Composition and health hazards of water-based construction paints: results from a survey in the Netherlands.
Water-based construction paints may have beneficial effects toward man's occupational and general environment when compared to traditional paints that contain large amounts of organic solvents. The aim of this study was to describe the health hazards of the application of these alternative paints. The composition of these paints was obtained by a questionnaire survey among the main producers and importers in The Netherlands. Physicochemical parameters and toxicity data of the constituents were used to estimate occupational and environmental health hazards. Mucous membrane of skin irritation and sensitization are predicted to be the most frequently occurring health hazards after contact with these paints during professional or do-it-yourself application. Health hazards from environmental pollution may be irritation of the mucous membranes when the indoor environment is painted and fish mortality due to slowly degradable polyacrylate binders. The health hazards can be reduced by replacing some toxic compounds with less toxic ones and by hygienic (ventilation, skincare, no cleaning of application materials under the tap) measures.


Minibrachium, a new subgenus of Rhamphobrachium (Annelida: Onuphidae) from Australia with the description of three new species.
This study describes a new subgenus of miniature, progenetic Rhamphobrachium species from eastern Australia. Minibrachium, n. subg. is characterised by such paedomorphic features as lack of peristomial cirri and branchiae, possession of only two pairs of modified parapodia with spiny recurved hooks and very early onset of subacicular hooks. Three new species are described, of which at least R. (Minibrachium) nutrix n. sp., the type species (from Lizard Island, Great Barrier Reef), is a fully grown adult, brooding several 16- to 20-chaetiger juveniles in the parental tubes. Rhamphobrachium (M.) talboti n. sp. (from off Sydney) and R. (M.) fractum n. sp. (from Bass Strait), although twice as large as the type species, have only partially developed frontal lips, indicating either incomplete growth or presenting an additional paedomorphic character. We discuss the position of the new subgenus in the Rhamphobrachium complex and present a key to the subgenera of Rhamphobrachium and species of R. (Minibrachium).


Frequency of D222G haemagglutinin mutant of pandemic (H1N1) pdm09 influenza virus in Tunisia between 2009 and 2011.
The novel pandemic A (H1N1) pdm09 virus was first identified in Mexico in April 2009 and since then it spread worldwide over a short period of time. Although the virus infection is generally associated with mild disease and a relatively low mortality, it is projected that mutations in specific regions of the viral genome, especially within the receptor binding domain of the haemagglutinin (HA) protein could result in more virulent virus stains, leading to a more severe pathogenicity. To monitor the genetic polymorphisms at position 222 of Haemagglutinin of influenza A(H1N1)pdm09 viruses from both outpatients with mild influenza and individuals with severe disease requiring hospitalization, during 2009-2010 and 2010-2011 seasons, a sequence-based genotypic assessment of viral populations to understand the prevalence of D222G mutation. The D222G was identified in clinical specimens from 3 out of 42 cases analyzed in Tunisia with severe outcome (7%). Interestingly, in one fatal case out of four viruses taken from fatal cases studied (25%). Also this mutation was found in one mild case out of 8 mild cases studied (0.1%). D222E substitution was found in virus taken from one patient with severe clinical syndrome (2%) out of 42 severe cases analyzed and E374K substitution was found in two severe cases (4%) out of 42 severe cases studied. A specific mutation in the viral haemagglutinin (D222G) was found in fatal, severe and mild case. Further virological, clinical and epidemiological investigations are needed to ascertain the role of this and other mutations that may alter the virulence and transmissibility of the pandemic influenza A (H1N1)pdm09. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1027334947811255.


Experimental hydatid disease of the liver.
Hydatid disease caused by Echinococcus granulosis is an endemic problem in many parts of the world and the liver is the most frequently involved organ. A suitable experimental model for hydatid disease of the liver, resembling naturally infected livers, is established in this study by injection of protoscolices via the mesenteric vein of the mice. This model can be used in assessment of the efficacy of various agents in treatment of hydatid disease of the liver.


Percutaneous toxicity of anticoagulant warfarin in rats.
Percutaneous toxicity of anticoagulant rodenticides is usually manifested by coagulopathy and/or fatal outcome. There are, however, virtually no data on other biological effects of this class of pesticides that gain access into the organism via skin. In this study, percutaneous toxicity of epicutaneously applied warfarin was evaluated by measuring changes in peripheral blood granulocytes in rats. Application of 10 mug (0.05 mg/kg) or 100 mug (0.5 mg/kg) of warfarin (WF) for 3 consecutive days resulted in an increase in prothrombin time, documenting the access of warfarin to systemic circulation. Application of warfarin led to an increase in relative numbers of granulocytes at higher dose, whereas both doses resulted in increased metabolical viability, evaluated by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT) reduction assay. Higher warfarin dose resulted in both granulocyte activation and priming (evaluated by cytochemical nitroblue tetrazolium, NBT, reduction assay of respiratory burst), whereas only a tendency toward activation was noted at lower WF dose. Soluble mediators from the circulation seem responsible for the observed effects, as exogenous plasma from WF-treated animals stimulated NBT reduction by isologous or naïve granulocytes. Data presented in this study are relevant for the recognition of biological effects, other than those affecting hemostasis, of anticoagulant rodenticides that gain access to systemic circulation through the skin.


Glucose-6-phosphate dehydrogenase deficiency and susceptibility to childhood diseases in Kilifi, Kenya.
Few previous studies have reported the effects of glucose-6-phosphate dehydrogenase (G6PD)-deficiency on child health in Africa. We conducted a case-control study in which cases (n = 6829) were children admitted, for any reason, to Kilifi County Hospital, Kenya, while controls (n = 10 179) were recruited from the surrounding community. Cases were subclassified based on their clinical and laboratory findings at admission. We calculated the prevalence of specific diseases by G6PD c.202 genotype, the only significant cause of G6PD-deficiency in this area, then estimated the association between genotype and admission with specific conditions using logistic regression. Among neonates, the prevalence of jaundice was higher in both G6PD c.202T heterozygotes (40/88; 45.5%; P = .004) and homo/hemizygotes (81/134; 60.5%; P < .0001) than in wild-type homozygotes (157/526; 29.9%). Median bilirubin levels also increased across the groups, being highest (239 mmol/L; interquartile range 96-390 mmol/L) in G6PD c.202T homo/hemizygotes. No differences were seen in admission hemoglobin concentrations or the prevalence of anemia or severe anemia by G6PD c.202 genotype. On case control analysis, G6PD heterozygosity was negatively associated with all-cause hospital admission (odds ratio 0.81; 95% confidence interval 0.73-0.90; P < .0001) and, specifically, admission with either pneumonia or Plasmodium falciparum parasitemia; while, conversely, it was positively associated with Gram-positive bacteremia. G6PD c.202T homo/heterozygosity was positively associated with neonatal jaundice, severe pneumonia, the receipt of a transfusion, and in-patient death. Our study supports the conclusion that G6PD c.202T is a balanced polymorphism in which a selective advantage afforded to heterozygous females against malaria is counterbalanced by increased risks of neonatal jaundice, invasive bacterial infections, and anemia.


Data-level Linkage of Multiple Surveys for Improved Understanding of Global Health Challenges.
Data-driven approaches can provide more enhanced insights for domain experts in addressing critical global health challenges, such as newborn and child health, using surveys (e.g., Demographic Health Survey). Though there are multiple surveys on the topic, data-driven insight extraction and analysis are often applied on these surveys separately, with limited efforts to exploit them jointly, and hence results in poor prediction performance of critical events, such as neonatal death. Existing machine learning approaches to utilise multiple data sources are not directly applicable to surveys that are disjoint on collection time and locations. In this paper, we propose, to the best of our knowledge, the first detailed work that automatically links multiple surveys for the improved predictive performance of newborn and child mortality and achieves cross-study impact analysis of covariates.


Coronavirus conspiracy beliefs, mistrust, and compliance with government guidelines in England.
An invisible threat has visibly altered the world. Governments and key institutions have had to implement decisive responses to the danger posed by the coronavirus pandemic. Imposed change will increase the likelihood that alternative explanations take hold. In a proportion of the general population there may be strong scepticism, fear of being misled, and false conspiracy theories. Our objectives were to estimate the prevalence of conspiracy thinking about the pandemic and test associations with reduced adherence to government guidelines. A non-probability online survey with 2501 adults in England, quota sampled to match the population for age, gender, income, and region. Approximately 50% of this population showed little evidence of conspiracy thinking, 25% showed a degree of endorsement, 15% showed a consistent pattern of endorsement, and 10% had very high levels of endorsement. Higher levels of coronavirus conspiracy thinking were associated with less adherence to all government guidelines and less willingness to take diagnostic or antibody tests or to be vaccinated. Such ideas were also associated with paranoia, general vaccination conspiracy beliefs, climate change conspiracy belief, a conspiracy mentality, and distrust in institutions and professions. Holding coronavirus conspiracy beliefs was also associated with being more likely to share opinions. In England there is appreciable endorsement of conspiracy beliefs about coronavirus. Such ideas do not appear confined to the fringes. The conspiracy beliefs connect to other forms of mistrust and are associated with less compliance with government guidelines and greater unwillingness to take up future tests and treatment.


Essential key messages about diagnosis, imaging, and self-care for people with low back pain: a modified Delphi study of consumer and expert opinions.
People with back pain regularly search for information online; however, the quality of this online information is often poor. We established a list of the most important messages about diagnosis, imaging, and self-care for people with low back pain, based on consensus opinion and prioritised in order of importance. A list of key messages was derived from clinical practice guidelines for back pain. During 2 survey rounds, a Delphi panel of consumers with back pain and experts rated the importance of each item and suggested additional statements. Messages were retained that were rated as important by more than 70% of the panel. Retained messages were reviewed by consumer focus groups. A priority pairwise ranking activity determined the rank order of the important messages. A final online survey determined the robustness and currency of the final list of statements. The Delphi process and consumer focus groups resulted in 30 unique messages. Experts considered that the most important messages for patients are (1) remain active and (2) reassurance that back pain is a normal experience and not necessarily related to serious harm. This differed from the preferences of people with back pain who prioritised messages related to (1) identification of more serious pathology and (2) principles of management. This list of important key messages about diagnosis, imaging, and general self-care for people with back pain can be used to inform the development of education resources, including new web sites, as well as to direct clinicians in the information they provide to patients.


