Life cycle-based water assessment of a hand dishwashing product: opportunities and limitations.
It is only recently that life cycle-based indicators have been used to evaluate products from a water use impact perspective. The applicability of some of these methods has been primarily demonstrated on agricultural materials or products, because irrigation requirements in food production can be water-intensive. In view of an increasing interest on life cycle-based water indicators from different products, we ran a study on a hand dishwashing product. A number of water assessment methods were applied with the purpose of identifying both product improvement opportunities, as well as understanding the potential for underlying database and methodological improvements. The study covered the entire life cycle of the product and focused on environmental issues related to water use, looking in-depth at inventory, midpoint, and endpoint methods. "Traditional" water emission driven methods, such as freshwater eutrophication, were excluded from the analysis. The use of a single formula with the same global supply chain, manufactured in 1 location was evaluated in 2 countries with different water scarcity conditions. The study shows differences ranging up to 4 orders in magnitude for indicators with similar units associated with different water use types (inventory methods) and different cause-effect chain models (midpoint and endpoint impact categories). No uncertainty information was available on the impact assessment methods, whereas uncertainty from stochastic variability was not available at the time of study. For the majority of the indicators studied, the contribution from the consumer use stage is the most important (>90%), driven by both direct water use (dishwashing process) as well as indirect water use (electricity generation to heat the water). Creating consumer awareness on how the product is used, particularly in water-scarce areas, is the largest improvement opportunity for a hand dishwashing product. However, spatial differentiation in the inventory and impact assessment model may lead to very different results for the product used under exactly the same consumer use conditions, making the communication of results a real challenge. From a practitioner's perspective, the data collection step in relation to the goal and scope of the study sets high requirements for both foreground and background data. In particular, databases covering a broad spectrum of inventory data with spatially differentiated water use information are lacking. For some impact methods, it is unknown as to whether or not characterization factors should be spatially differentiated, which creates uncertainty in their interpretation and applicability. Finally, broad application of life cycle-based water assessment will require further development of commercial life cycle assessment software.


Regional brain hypometabolism is unrelated to regional amyloid plaque burden.
In its original form, the amyloid cascade hypothesis of Alzheimer's disease holds that fibrillar deposits of amyloid are an early, driving force in pathological events leading ultimately to neuronal death. Early clinicopathological investigations highlighted a number of inconsistencies leading to an updated hypothesis in which amyloid plaques give way to amyloid oligomers as the driving force in pathogenesis. Rather than focusing on the inconsistencies, amyloid imaging studies have tended to highlight the overlap between regions that show early amyloid plaque signal on positron emission tomography and that also happen to be affected early in Alzheimer's disease. Recent imaging studies investigating the regional dependency between metabolism and amyloid plaque deposition have arrived at conflicting results, with some showing regional associations and other not. We extracted multimodal neuroimaging data from the Alzheimer's disease neuroimaging database for 227 healthy controls and 434 subjects with mild cognitive impairment. We analysed regional patterns of amyloid deposition, regional glucose metabolism and regional atrophy using florbetapir ((18)F) positron emission tomography, (18)F-fluordeoxyglucose positron emission tomography and T1-weighted magnetic resonance imaging, respectively. Specifically, we derived grey matter density and standardized uptake value ratios for both positron emission tomography tracers in 404 functionally defined regions of interest. We examined the relation between regional glucose metabolism and amyloid plaques using linear models. For each region of interest, correcting for regional grey matter density, age, education and disease status, we tested the association of regional glucose metabolism with (i) cortex-wide florbetapir uptake; (ii) regional (i.e. in the same region of interest) florbetapir uptake; and (iii) regional florbetapir uptake while correcting in addition for cortex-wide florbetapir uptake. P-values for each setting were Bonferroni corrected for 404 tests. Regions showing significant hypometabolism with increasing cortex-wide amyloid burden were classic Alzheimer's disease-related regions: the medial and lateral parietal cortices. The associations between regional amyloid burden and regional metabolism were more heterogeneous: there were significant hypometabolic effects in posterior cingulate, precuneus, and parietal regions but also significant positive associations in bilateral hippocampus and entorhinal cortex. However, after correcting for global amyloid burden, few of the negative associations remained and the number of positive associations increased. Given the wide-spread distribution of amyloid plaques, if the canonical cascade hypothesis were true, we would expect wide-spread, cortical hypometabolism. Instead, cortical hypometabolism appears to be linked to global amyloid burden. Thus we conclude that regional fibrillar amyloid deposition has little to no association with regional hypometabolism.


