite of attempts to create a theoretical framework in the early 2000s, a thorough understanding of sports clubs as a setting for health promotion (HP) is lacking. Despite calls for more effective, sustainable, and theoretically grounded interventions, previous literature reviews have identified no controlled studies assessing HP interventions in sports clubs. This systematic mapping review details how the settings-based approach is applied through HP interventions in sports clubs and highlights facilitators and barriers for sports clubs to become health-promoting settings. In addition, the mapped facilitators and barriers have been used to reformulate previous guidelines of HP in sports clubs. Seven databases were searched for empirical research published between 1986 and 2017. Fifty-eight studies were included, principally coming from Australia and Europe, describing 33 unique interventions, which targeted mostly male participants in team sports. The settings-based approach was not yet applied in sports clubs, as more than half of the interventions implemented in sports club targeted only one level of the socio-ecological model, as well as focused only on study participants rather than the club overall. Based on empirical data, the analysis of facilitators and barriers helped develop revised guidelines for sports clubs to implement settings-based HP. This will be particularly useful when implementing HP initiatives to aid in the development of sports clubs working with a whole setting approach.


Design and preclinical evaluation of a multigene human immunodeficiency virus type 1 subtype C DNA vaccine for clinical trial.
In this study, the design and preclinical development of a multigene human immunodeficiency virus type 1 (HIV-1) subtype C DNA vaccine are described, developed as part of the South African AIDS Vaccine Initiative (SAAVI). Genetic variation remains a major obstacle in the development of an HIV-1 vaccine and recent strategies have focused on constructing vaccines based on the subtypes dominant in the developing world, where the epidemic is most severe. The vaccine, SAAVI DNA-C, contains an equimolar mixture of two plasmids, pTHr.grttnC and pTHr.gp150CT, which express a polyprotein derived from Gag, reverse transcriptase (RT), Tat and Nef, and a truncated Env, respectively. Genes included in the vaccine were obtained from individuals within 3 months of infection and selection was based on closeness to a South African subtype C consensus sequence. All genes were codon-optimized for increased expression in humans. The genes have been modified for safety, stability and immunogenicity. Tat was inactivated through shuffling of gene fragments, whilst maintaining all potential epitopes; the active site of RT was mutated; 124 aa were removed from the cytoplasmic tail of gp160; and Nef and Gag myristylation sites were inactivated. Following vaccination of BALB/c mice, high levels of cytotoxic T lymphocytes were induced against multiple epitopes and the vaccine stimulated strong CD8+ gamma interferon responses. In addition, high titres of antibodies to gp120 were induced in guinea pigs. This vaccine is the first component of a prime-boost regimen that is scheduled for clinical trials in humans in the USA and South Africa.


Determination of cloud effective particle size from the multiple-scattering effect on lidar integration-method temperature measurements.
A method is presented that permits the determination of the cloud effective particle size from Raman- or Rayleigh-integration temperature measurements that exploits the dependence of the multiple-scattering contributions to the lidar signals from heights above the cloud on the particle size of the cloud. Independent temperature information is needed for the determination of size. By use of Raman-integration temperatures, the technique is applied to cirrus measurements. The magnitude of the multiple-scattering effect and the above-cloud lidar signal strength limit the method's range of applicability to cirrus optical depths from 0.1 to 0.5. Our work implies that records of stratosphere temperature obtained with lidar may be affected by multiple scattering in clouds up to heights of 30 km and beyond.