Effects of two energy-restricted diets differing in the carbohydrate/protein ratio on weight loss and oxidative changes of obese men.
Low-carbohydrate, high-protein diets are a current challenge in the nutritional treatment of obesity. To compare the effect of a low-carbohydrate high-protein diet with a traditional hypocaloric diet on weight loss and mitochondrial oxidative metabolism. Nineteen obese men (age 36+/-6 years; body mass index 34+/-2 kg/m2) were randomized to follow one of the two diets-control diet (15% protein; 30% lipids; 55% carbohydrates) or high-protein diet (30% protein; 30% lipids; 40% carbohydrates)-over an 8-week period. Anthropometry, biochemical variables, resting energy expenditure and mitochondrial oxidation were measured at the start and at the end of the intervention. The high-protein diet produced a greater weight loss (-8.3+/-1.2% versus -5.5+/-2.5%, P = 0.012) than the control diet. Interestingly, an activation in the mitochondrial oxidation was found in the high-protein-fed group. This stimulation was positively correlated with the final resting energy expenditure and negatively associated with the final fat mass content. Low-carbohydrate high-protein diets could involve specific changes in mitochondrial oxidation that could be related to a higher weight loss.


Click Reactions in Chemistry of Triterpenes - Advances Towards Development of Potential Therapeutics.
Triterpenoids are natural compounds with a large variety of biological activities such as anticancer, antiviral, antibacterial, antifungal, antiparazitic, antiinflammatory and others. Despite their low toxicity and simple availability from the natural resources, their clinical use is still severely limited by their higher IC50 and worse pharmacological properties than in the currently used therapeutics. This fact encouraged a number of researchers to develop new terpenic derivatives more suitable for the potential clinical use. This review summarizes a new approach to improve both, the activity and ADME-Tox properties by connecting active terpenes to another modifying molecules using click reactions. Within the past few years, this synthetic approach was well explored yielding a lot of great improvements of the parent compounds along with some less successful attempts. A large quantity of the new compounds presented here are superior in both activity and ADME-Tox properties to their parents. This review should serve the researchers who need to promote their hit triterpenic structures towards their clinical use and it is intended as a guide for the chemical synthesis of better drug candidates.


Role of a Limited Transarticular Release in Severe Hallux Valgus Correction.
Hallux valgus (HV) treatment is continuously evolving, and no definitive treatment can be recommended. Osteotomies are the main surgical choice for these deformities, but no clear role for soft tissue procedures is available. To perform a retrospective comparison of the radiographic and clinical outcomes of 2 groups of patients with severe HV operated with the same osteotomy technique but differing on the type of lateral release. Two groups of patients with symptomatic moderate to severe HV deformities were operated with the same proximal metatarsal osteotomy, which differed on the type of lateral release: group 1 had limited transarticular lateral capsule release (n = 62), and group 2 complete lateral release, including capsule, adductor tendon, and intermetatarsal (IM) ligament (n = 57). We recorded the American Orthopaedic Foot & Ankle Society (AOFAS) score, HV and IM angles, first metatarsal shortening, concomitant metatarsal shortening osteotomies (Weil), Akin osteotomies, and complications. The postoperative AOFAS score in group 1 was similar to that of group 2. The HV and IM angles improved in both groups with no significant difference. The multivariate analysis showed no influence of any variable analyzed on HV or IM angle improvement. Regarding AOFAS score improvement, a limited lateral release was associated with a higher increase in AOFAS score (P = .019). No studies are available to identify which soft tissue structures are involved in HV deformities nor which have to be released, if any. A limited transarticular release can provide similar clinical and radiologic outcomes when compared with a classic open lateral release. Level IV, case series.


An integrated approach to the interpretation of single amino acid polymorphisms within the framework of CATH and Gene3D.
The phenotypic effects of sequence variations in protein-coding regions come about primarily via their effects on the resulting structures, for example by disrupting active sites or affecting structural stability. In order better to understand the mechanisms behind known mutant phenotypes, and predict the effects of novel variations, biologists need tools to gauge the impacts of DNA mutations in terms of their structural manifestation. Although many mutations occur within domains whose structure has been solved, many more occur within genes whose protein products have not been structurally characterized. Here we present 3DSim (3D Structural Implication of Mutations), a database and web application facilitating the localization and visualization of single amino acid polymorphisms (SAAPs) mapped to protein structures even where the structure of the protein of interest is unknown. The server displays information on 6514 point mutations, 4865 of them known to be associated with disease. These polymorphisms are drawn from SAAPdb, which aggregates data from various sources including dbSNP and several pathogenic mutation databases. While the SAAPdb interface displays mutations on known structures, 3DSim projects mutations onto known sequence domains in Gene3D. This resource contains sequences annotated with domains predicted to belong to structural families in the CATH database. Mappings between domain sequences in Gene3D and known structures in CATH are obtained using a MUSCLE alignment. 1210 three-dimensional structures corresponding to CATH structural domains are currently included in 3DSim; these domains are distributed across 396 CATH superfamilies, and provide a comprehensive overview of the distribution of mutations in structural space. The server is publicly available at http://3DSim.bioinfo.cnio.es/. In addition, the database containing the mapping between SAAPdb, Gene3D and CATH is available on request and most of the functionality is available through programmatic web service access.


Potential metal-binding domains in nucleic acid binding proteins.
A systematic search for sequences that potentially could form metal-binding domains in proteins has been performed. Five classes of proteins involved in nucleic acid binding or gene regulation were found to contain such sequences. These observations suggest numerous experiments aimed at determining whether metal-binding domains are present in these proteins and, if present, what roles such domains play in the processes of nucleic acid binding and gene regulation.


G1 arrest and differentiation can occur independently of Rb family function.
The ability of progenitor cells to exit the cell cycle is essential for proper embryonic development and homeostasis, but the mechanisms governing cell cycle exit are still not fully understood. Here, we tested the requirement for the retinoblastoma (Rb) protein and its family members p107 and p130 in G0/G1 arrest and differentiation in mammalian cells. We found that Rb family triple knockout (TKO) mouse embryos survive until days 9-11 of gestation. Strikingly, some TKO cells, including in epithelial and neural lineages, are able to exit the cell cycle in G0/G1 and differentiate in teratomas and in culture. This ability of TKO cells to arrest in G0/G1 is associated with the repression of key E2F target genes. Thus, G1 arrest is not always dependent on Rb family members, which illustrates the robustness of cell cycle regulatory networks during differentiation and allows for the identification of candidate pathways to inhibit the expansion of cancer cells with mutations in the Rb pathway.


Pharmacokinetics and pharmacodynamics of VEGF-neutralizing antibodies.
Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis, and its role in cancer biology has been widely studied. Many cancer therapies target angiogenesis, with a focus being on VEGF-mediated signaling such as antibodies to VEGF. However, it is difficult to predict the effects of VEGF-neutralizing agents. We have developed a whole-body model of VEGF kinetics and transport under pathological conditions (in the presence of breast tumor). The model includes two major VEGF isoforms VEGF121 and VEGF165, receptors VEGFR1, VEGFR2 and co-receptors Neuropilin-1 and Neuropilin-2. We have added receptors on parenchymal cells (muscle fibers and tumor cells), and incorporated experimental data for the cell surface density of receptors on the endothelial cells, myocytes, and tumor cells. The model is applied to investigate the action of VEGF-neutralizing agents (called "anti-VEGF") in the treatment of cancer. Through a sensitivity study, we examine how model parameters influence the level of free VEGF in the tumor, a measure of the response to VEGF-neutralizing drugs. We investigate the effects of systemic properties such as microvascular permeability and lymphatic flow, and of drug characteristics such as the clearance rate and binding affinity. We predict that increasing microvascular permeability in the tumor above 10-5 cm/s elicits the undesired effect of increasing tumor interstitial VEGF concentration beyond even the baseline level. We also examine the impact of the tumor microenvironment, including receptor expression and internalization, as well as VEGF secretion. We find that following anti-VEGF treatment, the concentration of free VEGF in the tumor can vary between 7 and 233 pM, with a dependence on both the density of VEGF receptors and co-receptors and the rate of neuropilin internalization on tumor cells. Finally, we predict that free VEGF in the tumor is reduced following anti-VEGF treatment when VEGF121 comprises at least 25% of the VEGF secreted by tumor cells. This study explores the optimal drug characteristics required for an anti-VEGF agent to have a therapeutic effect and the tumor-specific properties that influence the response to therapy. Our model provides a framework for investigating the use of VEGF-neutralizing drugs for personalized medicine treatment strategies.


The effect of surface functionalization of PLGA nanoparticles by heparin- or chitosan-conjugated Pluronic on tumor targeting.
The poly (lactide-co-glycolide) (PLGA)-based nanoparticles, coated by the heparin- or chitosan-Pluronic conjugate, were used to improve a relatively low tumor-targeting efficiency of the bare PLGA nanoparticles. The prepared nanoparticles were in the size range of 100-150nm, and the surface exposure of the functional moiety (heparin or chitosan) was confirmed by negatively or positively increased zeta potential values, respectively. The viability tests for both normal and tumor cells displayed minimal cytotoxicity of the nanoparticles. The stable surface coating, which was evident from no change in the size distribution profiles in spite of the surface charge changes in serum environment, effectively provided the desired functionalized surface that clearly enhanced the in vitro cellular uptake of the nanoparticles for both heparin and chitosan functionalization. The in vivo tumor model study, which was carried out in SCC7 tumor-bearing athymic mice, demonstrated that there was a limited, but positive effect of surface functionalization, more effective for chitosan functionalization. The accumulation of chitosan-functionalized PLGA nanoparticles in tumor was 2.4 folds higher than that of the control, PLGA nanoparticles coated with bare Pluronic, and the accumulation in liver was lower than the control. In the case of heparin functionalization, the mean value was 2.2 folds higher than that of the control, but the accumulation in liver was similar to that of the control. Therefore, the surface-functionalization by the chitosan- or heparin-conjugated Pluronic may be an effective approach for the hydrophobic nanoparticle systems aiming for the enhanced tumor imaging and therapy.