Engineering Tough, Injectable, Naturally Derived, Bioadhesive Composite Hydrogels.
Engineering mechanically robust bioadhesive hydrogels that can withstand large strains may open new opportunities for the sutureless sealing of highly stretchable tissues. While typical chemical modifications of hydrogels, such as increasing the functional group density of crosslinkable moieties and blending them with other polymers or nanomaterials have resulted in improved mechanical stiffness, the modified hydrogels have often exhibited increased brittleness resulting in deteriorated sealing capabilities under large strains. Furthermore, highly elastic hydrogels, such as tropoelastin derivatives are highly expensive. Here, gelatin methacryloyl (GelMA) is hybridized with methacrylate-modified alginate (AlgMA) to enable ion-induced reversible crosslinking that can dissipate energy under strain. The hybrid hydrogels provide a photocrosslinkable, injectable, and bioadhesive platform with an excellent toughness that can be tailored using divalent cations, such as calcium. This class of hybrid biopolymers with more than 600% improved toughness compared to GelMA may set the stage for durable, mechanically resilient, and cost-effective tissue sealants. This strategy to increase the toughness of hydrogels may be extended to other crosslinkable polymers with similarly reactive moieties.


Spinal loading during circuit weight-training and running.
Spinal shrinkage was used as an indicant of loading on the spine in circuit weight-training and running regimes. The loss of stature during two sets of a circuit of weight-training (n = 10), a 6 km run by novices (n = 9) and a 25 km run by trained runners (n = 7) was assessed in male subjects. Shrinkage was not significantly different between the weight-training regime and the 6 km run by novices, mean losses being 5.4 and 3.25 mm respectively. The rate of height loss in the experienced runners was 2.35 mm over 6 km run at 12.2 km.h-1, representing 0.4 mm.km-1 over the 6 km run, this shrinkage rate being continued over the last 19 km run at 14.7 km.h-1. The loss of height could not be predicted from a set of covariates. The magnitude of the circadian variation, mean 14.4 mm, exceeded the change in height during the 25 km run. The diurnal variation conformed to a cosine function, though a better fit was obtained with a power function equation. A marked diurnal pattern was also observed in lumbar extension. Though reversal of spinal shrinkage was observed during a night's sleep, no significant recovery occurred during a 20 min resting period immediately following the exercise regimes. These results have implications for the warm-up and timing of exercise regimes that impose significant loading on the spine.


Parasex Generates Phenotypic Diversity de Novo and Impacts Drug Resistance and Virulence in Candida albicans.
Candida albicans is a diploid fungus that is a frequent cause of mucosal and systemic infections in humans. This species exhibits an unusual parasexual cycle in which mating produces tetraploid cells that undergo a nonmeiotic program of concerted chromosome loss to return to a diploid or aneuploid state. In this work, we used a multipronged approach to examine the capacity of parasex to generate diversity in C. albicans First, we compared the phenotypic properties of 32 genotyped progeny and observed wide-ranging differences in fitness, filamentation, biofilm formation, and virulence. Strikingly, one parasexual isolate displayed increased virulence relative to parental strains using a Galleria mellonella model of infection, establishing that parasex has the potential to enhance pathogenic traits. Next, we examined parasexual progeny derived from homothallic, same-sex mating events, and reveal that parasex can generate diversity de novo from identical parental strains. Finally, we generated pools of parasexual progeny and examined resistance of these pools to environmental stresses. Parasexual progeny were generally less fit than control strains across most test conditions, but showed an increased ability to grow in the presence of the antifungal drug fluconazole (FL). FL-resistant progeny were aneuploid isolates, often being diploid strains trisomic for both Chr3 and Chr6. Passaging of these aneuploid strains frequently led to loss of the supernumerary chromosomes and a concomitant decrease in drug resistance. These experiments establish that parasex generates extensive phenotypic diversity de novo, and that this process has important consequences for both virulence and drug resistance in C. albicans populations.


Parental attitudes towards oral health and caries-risk in their children.
The aim of this study was to investigate whether parents can be matched with attitudes towards oral health by means of a short vignette sheet, developed based on the results of an earlier Q-methodological study. Furthermore, this study aims to explore how the attitudes associate with diet and oral hygiene habits and with clinical outcomes in children. A total of 170 parents of 6- to 9-year-old children completed a questionnaire including the vignette sheet and clinical scores (oral hygiene, caries) were retrieved from the follow-up measurement of a RCT on caries-preventive measures. Of the 170 respondents, 159 (93.5%) could be matched to a single best matching attitude. Respondents identified "well" to "very well" with at least one of the attitudes and seemed to be able to differentiate well the extent to which they matched to the different attitudes. Parents scoring high on different attitudes were found to be associated with different lifestyle patterns and clinical outcomes. It was concluded that using a self-assessed attitude tool, derived from the results of a Q-methodological study, it is possible to identify different groups of parents with different oral health-related risk factors. Of course, it is hardly likely that people are 100% only 1 type of parent; parents can be considered to be a mix of different typologies. However, information on the composition of that mix may be helpful for the dental professional to estimate risks and to deliver a more tailored prevention strategy in children.