Prenatal Material Hardships and Infant Regulatory Capacity at 10 Months Old in Low-Income Hispanic Mother-Infant Pairs.
Prenatal maternal stresses have been associated with infant temperament patterns linked to later behavioral difficulties. Material hardships, defined as inability to meet basic needs, are important prenatal stressors. Our objective was to determine the associations between prenatal material hardships and infant temperament at 10 months. This was a longitudinal study of mother-infant pairs in a randomized controlled trial of a primary care-based early obesity prevention program (Starting Early). Independent variables representing material hardship were: housing disrepair, food insecurity, difficulty paying bills, and neighborhood stress (neighborhood safety). Dependent variables representing infant temperament were assessed using questions from 3 subscales of the Infant Behavior Questionnaire: orienting/regulatory capacity, negative affect, and surgency/extraversion. We used linear regression to investigate associations between individual and cumulative hardships and each temperament domain, adjusting for confounders, and testing for depression as a moderator. Four hundred twelve mother-infant pairs completed 10-month assessments. Thirty-two percent reported food insecurity, 26% difficulty paying bills, 35% housing disrepair, and 9% neighborhood stress. In adjusted analyses, food insecurity was associated with lower orienting/regulatory capacity scores (β = -0.25; 95% confidence interval [CI], -0.47 to -0.04), as were neighborhood stress (β = -0.50; 95% CI, -0.83 to -0.16) and experiencing 3 to 4 hardships (compared with none; β = -0.54; 95% CI, -0.83 to -0.21). For neighborhood stress, the association was stronger among infants of mothers with prenatal depressive symptoms (interaction term P = .06). Prenatal material hardships were associated with lower orienting/regulatory capacity. These findings support the need for further research exploring how temperament relates to child behavior, and for policies to reduce prenatal material hardships.


Assessment of atherosclerosis in chronic granulomatous disease.
Patients with chronic granulomatous disease (CGD) experience immunodeficiency because of defects in the phagocyte NADPH oxidase and the concomitant reduction in reactive oxygen intermediates. This may result in a reduction in atherosclerotic injury. We prospectively assessed the prevalence of cardiovascular risk factors, biomarkers of inflammation and neutrophil activation, and the presence of magnetic resonance imaging and computed tomography quantified subclinical atherosclerosis in the carotid and coronary arteries of 41 patients with CGD and 25 healthy controls in the same age range. Univariable and multivariable associations among risk factors, inflammatory markers, and atherosclerosis burden were assessed. Patients with CGD had significant elevations in traditional risk factors and inflammatory markers compared with control subjects, including hypertension, high-sensitivity C-reactive protein, oxidized low-density lipoprotein, and low high-density lipoprotein. Despite this, patients with CGD had a 22% lower internal carotid artery wall volume compared with control subjects (361.3±76.4 mm(3) versus 463.5±104.7 mm(3); P<0.001). This difference was comparable in p47(phox)- and gp91(phox)-deficient subtypes of CGD and independent of risk factors in multivariate regression analysis. In contrast, the prevalence of coronary arterial calcification was similar between patients with CGD and control subjects (14.6%, CGD; 6.3%, controls; P=0.39). The observation by magnetic resonance imaging and computerized tomography of reduced carotid but not coronary artery atherosclerosis in patients with CGD despite the high prevalence of traditional risk factors raises questions about the role of NADPH oxidase in the pathogenesis of clinically significant atherosclerosis. Additional high-resolution studies in multiple vascular beds are required to address the therapeutic potential of NADPH oxidase inhibition in cardiovascular diseases. http://www.clinicaltrials.gov. Unique identifier: NCT01063309.


Localization of penicillin-binding proteins to the splitting system of Staphylococcus aureus septa by using a mercury-penicillin V derivative.
Precise localization of penicillin-binding protein (PBP)-antibiotic complexes in a methicillin-sensitive Staphylococcus aureus strain (BB255), its isogenic heterogeneous methicillin-resistant transductant (BB270), and a homogeneous methicillin-resistant strain (Col) was investigated by high-resolution electron microscopy. A mercury-penicillin V (Hg-pen V) derivative was used as a heavy metal-labeled, electron-dense probe for accurately localizing PBPs in situ in single bacterial cells during growth. The most striking feature of thin sections was the presence of an abnormally large (17 to 24 nm in width) splitting system within the thick cross walls or septa of Hg-pen V-treated bacteria of all strains. Untreated control cells possessed a thin, condensed splitting system, 7 to 9 nm in width. A thick splitting system was also distinguishable in unstained thin sections, thereby confirming that the electron contrast of this structure was not attributed to binding of bulky heavy metal stains usually used for electron microscopy. Biochemical analyses demonstrated that Hg-pen V bound to isolated plasma membranes as well as sodium dodecyl sulfate-treated cell walls and that two or more PBPs in each strain bound to this antibiotic. In contrast, the splitting system in penicillin V-treated bacteria was rarely visible after 30 min in the presence of antibiotic. These findings suggest that while most PBPs were associated with the plasma membrane, a proportion of PBPs were located within the fabric of the cell wall, in particular, in the splitting system. Inhibition of one or more high-M(r) PBPs by beta-lactam antibiotics modified the splitting system and cross-wall structure, therefore supporting a role for these PBPs in the synthesis and architectural design of these structures in S. aureus.


The Exposome: A New Frontier for Education.
The historic debate of nature vs. nurture has emerged as a central yin-yang of contemporary health and disease research. The Human Genome Project provided the capability to define the nature of an individual by one's genetic sequence. But tools are not available to sequence lifelong exposures (i.e., the nurture of an individual). Many believe that nurture has an even greater role than genetics in determining lifelong success, health, and well-being. In contemporary terminology, the cumulative measure of environmental influences and associated biological responses throughout the life span is termed the "exposome." This includes all external exposures from the environment, diet, behavior, societal influences and infections, and also cumulative biological responses to exposures and endogenous processes. Pursuit of a Human Exposome Project is a vision worthy of our youth: development of strategies and tools will require the brightest and most imaginative. Incorporation of the exposome into education curricula will foster discussion, development of interest, improvement of skills, and promotion of critical thinking to prepare students for civically engaged lives, ongoing study, and future career opportunities. The long-term vision is that sequencing the exposome will support better understanding of healthful and harmful lifelong exposures and lead to improved opportunity for the health and prosperity of all.


Engineering nanometre-scale coherence in soft matter.
Electronic delocalization in redox-active polymers may be disrupted by the heterogeneity of the environment that surrounds each monomer. When the differences in monomer redox-potential induced by the environment are small (as compared with the monomer-monomer electronic interactions), delocalization persists. Here we show that guanine (G) runs in double-stranded DNA support delocalization over 4-5 guanine bases. The weak interaction between delocalized G blocks on opposite DNA strands is known to support partially coherent long-range charge transport. The molecular-resolution model developed here finds that the coherence among these G blocks follows an even-odd orbital-symmetry rule and predicts that weakening the interaction between G blocks exaggerates the resistance oscillations. These findings indicate how sequence can be exploited to change the balance between coherent and incoherent transport. The predictions are tested and confirmed using break-junction experiments. Thus, tailored orbital symmetry and structural fluctuations may be used to produce coherent transport with a length scale of multiple nanometres in soft-matter assemblies, a length scale comparable to that of small proteins.


Associations between socioeconomic, parental and home environment factors and fruit and vegetable consumption of children in grades five and six in British Columbia, Canada.
Regular fruit and vegetable (FV) consumption has been associated with reduced chronic disease risk. Evidence from adults shows a social gradient in FV consumption. Evidence from pre-adolescent children varies and there is little Canadian data. This study assessed the FV intake of school children in British Columbia (BC), Canada to determine whether socio-economic status (SES), parental and the home environment factors were related to FV consumption. As part of the BC School Fruit and Vegetable Nutrition Program, 773 British Columbia fifth-and sixth-grade school children (Mean age 11.3 years; range 10.3-12.5) and their parents were surveyed to determine FV consumption and overall dietary intake. Students completed a web-based 24-hour dietary food recall, and a student measure of socio-economic status (The Family Affluence Scale). Parents completed a self-administered survey about their education, income, home environment and perceptions of their neighbourhood and children's eating habits. Correlations and multiple regression analyses were used to examine the association between SES, parental and home environment factors and FV consumption. Approximately 85.8% of children in this study failed to meet minimum Canadian guidelines for FV intake (6 servings). Parent income and education were not significantly associated with child FV consumption but were associated with each other, child-reported family affluence, neighbourhood environment, access to FV, and eating at the table or in front of the television. Significant positive associations were found between FV consumption and child-reported family affluence, meal-time habits, neighbourhood environment and parent perceptions of the healthiness of their child's diet; however, these correlations were weak (ranging from .089-.115). Multiple regression analysis showed that only child-reported family affluence significantly predicted FV consumption (std-β = 0.096 95% CI = 0.01 to 0.27). The majority of children in our study were not meeting guidelines for FV intake irrespective of SES, parent perceptions or home environment, making this a population wide concern. An almost trivial socio-economic gradient was observed for the child-reported SES measure only. These results are consistent with several other studies of children. Longitudinal research is needed to further explore individual and social factors associated with FV consumption in childhood and their development over time.


Kinase signalling in Plasmodium sexual stages and interventions to stop malaria transmission.
The symptoms of malaria, one of the infectious diseases with the highest mortality and morbidity world-wide, are caused by asexual parasites replicating inside red blood cells. Disease transmission, however, is effected by non-replicating cells which have differentiated into male or female gametocytes. These are the forms infectious to mosquito vectors and the insects are the only hosts where parasite sexual reproduction can take place. Malaria is thus a complex infection in which pharmacological treatment of symptoms may still allow transmission for long periods, while pharmacological blockage of infectivity may not cure symptoms. The process of parasite sexual differentiation and development is still being revealed but it is clear that kinase-mediated signalling mechanisms play a significant role. This review attempts to summarise our limited current knowledge on the signalling mechanisms involved in the transition from asexual replication to sexual differentiation and reproduction, with a brief mention to the effects of current treatments on the sexual stages and to some of the difficulties inherent in developing pharmacological interventions to curtail disease transmission.


Large Scale 3D Morphable Models.
We present large scale facial model (LSFM)-a 3D Morphable Model (3DMM) automatically constructed from 9663 distinct facial identities. To the best of our knowledge LSFM is the largest-scale Morphable Model ever constructed, containing statistical information from a huge variety of the human population. To build such a large model we introduce a novel fully automated and robust Morphable Model construction pipeline, informed by an evaluation of state-of-the-art dense correspondence techniques. The dataset that LSFM is trained on includes rich demographic information about each subject, allowing for the construction of not only a global 3DMM model but also models tailored for specific age, gender or ethnicity groups. We utilize the proposed model to perform age classification from 3D shape alone and to reconstruct noisy out-of-sample data in the low-dimensional model space. Furthermore, we perform a systematic analysis of the constructed 3DMM models that showcases their quality and descriptive power. The presented extensive qualitative and quantitative evaluations reveal that the proposed 3DMM achieves state-of-the-art results, outperforming existing models by a large margin. Finally, for the benefit of the research community, we make publicly available the source code of the proposed automatic 3DMM construction pipeline, as well as the constructed global 3DMM and a variety of bespoke models tailored by age, gender and ethnicity.


Emergency department management and follow-up of children with bicycle spoke injuries.
Evidence for a standard x-ray study and cast immobilization in emergency department (ED) management and follow-up of children with bicycle spoke injury (BSI) is absent. To describe the injury pattern and outpatient follow-up and care of ED patients with BSI. In addition, patient characteristics predicting the presence of a fracture and long-term follow-up were assessed. This was a retrospective study including BSI patients < 9 years of age. Kruskal-Wallis test was used to compare groups with a fracture, soft tissue injury, and mild skin abrasion. Multivariable logistic regression analysis was used to identify independent predictors of a fracture and long-term outpatient follow-up. Twenty-three percent of 141 included patients had a fracture, with a median (interquartile range) follow-up of 27 (23-40) days. For soft tissue injury and mild abrasions this was 9 (6-14) and 7 (5-9) days, respectively (p < 0.001). No clinical variables could predict a fracture. Fifty-six (40%) patients required no further care after the first outpatient visit at ∼1 week. Triage category yellow and swelling were independent predictors for more than one outpatient visit, besides presence of fracture. Corrected odds ratios (95% confidence interval) were 2.42 (0.99-5.88) and 4.76 (1.38-16.39), respectively. Only 12% of 141 patients had none of these predictors at ED presentation. A quarter of ED patients with BSI have a fracture with no clinical signs that could predict the presence of a fracture, justifying a standard x-ray study in ED management. Only 12% of ED patients with BSI have no fracture and no signs that predict long-term follow-up. In this group, further studies are warranted to investigate the benefit of cast immobilization for fractures and soft tissue injury.


High-energy, phase-stable, ultrabroadband kHz OPCPA at 2.1 μm pumped by a picosecond cryogenic Yb:YAG laser.
We report on a kHz, mJ-level, carrier-envelope phase (CEP)-stable ultrabroadband optical parametric chirped-pulse amplifier (OPCPA) at 2.1-μm wavelength, pumped by a high-energy, 14 ps, cryogenic Yb:YAG pump laser, and its application to high-order harmonic generation (HHG) with Xe. The pre-amplifier chain is pumped by a 12-ps Nd:YLF pump laser and both pump lasers are optically synchronized to the signal pulse of the OPCPA. An amplified pulse energy of 0.85 mJ was obtained at the final OPCPA stage with good beam profile. The pulse is compressed to 4.5 optical cycles (<32 fs) with a spectral bandwidth of 474 nm supporting 3.5 optical cycles. The CEP stability was measured to be 194 mrad and the super-fluorescence noise is estimated to be ~9%. First HHG results are demonstrated with Xe showing significant cutoff extension to >85 eV with an efficiency of ~10-10 per harmonic, limited by the maximum gas pressure and flow into the chamber. This demonstrates the potential of this 2.1-μm source for scaling of photon energy and flux in the water-window range when applied to Ne and He at kHz repetition rate.


Automated extraction of ejection fraction for quality measurement using regular expressions in Unstructured Information Management Architecture (UIMA) for heart failure.
Left ventricular ejection fraction (EF) is a key component of heart failure quality measures used within the Department of Veteran Affairs (VA). Our goals were to build a natural language processing system to extract the EF from free-text echocardiogram reports to automate measurement reporting and to validate the accuracy of the system using a comparison reference standard developed through human review. This project was a Translational Use Case Project within the VA Consortium for Healthcare Informatics. We created a set of regular expressions and rules to capture the EF using a random sample of 765 echocardiograms from seven VA medical centers. The documents were randomly assigned to two sets: a set of 275 used for training and a second set of 490 used for testing and validation. To establish the reference standard, two independent reviewers annotated all documents in both sets; a third reviewer adjudicated disagreements. System test results for document-level classification of EF of <40% had a sensitivity (recall) of 98.41%, a specificity of 100%, a positive predictive value (precision) of 100%, and an F measure of 99.2%. System test results at the concept level had a sensitivity of 88.9% (95% CI 87.7% to 90.0%), a positive predictive value of 95% (95% CI 94.2% to 95.9%), and an F measure of 91.9% (95% CI 91.2% to 92.7%). An EF value of <40% can be accurately identified in VA echocardiogram reports. An automated information extraction system can be used to accurately extract EF for quality measurement.


Guidelines for reasonable and appropriate care in the emergency department (GRACE): Recurrent, low-risk chest pain in the emergency department.
This first Guideline for Reasonable and Appropriate Care in the Emergency Department (GRACE-1) from the Society for Academic Emergency Medicine is on the topic: Recurrent, Low-risk Chest Pain in the Emergency Department. The multidisciplinary guideline panel used The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the certainty of evidence and strength of recommendations regarding eight priority questions for adult patients with recurrent, low-risk chest pain and have derived the following evidence based recommendations: (1) for those >3 h chest pain duration we suggest a single, high-sensitivity troponin below a validated threshold to reasonably exclude acute coronary syndrome (ACS) within 30 days; (2) for those with a normal stress test within the previous 12 months, we do not recommend repeat routine stress testing as a means to decrease rates of major adverse cardiac events at 30 days; (3) insufficient evidence to recommend hospitalization (either standard inpatient admission or observation stay) versus discharge as a strategy to mitigate major adverse cardiac events within 30 days; (4) for those with non-obstructive (<50% stenosis) coronary artery disease (CAD) on prior angiography within 5 years, we suggest referral for expedited outpatient testing as warranted rather than admission for inpatient evaluation; (5) for those with no occlusive CAD (0% stenosis) on prior angiography within 5 years, we recommend referral for expedited outpatient testing as warranted rather than admission for inpatient evaluation; (6) for those with a prior coronary computed tomographic angiography within the past 2 years with no coronary stenosis, we suggest no further diagnostic testing other than a single, normal high-sensitivity troponin below a validated threshold to exclude ACS within that 2 year time frame; (7) we suggest the use of depression and anxiety screening tools as these might have an effect on healthcare use and return emergency department (ED) visits; and (8) we suggest referral for anxiety or depression management, as this might have an impact on healthcare use and return ED visits.


A synergy-based hand control is encoded in human motor cortical areas.
How the human brain controls hand movements to carry out different tasks is still debated. The concept of synergy has been proposed to indicate functional modules that may simplify the control of hand postures by simultaneously recruiting sets of muscles and joints. However, whether and to what extent synergic hand postures are encoded as such at a cortical level remains unknown. Here, we combined kinematic, electromyography, and brain activity measures obtained by functional magnetic resonance imaging while subjects performed a variety of movements towards virtual objects. Hand postural information, encoded through kinematic synergies, were represented in cortical areas devoted to hand motor control and successfully discriminated individual grasping movements, significantly outperforming alternative somatotopic or muscle-based models. Importantly, hand postural synergies were predicted by neural activation patterns within primary motor cortex. These findings support a novel cortical organization for hand movement control and open potential applications for brain-computer interfaces and neuroprostheses.


Modeling Forest Productivity Using Envisat MERIS Data.
The aim of this study was to derive land cover products with a 300-m pixelresolution of Envisat MERIS (Medium Resolution Imaging Spectrometer) to quantify netprimary productivity (NPP) of conifer forests of Taurus Mountain range along the EasternMediterranean coast of Turkey. The Carnegie-Ames-Stanford approach (CASA) was usedto predict annual and monthly regional NPP as modified by temperature, precipitation,solar radiation, soil texture, fractional tree cover, land cover type, and normalizeddifference vegetation index (NDVI). Fractional tree cover was estimated using continuoustraining data and multi-temporal metrics of 47 Envisat MERIS images of March 2003 toSeptember 2005 and was derived by aggregating tree cover estimates made from high-resolution IKONOS imagery to coarser Landsat ETM imagery. A regression tree algorithmwas used to estimate response variables of fractional tree cover based on the multi-temporal metrics. This study showed that Envisat MERIS data yield a greater spatial detailin the quantification of NPP over a topographically complex terrain at the regional scalethan those used at the global scale such as AVHRR.


Relationship between hospital ward design and healthcare-associated infection rates: a systematic review and meta-analysis.
The influence of the hospital's infrastructure on healthcare-associated colonization and infection rates has thus far infrequently been examined. In this review we examine whether healthcare facility design is a contributing factor to multifaceted infection control strategies. We searched PubMed/MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) from 1990 to December 31st, 2015, with language restriction to English, Spanish, German and French. We identified three studies investigating accessibility of the location of the antiseptic hand rub dispenser. Each of them showed a significant improvement of hand hygiene compliance or agent consumption with the implementation of accessible dispensers near the patient bed. Nine eligible studies evaluated the impact of single-patient rooms on the acquisition of healthcare-associated colonization and infections in comparison to multi-bedrooms or an open ward design. Six of these studies showed a significant benefit of single-patient bedrooms in reducing the healthcare-associated colonization and infection rate, whereas three studies found that single-patient rooms are neither a protective nor risk factor. In meta-analyses, the overall risk ratio for acquisition of healthcare-associated colonization and infection was 0.55 (95% CI: 0.41 to 0.74), for healthcare-associated colonization 0.52 (95% CI: 0.32 to 0.85) and for bacteremia 0.64 (95% CI: 0.53 to 0.76), all in favor of patient care in single-patient bedrooms. Implementation of single-patient rooms and easily accessible hand rub dispensers located near the patient's bed are beneficial for infection control and are useful parts of a multifaceted strategy for reducing healthcare-associated colonization and infections.