An overweight or obese status in childhood predicts subclinical atherosclerosis and prehypertension/hypertension in young adults.
The aim of this study, the YOung TAiwanese Cohort (YOTA) Study, was to investigate the relationship between a childhood overweight/obese status and young adult preclinical atherosclerosis, including assessments of the carotid intima-media thickness (CIMT) and prehypertension or hypertension. From among children who participated in the 1992-2000 mass urine screening program in Taiwan, we recruited 303 subjects with an elevated blood pressure (EBP) and 486 subjects with a normal BP in childhood during the period of 2006-2008. These 789 young adults received health check-ups for cardiovascular health, including examinations of blood and urine parameters, anthropometrics, BP and the CIMT, a subclinical cardiovascular risk index. Data analyses were used to evaluate the associated risks in both childhood and young adulthood. The school students with a childhood overweight/obese status had a higher risk of prehypertension or hypertension, with a relative risk of 3.20 (1.40-7.33) for being overweight and 6.51 (3.36-12.63) for being obese in young adulthood at an average age of 21. A childhood overweight/obese status also predicted a higher risk of having a thicker CIMT, with a relative risk of 2.82 (1.26-6.28) and 4.17 (2.21-7.85) for being overweight and obese in adulthood, respectively, after a mean follow-up of 8.5 years. The body mass index exhibited a consistent trend from childhood to adulthood, with an adjusted R square of 0.551. The participants who were not overweight/obese in childhood also demonstrated a higher risk of prehypertension or hypertension if they became overweight or obese in adulthood. This study highlights the importance of preventing and treating an overweight or obese status in childhood for the primary prevention of cardiovascular disease in adulthood.


Selection of the optimal personalized treatment from multiple treatments with multivariate outcome measures.
In this work, we propose a novel method for individualized treatment selection when the treatment response is multivariate. For the K treatment (K ≥2) scenario we compare quantities that are suitable indexes based on outcome variables for each treatment conditional on patient-specific scores constructed from collected covariate measurements. Our method covers any number of treatments and outcome variables, and it can be applied for a broad set of models. The proposed method uses a rank aggregation technique to estimate an ordering of treatments based on ranked lists of treatment performance measures such as smooth conditional means and conditional probability of a response for one treatment dominating others. The method has the flexibility to incorporate patient and clinician preferences to the optimal treatment decision on an individual case basis. A simulation study demonstrates the performance of the proposed method in finite samples. We also present data analyses using HIV and Diabetes clinical trials data to show the applicability of the proposed procedure for real data.


A conceptual model of HIV disclosure in casual sexual encounters among men who have sex with men.
HIV/AIDS continues to disproportionately impact men who have sex with men (MSM). Advances in highly active antiretroviral therapies (HAART) have successfully helped HIV-infected individuals lead longer, healthier, and presumably more sexually active lives. Consequently, secondary prevention approaches aimed at reducing the rate of HIV transmission have raised important questions about the role of sexual communication, namely HIV disclosure, as a primary target for intervention. This paper proposes a conceptual model of HIV disclosure in casual sexual encounters among MSM informed by Goffman's work on stigma and based on existing empirical research. The article concludes with an agenda for research based in this integrative model.


Immune reconstitution during maintenance therapy in children with acute lymphoblastic leukemia, relation to co-existing infection.
Immunosuppression is a major side effect of cancer chemotherapy. The process of immune reconstitution can be dissimilar according to the nature of the disease, type and doses of drugs, and age of the patients. Recently, several studies have examined immune reconstitution in children and young adults after intensive chemotherapy for solid tumours or stem cell transplantation. The aim of the present study is to evaluate immune reconstitution (cellular and humoral) in children with acute lymphoblastic leukemia during the maintenance phase of therapy and to correlate between the complicating infections and the abnormalities in immune system during reconstitution. To achieve this goal, 36 children with acute lymphoblastic leukemia (24 females and 12 males) in the maintenance phase of therapy with 12 healthy children of matched age and sex served as a control group were recruited in this study. The patients were taken consecutively from the Hematology/Oncology Outpatient Clinic of Mansoura University Children's Hospital (MUCH). They were subjected to thorough history taking, clinical examination and laboratory investigations in the form of: complete blood count, serum creatinine, liver function tests and evaluation of the immune system by estimation of CD3, CD4, CD8, CD19 and CD56 (cellular immunity) by flow cytometry and immunoglobulins A, M and G (humoral immunity) at the first and the third month of maintenance therapy. The results of the study documented presence and persistence of leucopenia and lymphopenia during maintenance therapy with decreased medians of CD3, CD4 and CD8 from the first to the third month of therapy and in comparison to the control group. The other markers CD19, CD56, IgA, IgM, IgG and CD4/CD8 ratio showed increasing median from the first to the third month of therapy. Also we detect a significant correlation between infection and CD19 and serum IgM at the first month and between infection and CD19, IgM and CD4/CD8 ratio at the third month of therapy. In conclusion, persistent immunosuppression is documented in children with acute lymphoblastic leukemia during maintenance therapy. Reconstitution of B lymphocytes and Natural killer cells occurs early while T cell reconstitution shows delayed recovery of both T helper and T suppressor cells. Immunosupression during maintenance therapy has no major clinical impact in terms of increased incidence or severity of systemic infections.