Infections and Wegener's granulomatosis--a cause and effect relationship?
The association of infections and autoimmune disease has been noted by various authors. Several mechanisms have been proposed to explain this, with no current consensus. Wegener's granulomatosis (WG) is an autoimmune disease involving predominantly the pulmonary and renal systems, and is associated with a distinct autoantibody-the anti neutrophil cytoplasmic antibody (ANCA). Although no solid evidence implicates infections in the emergence of WG, direct and circumstantial data suggest this relation. We review this evidence and discuss possible underlying mechanisms. We emphasize the relationship between infections and ANCA, and their role in the maintenance of the 'on-going' inflammatory response.


Randomized, double-blinded, placebo-controlled trial of amoxicillin/clavulanic acid to prevent preterm delivery in twin gestation.
The objective of this study was to determine whether prophylactic treatment with oral broad-spectrum antimicrobial therapy improves pregnancy outcomes in twin gestations. Patients with twin gestations between 24 and 32 weeks were randomized to receive amoxicillin/clavulanic acid or placebo. Those patients randomized before 24 weeks received a 1-week course at 24 and at 28 weeks gestation. Those patients entered later than 24 weeks received a 1-week course either at 28 weeks or at enrollment (up to 32 weeks). Other than antibiotic use, the management of the groups was identical and unchanged from the routine care of twin gestations. Of 149 twin pregnancies enrolled, 76 were randomized to the drug group and 73 to the placebo group. There was no significant difference in mean gestational age at delivery (35.9 vs. 35.7 weeks), birth weight (2,358 vs. 2,344 g), mean neonatal nursery stay (9.9 vs. 11.7 days), or respiratory distress syndrome (6/76 vs. 4/73) in the drug vs. placebo group, respectively. The addition of prophylactic oral broad-spectrum antimicrobial therapy to the standard antepartum management of twin gestations had no demonstrable effect on the gestational age at delivery, birth weight, or neonatal complications. There did not appear to be any beneficial effect of the prophylactic use of amoxicillin/clavulanic acid in this clinical setting.


Deregulated microRNA expression and its pathogenetic implications for myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) include a heterogeneous group of clonal hematological stem cell disorders characterized by ineffective hematopoiesis, cytopenias. MicroRNAs (miRNAs) are short non-coding RNA molecules that repress gene expression at the post-transcriptional level. In this review, we summarize advanced investigations that underscore deregulated miRNA expression in MDS, and discuss the implications of miRNAs in the molecular pathogenesis of MDS. Relevant English-language literatures were searched and retrieved from PubMed using the terms MDS and miRNAs. The majority of studies have focused on profiling miRNA expression in MDS, only a small number of studies have investigated the exact pathogenic role of miRNAs in MDS. In the hematopoietic system, miRNAs are critical regulators of the differentiation of hematopoietic stem/progenitor cells. Thus, it is not surprising that dysregulation of miRNAs can lead to hematopoietic stem cell anomalies and further cause MDS. Deregulated miRNA expression has been identified in MDS, and it contributes to the pathogenesis and progression of MDS. Chromosomal aberrations, hypermethylation of miRNA promoters, and mutations of miRNA genes may lead to dysregulation of miRNA in MDS. However, the complex regulatory networks between miRNAs and their potential target genes in MDS still need to be explored in further studies. Although the function of miRNAs is not fully understood, these small non-coding RNAs represent novel pathogenetic and clinical implications in MDS. The studies of miRNAs may guide us towards a better understanding of this disease and shed light on the development of new therapeutic strategies.


Can social support work virtually? Evaluation of rheumatoid arthritis patients' experiences with an interactive online tool.
There is strong empirical evidence that the support that chronic patients receive from their environment is fundamental for the way they cope with physical and psychological suffering. Nevertheless, in the case of rheumatoid arthritis (RA), providing the appropriate social support is still a challenge, and such support has often proven to be elusive and unreliable in helping patients to manage the disease. To explore whether and how social support for RA patients can be provided online, and to assess the conditions under which such support is effective. An online support tool was designed to provide patients with both tailored information and opportunities to interact online with health professionals and fellow sufferers. The general purpose was to identify where the support provided did - or did not - help patients, and to judge whether the determinants of success lay more within patients - their engagement and willingness to participate - or within the design of the website itself. The present study reports qualitative interviews with 19 users of the tool. A more specific purpose was to elaborate qualitatively on results from a quantitative survey of users, which indicated that any positive impact was confined to practical matters of pain management rather than extending to more fundamental psychological outcomes such as acceptance. Overall, online learning and interaction can do much to help patients with the everyday stresses of their disease; however, its potential for more durable positive impact depends on various individual characteristics such as personality traits, existing social networks, and the severity and longevity of the disease.


Can pharmacogenomics improve malaria drug policy?
Coordinated global efforts to prevent and control malaria have been a tour-de-force for public health, but success appears to have reached a plateau in many parts of the world. While this is a multifaceted problem, policy strategies have largely ignored genetic variations in humans as a factor that influences both selection and dosing of antimalarial drugs. This includes attempts to decrease toxicity, increase effectiveness and reduce the development of drug resistance, thereby lowering health care costs. We review the potential hurdles to developing and implementing pharmacogenetic-guided policies at a national or regional scale for the treatment of uncomplicated falciparum malaria. We also consider current knowledge on some component drugs of artemisinin combination therapies and ways to increase our understanding of host genetics, with the goal of guiding policy decisions for drug selection.


The effect of processing load on loss of information from short-term memory.
We report an experiment in which we varied the nature of the articulatory suppression task being performed during a filled retention interval in serial recall. During the retention interval participants performed one of three computer-paced colour naming tasks designed to prevent subvocal rehearsal: A Stroop color-interference task with items presented at a rate of one every 750 ms, and two color-consistent control tasks at a rate of either 750 ms or 500 ms per item. Memory performance over a 12 s interval declined much more dramatically with the Stroop task and the 500 ms control task than with the 750 ms control. There was no difference between the Stroop condition and the 500 ms control. These results pose problems for models that assume that loss of information from memory is determined entirely by interference, as there are more interfering events in the control 500 ms condition than the 750 ms Stroop. They also pose problems for models relying solely on time-based decay and articulatory rehearsal because all three conditions should block rehearsal and produce equivalent performance. The results illustrate that articulatory suppression tasks are not all equivalent, and suggest that the rate of decay from short-term memory is strongly influenced by the resource demands of concurrent processing.


A Novel Environmentally Friendly Synergistic Mixture for Steel Corrosion Inhibition in 0.51 M NaCl.
The ubiquitous use of plain and low-alloy steels in neutral, chloride bearing environments presents an everyday challenge for corrosion protection professionals. This paper explores the possibility of developing a non-toxic and environmentally friendly synergistic inhibitor mixture made of propolis, tannin, sodium benzoate, PEG400 and starch that could be applied into the solution to induce the formation of a persistent protective layer on steel. Components of the mixture were chosen based on the references giving their characteristics relevant to their possible action in the solution and/or at the surface of the steel. The efficiency of the protective layer formed under the influence of the inhibitor mixture, and then measured by the LPR probe in the inhibitor-free solution, was the lowest under quiescent conditions (75%) and the highest (95%) under flow conditions. Both, LPR and EIS data indicate that the inhibitor modified layer presents a barrier for diffusion of oxygen that acts as a primary corrosion reaction depolarizer in the investigated neutral chloride solution. The demonstrated persistence of the inhibitor modified layer is of primary interest as it gives possibility batch application.


Comparative risk of thrombosis with thrombocytopenia syndrome or thromboembolic events associated with different covid-19 vaccines: international network cohort study from five European countries and the US.
To quantify the comparative risk of thrombosis with thrombocytopenia syndrome or thromboembolic events associated with use of adenovirus based covid-19 vaccines versus mRNA based covid-19 vaccines. International network cohort study. Routinely collected health data from contributing datasets in France, Germany, the Netherlands, Spain, the UK, and the US. Adults (age ≥18 years) registered at any contributing database and who received at least one dose of a covid-19 vaccine (ChAdOx1-S (Oxford-AstraZeneca), BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), or Ad26.COV2.S (Janssen/Johnson & Johnson)), from December 2020 to mid-2021. Thrombosis with thrombocytopenia syndrome or venous or arterial thromboembolic events within the 28 days after covid-19 vaccination. Incidence rate ratios were estimated after propensity scores matching and were calibrated using negative control outcomes. Estimates specific to the database were pooled by use of random effects meta-analyses. Overall, 1 332 719 of 3 829 822 first dose ChAdOx1-S recipients were matched to 2 124 339 of 2 149 679 BNT162b2 recipients from Germany and the UK. Additionally, 762 517 of 772 678 people receiving Ad26.COV2.S were matched to 2 851 976 of 7 606 693 receiving BNT162b2 in Germany, Spain, and the US. All 628 164 Ad26.COV2.S recipients from the US were matched to 2 230 157 of 3 923 371 mRNA-1273 recipients. A total of 862 thrombocytopenia events were observed in the matched first dose ChAdOx1-S recipients from Germany and the UK, and 520 events after a first dose of BNT162b2. Comparing ChAdOx1-S with a first dose of BNT162b2 revealed an increased risk of thrombocytopenia (pooled calibrated incidence rate ratio 1.33 (95% confidence interval 1.18 to 1.50) and calibrated incidence rate difference of 1.18 (0.57 to 1.8) per 1000 person years). Additionally, a pooled calibrated incidence rate ratio of 2.26 (0.93 to 5.52) for venous thrombosis with thrombocytopenia syndrome was seen with Ad26.COV2.S compared with BNT162b2. In this multinational study, a pooled 30% increased risk of thrombocytopenia after a first dose of the ChAdOx1-S vaccine was observed, as was a trend towards an increased risk of venous thrombosis with thrombocytopenia syndrome after Ad26.COV2.S compared with BNT162b2. Although rare, the observed risks after adenovirus based vaccines should be considered when planning further immunisation campaigns and future vaccine development.


Potential Role of the Formation of Tunneling Nanotubes in HIV-1 Spread in Macrophages.
Tunneling nanotubes (TNTs), the long membrane extensions connecting distant cells, have emerged as a novel form of cell-to-cell communication. However, it is not fully understood how and to what extent TNTs contribute to intercellular spread of pathogens including HIV-1. In this study, we show that HIV-1 promotes TNT formation per se via its protein Nef and a cellular protein M-Sec, which appears to mediate approximately half of viral spread among monocyte-derived macrophages (MDMs). A small compound that inhibits M-Sec-induced TNT formation reduced HIV-1 production by almost half in MDMs. Such inhibition was not observed with Nef-deficient mutant HIV-1 that fails to promote TNT formation and replicates less efficiently than the wild-type HIV-1 in MDMs. The TNT inhibitor-sensitive/Nef-promoting viral production was also observed in a T cell line ectopically expressing M-Sec, but not in another M-Sec(-) T cell line. Our results suggest the importance of TNTs in HIV-1 spread among MDMs and might answer the long-standing question how Nef promotes HIV-1 production in a cell type-specific manner.


Specular neutron reflectivity and the structure of artificial protein maquettes vectorially oriented at interfaces.
Artificial peptides can be designed to possess a variety of functionalities. If these peptides can be ordered in an ensemble, the functionality can impart macroscopic material properties to the ensemble. Neutron reflectivity is shown to be an effective probe of the intramolecular structures of such peptides vectorially oriented at an interface, key to ensuring that the designed molecular structures translate into the desired material properties of the interface. A model-independent method is utilized to analyze the neutron reflectivity from an alkylated, di- alpha -helical peptide, containing perdeuterated leucine residues at one or two pre-selected positions, in mixed Langmuir monolayers with a phospholipid. The results presented here are more definitive than prior work employing x-ray reflectivity. They show explicitly that the di-helical peptide retains its designed alpha -helical secondary structure at the interface, when oriented perpendicular to the interface at high surface pressure, with the helices projecting into the aqueous subphase without penetrating the layer of phospholipid headgroups.


Dynamic metabolic transformation in tumor invasion and metastasis in mice with LM-8 osteosarcoma cell transplantation.
While extensive evidence indicates that tumor cells shift their global metabolic programs, the molecular details of the metabolic transformation in tumor invasion, progression, and metastasis remain largely unknown. Characterization of the time-dependent metabolic shift during the tumor invasion, development, and metastasis will describe an important aspect of tumor phenotypes and potentially allow us to design therapies that inhibit tumor cell movement. In this study, a metabonomic study was performed to characterize the global metabolic changes during the process of tumor invasion and metastasis to lung in a mouse model with subcutaneous transplantation of murine osteosarcoma cell line (LM8). The serum metabolic profiling revealed that many key metabolites in glycolysis and tricarboxylic acid (TCA) cycle, as well as most of the amino acids were elevated at rapidly growing stage of tumor, presumably resulting from a high energy demand and turnover of anabolic metabolism during the tumor cell proliferation. Serum levels of succinic acid and proline significantly increased (with fold change FC = 10.75 and 4.43, relative to controls) among all the metabolites in the third week. The serum metabolic profile of lung metastasis at week 4 was different from that at week 3, in that most of previously increased serum metabolites were found decreased, except for cholesterol and several free fatty acids, suggesting lowered carbohydrate and amino acids metabolism, but an elevated lipid metabolism associated with tumor metastasis.


MTG1 couples mitoribosome large subunit assembly with intersubunit bridge formation.
Mammalian mitochondrial ribosomes (mitoribosomes) synthesize 13 proteins, essential components of the oxidative phosphorylation system. They are linked to mitochondrial disorders, often involving cardiomyopathy. Mitoribosome biogenesis is assisted by multiple cofactors whose specific functions remain largely uncharacterized. Here, we examined the role of human MTG1, a conserved ribosome assembly guanosine triphosphatase. MTG1-silencing in human cardiomyocytes and developing zebrafish revealed early cardiovascular lesions. A combination of gene-editing and biochemical approaches using HEK293T cells demonstrated that MTG1 binds to the large subunit (mtLSU) 16S ribosomal RNA to facilitate incorporation of late-assembly proteins. Furthermore, MTG1 interacts with mtLSU uL19 protein and mtSSU mS27, a putative guanosine triphosphate-exchange factor (GEF), to enable MTG1 release and the formation of the mB6 intersubunit bridge. In this way, MTG1 establishes a quality control checkpoint in mitoribosome assembly. In conclusion, MTG1 controls mitochondrial translation by coupling mtLSU assembly with intersubunit bridge formation using the intrinsic GEF activity acquired by the mtSSU through mS27, a unique occurrence in translational systems.


Improved sensing performance of D-fiber/planar waveguide couplers.
Wavelength selective coupling is demonstrated between the core of a D-shaped optical fiber and a multimode planar waveguide. The fabrication process consists of wet chemical etching of the D-fiber and spin coating or molding to produce the planar waveguide. This fabrication process is shown to produce weak coupling and long interaction length, which exhibits transmission dips with narrow wavelength linewidths. A comb filter is demonstrated with peak separations of 12nm, transmission dips of -20dB, and linewidths of 0.25nm. High sensitivity is demonstrated by showing shift in the transmission dips of -3.16 nm/degree C.


Augmentation of in vitro humoral immune responses in the mouse by an antibody to IgD.
Heterologous anti-delta-chain antibodies have an adjuvant effect on specific in vivo humoral immune responses to simultaneously, or subsequently, injected antigens in the rat and rhesus monkey. We have used a hybridoma-secreted antibody that binds murine delta-chain of the allotype (4.22aM delta a) to study this phenomenon in the mouse and to investigate the mechanism of this effect. Injection of 4.22aM delta a into BALB/c mice removes almost all surface IgD (sIgD) from splenic B lymphocites. sIgD does not reappear until the serum level of 4.22aM delta a decreased 5-7 d after injection. 4.22aM delta a fails to induce detectable proliferation or to raise total serum Ig levels substantially above control values. However, 4.22aM dalta a injected 24 h before antigen elicits an approximately twofold enhancement of serum IgM and a 3- to 10-fold enhancement of serum IgG anti-trintriphenyl (TNP) antibodies in response to immunization with optimal doses of TNP-Ficoll or TNP-sheep red blood cells (TNP-SRBC). 4.22aM delta a injected 1 wk before or 3 d after TNP-SRBC, however, has no effect on IgG anti-TNP levels. The adjuvant effect of anti-delta-chain antibody was markedly decreased when suboptimal antigen doses were used. Furthermore, even in the case of TNP-Ficoll, a relatively T-independent antigen, the ability of 4.22aM dalta a to enhance the anti-TNP antibody response was T cell dependent. Our data suggest that the binding of anti-delta-chain antibody to cell sIgD may partially activate B lymphocytes and make them more capable of differentiating into antibody-secreting cells when stimulated by antigen-specific T cell help.


Percutaneous transluminal dilatation or surgery in the management of renal vascular hypertension?
1. Twelve patients with renal artery stenosis due to fibromuscular disease (FMD) were treated with percutaneous transluminal dilation (PTD) and their results (first year) compared with those for 26 patients treated with attempted renal artery bypass. The cumulative probability of cure at 1 year was 0.67 for PTD and 0.36 for surgery (P = N.S.) in patients with FMD. The cumulative probability of being improved or cured was 0.92 for PTD and 0.88 for surgery. 2. Eighteen patients with renal artery stenosis due to atherosclerosis were treated with PTD and their results compared with those of 28 patients treated by surgery. The cumulative probability of cure at 1 year was 0.11 for PTD and 0.17 for surgery (P = N.S.). The cumulative probability for cure or improvement at 1 year was 0.30 for PTD and 0.88 for surgery (P less than 0.001). 3. We conclude that PTD may be a satisfactory alternative to surgery in fibromuscular disease, but is inferior to surgery in atherosclerotic disease causing renal artery stenosis. 4. A randomized clinical trial is needed to define the role of PTD and surgery in renal artery stenosis.


Mapping neuroreceptors with metal-labeled radiopharmaceuticals.
The growing epidemiological and economic burden of neurological diseases on society is tremendous. A correct and timely diagnosis can help in lowering the burden and improving the life quality of both the diseased person and the caretaker. Imaging of the brain (neuroimaging) using CT, MRI, and nuclear imaging methods can provide anatomical and functional information. Neuroreceptors are central to neurotransmission and neuromodulation in the CNS. In vivo imaging of receptors in the brain provides powerful tools for the functional study of the central nervous system (CNS) in normal or diseased states. Presently, PET imaging using non-metallic radiotracers dominates the imaging of neuroreceptors. Metal-based probes for SPECT and PET can be economical and logistically easier to use without compromising the information. This review focuses on the development of metallic radiotracers for (99mTc) SPECT and (68Ga) PET along with future directions based on the metallic probes developed for other imaging modalities namely MRI.


Cdc13 cooperates with the yeast Ku proteins and Stn1 to regulate telomerase recruitment.
The Saccharomyces cerevisiae CDC13 protein binds single-strand telomeric DNA. Here we report the isolation of new mutant alleles of CDC13 that confer either abnormal telomere lengthening or telomere shortening. This deregulation not only depended on telomerase (Est2/TLC1) and Est1, a direct regulator of telomerase, but also on the yeast Ku proteins, yKu70/Hdf1 and yKu80/Hdf2, that have been previously implicated in DNA repair and telomere maintenance. Expression of a Cdc13-yKu70 fusion protein resulted in telomere elongation, similar to that produced by a Cdc13-Est1 fusion, thus suggesting that yKu70 might promote Cdc13-mediated telomerase recruitment. We also demonstrate that Stn1 is an inhibitor of telomerase recruitment by Cdc13, based both on STN1 overexpression and Cdc13-Stn1 fusion experiments. We propose that accurate regulation of telomerase recruitment by Cdc13 results from a coordinated balance between positive control by yKu70 and negative control by Stn1. Our results represent the first evidence of a direct control of the telomerase-loading function of Cdc13 by a double-strand telomeric DNA-binding complex.