A comparative evaluation of multiple micronutrient and iron-folic acid supplementation during pregnancy in Pakistan: impact on pregnancy outcomes.
Maternal micronutrient deficiencies are widespread in Pakistan and are potentially associated with maternal undernutrition and intrauterine growth retardation. Intervention strategies largely consist of administration of iron-folic acid supplements during pregnancy. We evaluated the acceptability of multiple micronutrient supplementation and its potential benefits on pregnancy outcomes and maternal micronutrient status in a cohort of pregnant women in rural and urban Sindh through a cluster-randomized design. We randomly assigned 2378 pregnant women to receive either iron-folic acid or multiple micronutrient supplements. The supplements were administered fortnightly by community health workers who performed home visits to assess tolerance and observe the mothers. The women in both groups consumed about 75% of the supplements provided, and few reported adverse effects such as vomiting, abdominal pain, etc. There was a small (70 g) but significant increase in birthweight among infants of mothers receiving multiple micronutrients as compared with infants of mothers receiving iron-folic acid supplements (2.95 +/- 0.6 vs. 2.88 +/- 0.5 kg, p = .01). This translated into a 10% reduction (p < 0.17) in the proportion of low-birthweight infants among infants of mothers receiving multiple micronutrients. Although stillbirth rates were comparable in the two groups, the early neonatal mortality rate in the group receiving multiple micronutrients was higher, although not significantly, than that in the group receiving iron-folic acid (43.2 vs. 23.5 deaths per 1000 live births; RR = 1.64; 95% CI, 0.94 to 2.87). Comparable reductions in anemia (hemoglobin < 11 g/dL) were observed, although the proportion with low iron stores (assessed by serum ferritin) was lower in the iron-folic acid group in the postnatal period. Although the proportion of women with subclinical vitamin A deficiency after supplementation did not differ between the two groups, the iron-folic acid group had a higher proportion with lower serum zinc levels in the immediate postpartum period. These data suggest that multiple micronutrient supplements are well tolerated during pregnancy, but the effect on birthweight is modest. The observed effect on early neonatal mortality suggests the need for further studies and careful assessment of the intervention in health system settings.


Mode of action and variability in efficacy of plant essential oils showing toxicity against the poultry red mite, Dermanyssus gallinae.
This paper describes a series of experiments to examine the mode of action and toxicity of three plant essential oils (thyme, manuka and pennyroyal) to the poultry red mite, Dermanyssus gallinae (De Geer), a serious ectoparasitic pest of laying hens. All three oils were found to be toxic to D. gallinae in laboratory tests with LC(50), LC(90) and LC(99) values below 0.05, 0.20 and 0.30mg/cm(3), respectively, suggesting that these products may make for effective acaricides against this pest. Further experiments demonstrated that when mites were exposed to only the vapour phase of the essential oil without contact with the oil itself, mortality was consistently higher in closed arenas than in arenas open to the surrounding environment, or in control arenas. This suggests that all three essential oils were toxic to D. gallinae by fumigant action. In addition, in an experiment where mites were allowed contact with the essential oil in either open or closed arenas, mortality was always reduced in the open arenas where this was comparable to control mortality for thyme and pennyroyal essential oil treatments. This supports the findings of the previous experiment and also suggests that, with the possible exception of manuka, the selected essential oils were not toxic to D. gallinae on contact. Statistical comparisons were made between the toxicity of the selected essential oils to D. gallinae in the current work and in a previous study conducted in the same laboratory. The results demonstrated considerable variation in LC(50), LC(90) and LC(99) values. Since both the essential oils and the mites were obtained from identical sources in the two studies, it is hypothesized that this variation resulted from the use of different 'batches' of essential oil, which could have varied in chemistry and hence acaricidal activity.


Conditions for success in introducing telemedicine in diabetes foot care: a qualitative inquiry.
The uptake of various telehealth technologies to deliver health care services at a distance is expanding; however more knowledge is needed to help understand vital components for success in using telehealth in different work settings. This study was part of a larger trial designed to investigate the effect of an interactive telemedicine platform. The platform consisted of a web based ulcer record linked to a mobile phone to provide care for people with diabetic foot ulcers in outpatient clinics in specialist hospital care in collaboration with primary health care. The aim of this qualitative study was to identify perceptions of health care professionals in different working settings with respect to facilitators to engagement and participation in the application of telemedicine. Ten focus groups were conducted with health care professionals and leaders in Western Norway between January 2014 and June 2015 using Interpretive Description, an applied qualitative research strategy. Four key conditions for success in using telemedicine as a new technology in diabetes foot care were identified: technology and training that were user-friendly; having a telemedicine champion in the work setting; the support of committed and responsible leaders; and effective communication channels at the organizational level. Successful larger scale implementation of telemedicine must involve consideration of complex contextual and organizational factors associated with different work settings. This form of new care technology in diabetes foot care often involves health care professionals working across different settings with different management systems and organizational cultures. Therefore, attention to the distinct needs of each staff group seems an essential condition for effective implementation.


A crucial role of L-selectin in C protein-induced experimental polymyositis in mice.
To investigate the role of adhesion molecules in C protein-induced myositis (CIM), a murine model of polymyositis (PM). CIM was induced in wild-type mice, L-selectin-deficient (L-selectin(-/-) ) mice, intercellular adhesion molecule 1 (ICAM-1)-deficient (ICAM-1(-/-) ) mice, and mice deficient in both L-selectin and ICAM-1 (L-selectin(-/-) ICAM-1(-/-) mice). Myositis severity, inflammatory cell infiltration, and messenger RNA expression in the inflamed muscles were analyzed. The effect of dendritic polyglycerol sulfate, a synthetic inhibitor that suppresses the function of L-selectin and endothelial P-selectin, was also examined. L-selectin(-/-) mice and L-selectin(-/-) ICAM-1(-/-) mice developed significantly less severe myositis compared to wild-type mice, while ICAM-1 deficiency did not inhibit the development of myositis. L-selectin(-/-) mice that received wild-type T cells developed myositis. Treatment with dendritic polyglycerol sulfate significantly diminished the severity of myositis in wild-type mice compared to treatment with control. These data indicate that L-selectin plays a major role in the development of CIM, whereas ICAM-1 plays a lesser role, if any, in the development of CIM. L-selectin-targeted therapy may be a candidate for the treatment of PM.


Effects of sample selection bias on the accuracy of population structure and ancestry inference.
Population stratification is an important task in genetic analyses. It provides information about the ancestry of individuals and can be an important confounder in genome-wide association studies. Public genotyping projects have made a large number of datasets available for study. However, practical constraints dictate that of a geographical/ethnic population, only a small number of individuals are genotyped. The resulting data are a sample from the entire population. If the distribution of sample sizes is not representative of the populations being sampled, the accuracy of population stratification analyses of the data could be affected. We attempt to understand the effect of biased sampling on the accuracy of population structure analysis and individual ancestry recovery. We examined two commonly used methods for analyses of such datasets, ADMIXTURE and EIGENSOFT, and found that the accuracy of recovery of population structure is affected to a large extent by the sample used for analysis and how representative it is of the underlying populations. Using simulated data and real genotype data from cattle, we show that sample selection bias can affect the results of population structure analyses. We develop a mathematical framework for sample selection bias in models for population structure and also proposed a correction for sample selection bias using auxiliary information about the sample. We demonstrate that such a correction is effective in practice using simulated and real data.


Nanophotonic projection system.
Low-power integrated projection technology can play a key role in development of low-cost mobile devices with built-in high-resolution projectors. Low-cost 3D imaging and holography systems are also among applications of such a technology. In this paper, an integrated projection system based on a two-dimensional optical phased array with fast beam steering capability is reported. Forward biased p-i-n phase modulators with 200MHz bandwidth are used per each array element for rapid phase control. An optimization algorithm is implemented to compensate for the phase dependent attenuation of the p-i-n modulators. Using rapid vector scanning technique, images were formed and recorded within a single snapshot of the IR camera.


Patterns of Antipsychotic Prescribing by Physicians to Young Children.
Antipsychotic use among young children has grown rapidly despite a lack of approval by the U.S. Food and Drug Administration (FDA) for broad use in this age group. Characteristics of physicians who prescribed antipsychotics to young children were identified, and prescribing patterns involving young children and adults were compared. Physician-level prescribing data from IMS Health's Xponent database were linked with American Medical Association Masterfile data and analyzed. The sample included all U.S. psychiatrists and a random sample of 5% of family medicine physicians who wrote at least ten antipsychotic prescriptions per year from 2008 to 2011 (N=31,713). Logistic and hierarchical binomial regression models were estimated to examine physician prescribing for children ages zero to nine, and the types and numbers of ingredients used for children versus adults ages 20 to 64 were compared. Among antipsychotic prescribers, 42.2% had written at least one antipsychotic prescription for young children. Such prescribing was more likely among physicians age ≤39 versus ≥60 (odds ratio [OR]=1.70) and physicians in rural versus nonrural areas (OR=1.11) and was less likely among males (OR=.93) and graduates of a top-25 versus a lower-ranked U.S. medical school (OR=.87). Among physicians who prescribed antipsychotics to young children and adults, 75.0% of prescriptions for children and 35.7% of those for adults were for drugs with an FDA-approved indication for that age. Fewer antipsychotic agents were prescribed for young children (median=2) versus adults (median=7). Prescribing antipsychotics for young children was relatively common, but prescribing patterns differed between young children and adults.