Role of alkaline phosphatase in colitis in man and rats.
Crohn's disease (CD) and ulcerative colitis (UC) are chronic multifactorial inflammatory bowel diseases (IBDs) with unknown aetiology, but a deregulated mucosal immune response to gut-derived bacterial antigens is thought to be involved. Toll-like receptor ligands, especially lipopolysaccharide (LPS), contribute to the maintenance of the disease. It has previously been shown that the enzyme alkaline phosphatase (AP) is able to detoxify LPS, and the aim of this study was to examine a possible role in IBDs. Intestinal AP (iAP) mRNA expression and LPS dephosphorylation in intestinal biopsies of control subjects and patients with IBD were examined, and the effect of orally administered iAP tablets on the progression of dextran sodium sulfate-induced colitis in rats was subsequently studied. In healthy persons, iAP mRNA and enzyme activity was high in the ileum relative to the colon. In patients with UC and CD, iAP mRNA expression was found to be markedly reduced when inflamed tissue was compared with non-inflamed tissue. Oral administration of iAP tablets to colitic rats resulted in a significant attenuation of colonic inflammation as reflected by reduced mRNA levels for tumour necrosis factor alpha, interleukin 1 beta, interleukin 6 and inducible nitric oxide synthase NOS (iNOS), a reduced iNOS staining and inflammatory cell influx, and a significantly improved morphology of the intestinal wall. The present study shows that epithelial iAP mRNA expression is reduced in patients with UC and CD. The rat model demonstrates that oral administration of active iAP enzymes in the intestinal tract results in a significant reduction of inflammation. This provides new insight on IBD pathology and a novel treatment approach to this severe inflammatory disease.


Biochemical and molecular analysis of phospholipase C and phospholipase D activity in mycobacteria.
Resurgence of mycobacterial infections in the United States has led to an intense effort to identify potential virulence determinants in the genus Mycobacterium, particularly ones that would be associated with the more virulent species (e.g., Mycobacterium tuberculosis). Thin-layer chromatography (TLC) using radiolabeled phosphatidylcholine and sphingomyelin as substrates indicated that cell extracts of M. tuberculosis contain both phospholipase C (PLC) and phospholipase D (PLD) activities. In contrast, only PLD activity was detected in cell extracts of M. smegmatis. Neither activity was detected in cell-free culture supernatants from these organisms. We and others recently identified two open reading frames in M. tuberculosis with the potential to encode proteins which are highly homologous to the nonhemolytic (PlcN) and hemolytic (PlcH) phospholipase C enzymes of Pseudomonas aeruginosa. In contrast to the plc genes in P. aeruginosa, which are considerably distal to each other (min 34 and 64 on the chromosome), the mycobacterial genes, designated mpcA and mpcB, are tandemly arranged in the same relative orientation and separated by only 191 bp. Both the mpcA and the mpcB genes were individually cloned in M. smegmatis, and PLC activity was expressed from each gene in this organism. Hybridization experiments using the mpcA and the mpcB genes as probes under conditions of moderate stringency identified sequences homologous to these genes in M. bovis, M. bovis BCG, and M. marinum but not in several other Mycobacterium species, including M. smegmatis, M. avium, and M. intracellulare. TLC analysis using radiolabeled substrates indicated that M. bovis and M. marinum cell extracts contain PLC and PLD activities, but only PLD activity was detected in M. bovis BCG cell extracts. Sphingomyelinase activity was also detected in whole-cell extracts of M. tuberculosis, M. marinum, M. bovis, and M. bovis BCG, but this activity was not detected in extracts of M. smegmatis. Sphingomyelinase activity was detected in cell extracts from M. smegmatis harboring either recombinant mpcA or mpcB. These data indicate that PLC and sphingomyelinase activities are associated with the most virulent mycobacterial species, while PLD activity was detected in both virulent and saprophytic strains.


Hippocampal mutant APP and amyloid beta-induced cognitive decline, dendritic spine loss, defective autophagy, mitophagy and mitochondrial abnormalities in a mouse model of Alzheimer's disease.
The purpose of our study was to determine the toxic effects of hippocampal mutant APP and amyloid beta (Aβ) in 12-month-old APP transgenic mice. Using rotarod and Morris water maze tests, immunoblotting and immunofluorescence, Golgi-cox staining and transmission electron microscopy, we assessed cognitive behavior, protein levels of synaptic, autophagy, mitophagy, mitochondrial dynamics, biogenesis, dendritic protein MAP2 and quantified dendritic spines and mitochondrial number and length in 12-month-old APP mice that express Swedish mutation. Mitochondrial function was assessed by measuring the levels of hydrogen peroxide, lipid peroxidation, cytochrome c oxidase activity and mitochondrial ATP. Morris water maze and rotarod tests revealed that hippocampal learning and memory and motor learning and coordination were impaired in APP mice relative to wild-type (WT) mice. Increased levels of mitochondrial fission proteins, Drp1 and Fis1 and decreased levels of fusion (Mfn1, Mfn2 and Opa1) biogenesis (PGC1α, NRF1, NRF2 and TFAM), autophagy (ATG5 and LC3BI, LC3BII), mitophagy (PINK1 and TERT), synaptic (synaptophysin and PSD95) and dendritic (MAP2) proteins were found in 12-month-old APP mice relative to age-matched non-transgenic WT mice. Golgi-cox staining analysis revealed that dendritic spines are significantly reduced. Transmission electron microscopy revealed significantly increased mitochondrial numbers and reduced mitochondrial length in APP mice. These findings suggest that hippocampal accumulation of mutant APP and Aβ is responsible for abnormal mitochondrial dynamics and defective biogenesis, reduced MAP2, autophagy, mitophagy and synaptic proteins and reduced dendritic spines and hippocampal-based learning and memory impairments, and mitochondrial structural and functional changes in 12-month-old APP mice.


Recovery of Theta Frequency Oscillations in Rats Following Lateral Fluid Percussion Corresponds With a Mild Cognitive Phenotype.
Whether from a fall, sports concussion, or even combat injury, there is a critical need to identify when an individual is able to return to play or work following traumatic brain injury (TBI). Electroencephalogram (EEG) and local field potentials (LFP) represent potential tools to monitor circuit-level abnormalities related to learning and memory: specifically, theta oscillations can be readily observed and play a critical role in cognition. Following moderate traumatic brain injury in the rat, lasting changes in theta oscillations coincide with deficits in spatial learning. We hypothesized, therefore, that theta oscillations can be used as an objective biomarker of recovery, with a return of oscillatory activity corresponding with improved spatial learning. In the current study, LFP were recorded from dorsal hippocampus and anterior cingulate in awake, behaving adult Sprague Dawley rats in both a novel environment on post-injury days 3 and 7, and Barnes maze spatial navigation on post-injury days 8-11. Theta oscillations, as measured by power, theta-delta ratio, peak theta frequency, and phase coherence, were significantly altered on day 3, but had largely recovered by day 7 post-injury. Injured rats had a mild behavioral phenotype and were not different from shams on the Barnes maze, as measured by escape latency. Injured rats did use suboptimal search strategies. Combined with our previous findings that demonstrated a correlation between persistent alterations in theta oscillations and spatial learning deficits, these new data suggest that neural oscillations, and particularly theta oscillations, have potential as a biomarker to monitor recovery of brain function following TBI. Specifically, we now demonstrate that oscillations are depressed following injury, but as oscillations recover, so does behavior.


Bleak future for pre- and paraclinical postgraduates in India.
In a bid to encourage medical graduates to opt for postgraduation in pre- and paraclinical courses, the Odisha Government, in January 2018, hiked the stipend for students pursuing these courses in state-run medical colleges. The state government also announced additional financial assistance of Rs 18,000 per month for pre- and paraclinical postgraduate students, along with the stipend money. The state's Health and Family Welfare Minister, Pratap Jena, said this would be applicable to both in-service and direct postgraduate students. This announcement in the newspapers gave rise to much discussion in the social media.


Cumulative lead dose and cognitive function in older adults.
The current population of older Americans has accumulated substantial lifetime lead doses, which raises concern about the possibility of adverse cognitive outcomes. We evaluated whether cumulative lead dose from environmental exposures is associated with cognitive function and decline, and whether such effects are persistent, reversible, or progressive. We used longitudinal linear modeling to evaluate associations of tibia lead concentration with cognitive function and decline in sociodemographically diverse, community-dwelling adults aged 50-70 years who were randomly selected from neighborhoods in Baltimore. Six summary measures of cognitive function were created from standard tests in the following domains: language, processing speed, eye-hand coordination, executive functioning, verbal memory and learning, and visual memory. The mean (SD) tibia lead level was 18.8 (11.6) microg/g. In models adjusted for demographic characteristics, socioeconomic status (SES), and race/ethnicity, higher tibia lead was associated with a progressive decline in eye-hand coordination. Tibia lead was associated with persistently impaired cognitive function in all 6 domains, although these associations weakened after increasing covariate control. In fully adjusted stratified analysis among white persons, persistent effects were apparent in eye-hand coordination, executive functioning, and verbal memory and learning. The study presents the strongest evidence to date of the effects of cumulative lead dose on adult cognitive function independent of SES. The study population was relatively young and the average total duration of follow-up short (<30 months); these findings may represent the lower bound of the impact of cumulative lead dose on cognitive function of older adults.