Specific detection of Pasteurella multocida in chickens with fowl cholera and in pig lung tissues using fluorescent rRNA in situ hybridization.
A Pasteurella multocida species-specific oligonucleotide probe, pmhyb449, targeting 16S rRNA was designed and evaluated by whole-cell hybridization against 22 selected reference strains in animal tissues. It differentiated P. multocida from other bacterial species of the families Pasteurellaceae and Enterobacteriaceae and also from divergent species of the order Cytophagales (except biovar 2 strains of Pasteurella avium and Pasteurella canis, which have high 16S rRNA similarity to P. multocida). The potential of the probe for specific identification and differentiation of P. multocida was further detected in formalin-fixed paraffin-embedded lung tissues from experimental fowl cholera in chickens and infections in pigs. In chicken lung tissues P. multocida cells were detected singly, in pairs, as microcolonies, and as massive colonies within air capillaries (septa and lumen), parabronchial septa, and blood vessels (wall and lumen). In pig lung, postmortem-injected P. multocida was detected in the alveoli (lumen and wall), and in both animals the bacterial cells were seen in the bronchi. The results showed that with the oligonucleotide probe pmhyb449, fluorescent in situ hybridization is a suitable and fast method for specific detection of P. multocida in histological formalin-fixed tissues. The test was replicable and reproducible and is recommended as a supplementary test for diagnosis and as a tool in pathogenesis studies of fowl cholera and respiratory tract infections in pigs due to P. multocida.


Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augmented DNA vaccination.
With accumulating evidence indicating the importance of cytotoxic T lymphocytes (CTLs) in containing human immunodeficiency virus-1 (HIV-1) replication in infected individuals, strategies are being pursued to elicit virus-specific CTLs with prototype HIV-1 vaccines. Here, we report the protective efficacy of vaccine-elicited immune responses against a pathogenic SHIV-89.6P challenge in rhesus monkeys. Immune responses were elicited by DNA vaccines expressing SIVmac239 Gag and HIV-1 89.6P Env, augmented by the administration of the purified fusion protein IL-2/Ig, consisting of interleukin-2 (IL-2) and the Fc portion of immunoglobulin G (IgG), or a plasmid encoding IL-2/Ig. After SHIV-89.6P infection, sham-vaccinated monkeys developed weak CTL responses, rapid loss of CD4+ T cells, no virus-specific CD4+ T cell responses, high setpoint viral loads, significant clinical disease progression, and death in half of the animals by day 140 after challenge. In contrast, all monkeys that received the DNA vaccines augmented with IL-2/Ig were infected, but demonstrated potent secondary CTL responses, stable CD4+ T cell counts, preserved virus-specific CD4+ T cell responses, low to undetectable setpoint viral loads, and no evidence of clinical disease or mortality by day 140 after challenge.


Hypocitraturia in patients with urolithiasis.
The urinary citrate/creatinine ratio was evaluated in 25 children with idiopathic calcium urolithiasis and 24 controls. The mean (SD) urinary citrate/creatinine ratio in controls and patients was 0.510 (0.205) and 0.181 (0.076), respectively, a statistically significant difference. In neither group was there a relation between age and urinary citrate excretion.


Results and SWOT Analysis of the 2022 Hong Kong Report Card on Physical Activity for Children and Adolescents With Special Educational Needs.
Following the 2019 Hong Kong Para Report Card, the 2022 Hong Kong Para Report Card aimed to provide an updated and evidence-based assessment for nine indicators related to physical activity in children and adolescents with special educational needs and to assess the results using a SWOT (strengths, weaknesses, opportunities, and threats) analysis. Using a systematic process, the best available data on nine indicators were searched from the past 10 years and were assessed by a research work group. Letter grades were assigned and considered by stakeholders and auditors. Four indicators were assigned a letter grade (overall physical activity: F [mixed device-measured and self-reported data]; sedentary behaviors: D [device-measured data]; active transportation: D-; government strategies & investment: C+). SWOT analysis highlighted opportunities for facilitating children and adolescents with special educational needs to achieve health recommendations. There were deteriorating trends in physical activity and sedentary behaviors. Effective, multilevel, and cross-sector interventions are recommended to promote active behavior in children and adolescents with special educational needs.


Granulocytic differentiation of human NB4 promyelocytic leukemia cells induced by all-trans retinoic acid metabolites.
The metabolism of all-trans retinoic acid (ATRA) has been reported to be partly responsible for the in vivo resistance to ATRA seen in the treatment of human acute promyelocytic leukemia (APL). However, ATRA metabolism appears to be involved in the growth inhibition of several cancer cell lines in vitro. The purpose of this study was to evaluate the in vitro activity of the principal metabolites of ATRA [4-hydroxy-retinoic acid (4-OH-RA), 18-hydroxy-retinoic acid (18-OH-RA), 4-oxo-retinoic acid (4-oxo-RA), and 5,6-epoxy-retinoic acid (5,6-epoxy-RA)] in NB4, a human promyelocytic leukemia cell line that exhibits the APL diagnostic t(15;17) chromosomal translocation and expresses the PML-RAR alpha fusion protein. We established that the four ATRA metabolites were indeed formed by the NB4 cells in vitro. NB4 cell growth was inhibited (69-78% at 120 h) and cell cycle progression in the G1 phase (82-85% at 120 h) was blocked by ATRA and all of the metabolites at 1 microM concentration. ATRA and its metabolites could induce NB4 cells differentiation with similar activity, as evaluated by cell morphology, by the nitroblue tetrazolium reduction test (82-88% at 120 h) or by the expression of the maturation specific cell surface marker CD11c. In addition, nuclear body reorganization to macropunctated structures, as well as the degradation of PML-RAR alpha, was found to be similar for ATRA and all of its metabolites. Comparison of the relative potency of the retinoids using the nitroblue tetrazolium reduction test showed effective concentrations required to differentiate 50% of cells in 72 h as follows: ATRA, 15.8 +/- 1.7 nM; 4-oxo-RA, 38.3 +/- 1.3 nM; 18-OH-RA, 55.5 +/- 1.8 nM; 4-OH-RA, 79.8 +/- 1.8 nM; and 5,6-epoxy-RA, 99.5 +/- 1.5 nM. The ATRA metabolites were found to exert their differentiation effects via the RAR alpha nuclear receptors, because the RAR alpha-specific antagonist BMS614 blocked metabolite-induced CD11c expression in NB4 cells. These data demonstrate that the principal ATRA Phase 1 metabolites can elicit leukemia cell growth inhibition and differentiation in vitro through the RAR alpha signaling pathway, and they suggest that these metabolites may play a role in ATRA antileukemic activity in vivo.


How contrast situations affect the assignment of causality in symmetric physical settings.
In determining the prime cause of a physical event, people often weight one of two entities in a symmetric physical relation as more important for bringing about the causal effect than the other. In a broad survey (Bender and Beller, 2011), we documented such weighting effects for different kinds of physical events and found that their direction and strength depended on a variety of factors. Here, we focus on one of those: adding a contrast situation that-while being formally irrelevant-foregrounds one of the factors and thus frames the task in a specific way. In two experiments, we generalize and validate our previous findings by using different stimulus material (in Experiment 1), by applying a different response format to elicit causal assignments, an analog rating scale instead of a forced-choice decision (in Experiment 2), and by eliciting explanations for the physical events in question (in both Experiments). The results generally confirm the contrast effects for both response formats; however, the effects were more pronounced with the force-choice format than with the rating format. People tended to refer to the given contrast in their explanations, which validates our manipulation. Finally, people's causal assignments are reflected in the type of explanation given in that contrast and property explanations were associated with biased causal assignments, whereas relational explanations were associated with unbiased assignments. In the discussion, we pick up the normative questions of whether or not these contrast effects constitute a bias in causal reasoning.


Novel functional MAR elements of double minute chromosomes in human ovarian cells capable of enhancing gene expression.
Double minute chromosomes or double minutes (DMs) are cytogenetic hallmarks of extrachromosomal genomic amplification and play a critical role in tumorigenesis. Amplified copies of oncogenes in DMs have been associated with increased growth and survival of cancer cells but DNA sequences in DMs which are mostly non-coding remain to be characterized. Following sequencing and bioinformatics analyses, we have found 5 novel matrix attachment regions (MARs) in a 682 kb DM in the human ovarian cancer cell line, UACC-1598. By electrophoretic mobility shift assay (EMSA), we determined that all 5 MARs interact with the nuclear matrix in vitro. Furthermore, qPCR analysis revealed that these MARs associate with the nuclear matrix in vivo, indicating that they are functional. Transfection of MARs constructs into human embryonic kidney 293T cells showed significant enhancement of gene expression as measured by luciferase assay, suggesting that the identified MARS, particularly MARs 1 to 4, regulate their target genes in vivo and are potentially involved in DM-mediated oncogene activation.


Pre-exposure to Tempting Food Reduces Subsequent Snack Consumption in Healthy-Weight but Not in Obese-Weight Individuals.
Obesity has become a severe worldwide problem. Compared to healthy-weight individuals, obese individuals seem to show an increased sensitivity to tempting food. In the present study, we test the pre-exposure effect, which implies that consumption of tempting food is decreased after exposure to tempting food cues in a context of a task that discourages food consumption. Healthy-weight and obese-weight participants were recruited via social media and university channels. Participants took part in a scrabble task with either candy letters or foam letters and subsequently engaged in a taste test. Results showed that in healthy-weight participants, consumption was reduced after solving the scrabble task with candy letters in comparison to foam letters. In obese-weight participants, consumption was reduced in the condition using foam letters (in comparison with healthy-weight participants). The pre-exposure effect was replicated in healthy-weight participants, but could not be observed in participants with obesity, since consumption was reduced in general in this group. Our results suggest that more work should be done to understand how food nudges work in the context of obesity.