Resolution of sexual dysfunction during double-blind treatment of major depression with reboxetine or paroxetine.
The selective noradrenaline re-uptake inhibitor reboxetine may have advantages over the selective serotonin re-uptake inhibitors fluoxetine and citalopram, in effects on sexual function and satisfaction. The effects of reboxetine and paroxetine on sexual function were compared by examining data from the UK centres in an international double-blind flexible-dose parallel-group multi-centre randomized controlled trial of acute treatment of patients with DSM-IV major depression. Patients were randomly assigned to receive reboxetine (4 mg b.d.) or paroxetine (20 mg mane) using a double-dummy technique to preserve the blind. The dosage could be increased at day 28 (to reboxetine 4 mg mane, 6 mg nocte; or paroxetine 20 mg b.d.). Antidepressant efficacy was assessed by the 21-item Hamilton Rating Scale for Depression (HAM-D) and Clinical Global Impression Scale for Severity (CGI-S) at all study visits, and the Clinical Global Impression of Improvement (CGI-I) at each visit after randomization. Sexual function and satisfaction was assessed by visual analogue scale (VAS) items of the Rush Sexual Inventory completed at baseline and days 28 and 56. There were no significant differences between groups in demographic or clinical features at baseline. There was a gradual reduction in severity of depressive symptoms (reboxetine, 14.3; paroxetine, 12.0: observed case analysis), with no significant differences between groups. There were significant differences (p 0.05), with advantages for reboxetine, at Week 4 and Week 8 on the VAS item assessing ability to become sexually excited, and non-significant trends with advantages for reboxetine, in frequency of sexual thoughts at Week 4 (p 0.05) and Week 8 (p 0.08); and in desire to initiate sexual activity at Week 4 (p 0.09). Exclusion of patients who had ever experienced sexual dysfunction with any medication prior to participation in this study (n 10) reduced the statistical significance of the findings, although there were still numerical advantages for reboxetine. Sexual function and satisfaction in depressed patients improves during double-blind acute treatment with reboxetine or paroxetine, but this improvement is greater and more rapid with reboxetine.


Consensus Statement of Standards for Interventional Cardiovascular Nursing Practice.
Interventional cardiovascular nursing is a critical care nursing specialty providing complex nursing interventions to patients prone to clinical deterioration, through the combined risks of the pathophysiology of their illness and undergoing technically complex interventional cardiovascular procedures. No guidelines were identified worldwide to assist health care providers and educational institutions in workforce development and education guidelines to minimise patients' risk of adverse events. The Interventional Nurses Council (INC) developed a definition and scope of practice for interventional cardiac nursing (ICN's) in 2013. The INC executive committee established a working party of seven representatives from Australia and New Zealand. Selection was based on expertise in interventional cardiovascular nursing and experience providing education and mentoring in the clinical and postgraduate environment. A literature search of the electronic databases Science Direct, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Medline and Health Source was performed, using the search terms: clinical deterioration, ST elevation myocardial infarction, vital signs, primary percutaneous coronary intervention, PCI, AMI, STEMI, acute coronary syndrome, peri-procedural care, unstable angina, PCI complications, structural heart disease, TAVI, TAVR, cardiac rhythm management, pacing, electrophysiology studies, vascular access, procedural sedation. Articles were limited to the cardiac catheterisation laboratory and relevance to nursing based outcomes. Reference lists were examined to identify relevant articles missed in the initial search. The literature was compared with national competency standards, quality and safety documents and the INC definition and scope of practice. Consensus of common themes, a taxonomy of education and seven competency domains were achieved via frequent teleconferences and two face-to-face meetings. The working party finalised the standards on 14 July 2017, following endorsement from the CSANZ, INC, Heart Rhythm Council, CSANZ Quality Standards Committee and the Australian College of Critical Care Nurses (ACCCN). The resulting document provides clinical practice and education standards for interventional cardiac nursing practice.


Prothrombotic skeletal muscle myosin directly enhances prothrombin activation by binding factors Xa and Va.
To test the hypothesis that skeletal muscle myosins can directly influence blood coagulation and thrombosis, ex vivo studies of the effects of myosin on thrombogenesis in fresh human blood were conducted. Addition of myosin to blood augmented the thrombotic responses of human blood flowing over collagen-coated surfaces (300 s-1 shear rate). Perfusion of human blood over myosin-coated surfaces also caused fibrin and platelet deposition, evidencing myosin's thrombogenicity. Myosin markedly enhanced thrombin generation in both platelet-rich plasma and platelet-poor plasma, indicating that myosin promoted thrombin generation in plasma primarily independent of platelets. In purified reaction mixtures composed only of factor Xa, factor Va, prothrombin, and calcium ions, myosin greatly enhanced prothrombinase activity. The Gla domain of factor Xa was not required for myosin's prothrombinase enhancement. When binding of purified clotting factors to immobilized myosin was monitored using biolayer interferometry, factors Xa and Va each showed favorable binding interactions. Factor Va reduced by 100-fold the apparent Kd of myosin for factor Xa (Kd ∼0.48 nM), primarily by reducing koff, indicating formation of a stable ternary complex of myosin:Xa:Va. In studies to assess possible clinical relevance for this discovery, we found that antimyosin antibodies inhibited thrombin generation in acute trauma patient plasmas more than in control plasmas (P = .0004), implying myosin might contribute to acute trauma coagulopathy. We posit that myosin enhancement of thrombin generation could contribute either to promote hemostasis or to augment thrombosis risk with consequent implications for myosin's possible contributions to pathophysiology in the setting of acute injuries.


Initial development of pathological personality trait domain measures using the Personality Assessment Inventory (PAI).
This study set out to create measures of the five personality disorder trait domains outlined in Section III of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (American Psychiatric Association, 2013) from the Personality Assessment Inventory items (Morey, 2007). Rasch rating scale model analyses and classical test theory analyses were applied to existing data sets (N = 3,877; community, clinical, offender, college) to identify relevant items. Five scales were created that had acceptable unidimensionality and generally conformed to Rasch model expectations. The ability of the items to cover the underlying construct and their differential item function by sex were acceptable, though a few of the proposed scales had weaknesses in these areas. Internal consistency was acceptable for all scales and the factor structure was generally consistent with expectations, but some scales had concerning cross-loadings. Preliminary analyses demonstrated validity of the scales in relation to history of mental health treatment/current symptoms, substance abuse, and, for one scale, violent rearrests. There were small-to-moderate associations with noncorresponding traits, suggesting a degree of saturation with general personality impairment. The relevance of the proposed scales for the assessment of Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition personality disorder is discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Gender-specific association of the plasminogen activator inhibitor-1 4G/5G polymorphism with central arterial blood pressure.
The functional plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism has previously been associated with hypertension. In recent years, central blood pressure, rather than brachial has been argued a better measure of cardiovascular damage and clinical outcome. The aim of this study was to investigate the possible influence of the 4G/5G polymorphism on central arterial blood pressure in a cohort of elderly individuals. We studied 410 individuals, 216 men and 194 women, aged 70-88. Central pressures and pulse waveforms were calculated from the radial artery pressure waveform by the use of the SphygmoCor system and a generalized transfer function. Brachial pressure was recorded using oscillometric technique (Dinamap, Critikon, Tampa, FL). PAI-1 antigen was determined in plasma. The results showed that central pressures were higher in women carrying the PAI-1 4G/4G genotype compared to female carriers of the 5G/5G genotype, (P = 0.025, P = 0.002, and P = 0.002 for central systolic-, diastolic-, and mean arterial pressure, respectively). The association remained after adjustment for potentially confounding factors related to hypertension. No association of the PAI-1 genotype with blood pressure was found in men. Multiple regression analysis revealed an association between PAI-1 genotype and plasma PAI-1 levels (P = 0.048). Our findings show a gender-specific association of the PAI-1 4G/5G polymorphism with central arterial blood pressure. The genotype effect was independent of other risk factors related to hypertension, suggesting that impaired fibrinolytic potential may play an important role in the development of central hypertension in women.


Reliability of psychiatric diagnosis in hospitalized adolescents. Interrater agreement using DSM-III.
To determine the reliability of psychiatric diagnosis in hospitalized adolescents, 95 consecutively admitted patients were diagnosed independently by two experienced clinicians using DSM-III criteria. Diagnostic judgments were based on joint interview of the patient via a structured mental-status examination, nursing observations, and referral materials. Concordance was analyzed by the kappa coefficient. A total of 13 DSM-III categories were used to classify this cohort, with the majority of categories representing traditional syndromes of functional psychopathology. There was complete agreement between the raters for more than three fourths of the patients. Levels of agreement for the categories of schizophrenia and major affective disorder were similar to values obtained in recent studies of adult patients. The results are discussed in relation to historical conceptions of adolescent psychopathology.


The longitudinal biochemical profiling of TBI in a drop weight model of TBI.
Traumatic brain injury (TBI) is a major cause of mortality and disability worldwide, particularly among individuals under the age of 45. It is a complex, and heterogeneous disease with a multifaceted pathophysiology that remains to be elucidated. Metabolomics has the potential to identify metabolic pathways and unique biochemical profiles associated with TBI. Herein, we employed a longitudinal metabolomics approach to study TBI in a weight drop mouse model to reveal metabolic changes associated with TBI pathogenesis, severity, and secondary injury. Using proton nuclear magnetic resonance (1H NMR) spectroscopy, we biochemically profiled post-mortem brain from mice that suffered mild TBI (N = 25; 13 male and 12 female), severe TBI (N = 24; 11 male and 13 female) and sham controls (N = 16; 11 male and 5 female) at baseline, day 1 and day 7 following the injury. 1H NMR-based metabolomics, in combination with bioinformatic analyses, highlights a few significant metabolites associated with TBI severity and perturbed metabolism related to the injury. We report that the concentrations of taurine, creatinine, adenine, dimethylamine, histidine, N-Acetyl aspartate, and glucose 1-phosphate are all associated with TBI severity. Longitudinal metabolic observation of brain tissue revealed that mild TBI and severe TBI lead distinct metabolic profile changes. A multi-class model was able to classify the severity of injury as well as time after TBI with estimated 86% accuracy. Further, we identified a high degree of correlation between respective hemisphere metabolic profiles (r > 0.84, p < 0.05, Pearson correlation). This study highlights the metabolic changes associated with underlying TBI severity and secondary injury. While comprehensive, future studies should investigate whether: (a) the biochemical pathways highlighted here are recapitulated in the brain of TBI sufferers and (b) if the panel of biomarkers are also as effective in less invasively harvested biomatrices, for objective and rapid identification of TBI severity and prognosis.