Effects of naftidrofuryl on adrenergic nerves, endothelium and smooth muscle in isolated canine blood vessels.
Experiments were designed to determine the effects of the vasoactive drug naftidrofuryl on vascular smooth muscle, endothelial cells and adrenergic nerves in isolated canine blood vessels. Naftidrofuryl inhibited contractions of basilar arteries (in a decreasing order of potency), evoked by 5-hydroxytryptamine greater than KCl = anoxia (in rings with endothelium) greater than prostaglandin F2 alpha = uridine-5'-triphosphate. Naftidrofuryl antagonized competitively the contractions evoked by 5-hydroxytryptamine in the femoral artery and the saphenous vein. Naftidrofuryl caused the release of an endothelium-derived relaxing factor(s) from the endothelium of femoral arteries. The compound depressed contractions of saphenous veins evoked by electrical stimulation of the adrenergic nerve endings, but not those caused by the indirect sympathomimetic amine tyramine or exogenous norepinephrine. In saphenous veins incubated previously with [3H]norepinephrine, the drug inhibited the contractions and the release of transmitter evoked by electrical stimulation. Thus, naftidrofuryl acts at different levels in the blood vessel wall to cause: release of endothelium-derived relaxing factor(s); inhibition of S2-serotonergic receptors on vascular smooth muscle; prejunctional inhibition of adrenergic neurotransmission; and nonselective inhibition of the contractile process in vascular smooth muscle, which is particularly pronounced in cerebral arteries.


Advanced Androgen Blockage in Nonmetastatic Castration-resistant Prostate Cancer: An Indirect Comparison of Apalutamide and Enzalutamide.
Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) have historically had few treatment options. Recently, randomized controlled trials have examined the benefit of apalutamide and enzalutamide in these patients. We sought to perform an indirect treatment comparison using a network meta-analysis approach to compare the relative efficacy and toxicity of these two agents. The primary outcome of this analysis was metastasis-free survival (MFS) while secondary outcomes were time to prostate-specific antigen progression, overall survival, and adverse events. The Bucher technique for indirect comparison was used to compare apalutamide and enzalutamide using the common placebo comparator. We found no evidence of a significant difference in MFS (hazard ratio 1.04, 95% confidence interval 0.78-1.37) between enzalutamide and apalutamide. Similarly, there were no differences for any of the secondary outcomes. While indirect comparisons cannot supplant direct comparative data, this analysis suggests that apalutamide and enzalutamide are similarly effective in delaying metastases for patients with nmCRPC. PATIENT SUMMARY: Historically, there have been few treatment options for prostate cancer patients receiving androgen deprivation therapy who have rising prostate-specific antigen levels without obvious recurrence of cancer. Recent randomized controlled trials demonstrated that treatment with enzalutamide and apalutamide delayed the development of metastatic cancer. This study demonstrates through an indirect comparison that both medications are likely to have similar efficacy and side-effect profiles.


Implementation and impact of a consensus diagnostic and management algorithm for complicated pneumonia in children.
Variable treatment exists for children with bacterial pneumonia complications such as pleural effusion and empyema. Subspecialists at an urban academic tertiary children's hospital created a literature-based diagnosis and management algorithm for complicated pneumonia in children. We proposed that algorithm implementation would reduce use of computed tomography (CT) for diagnosis of pleural infection, thereby decreasing radiation exposure, without increased adverse outcomes. A cross-sectional study was undertaken in children (3 months to 20 years old) with principal or secondary diagnosis codes for empyema and/or pleural effusion in conjunction with bacterial pneumonia. Study cohorts consisted of subjects admitted 15 months before (cohort 1, n = 83) and after (cohort 2, n = 87) algorithm implementation. Data were collected using clinical and financial data systems. Imaging studies and procedures were identified using Current Procedural Terminology codes. Statistical analysis included χ test, linear and ordinal regression, and analysis of variance. Age (P = 0.56), sex (P = 0.30), diagnoses (P = 0.12), and severity level (P = 0.84) were similar between cohorts. There was a significant decrease in CT use in cohort 2 (cohort 1, 60% vs cohort 2, 17.2%; P = 0.001) and reduction in readmission rate (7.7% vs 0%; P = 0.01) and video-assisted thoracoscopic surgery procedures (44.6% vs 28.7; P = 0.03), without concomitant increases in vancomycin use (34.9% vs 34.5%; P = 0.95) or hospital length of stay (6.4 vs 7.6 days; P = 0.4). Among patients who received video-assisted thoracoscopic surgery drainage (n = 57), there were no significant differences between cohorts in median time from admission to video-assisted thoracoscopic surgery (2 days; P = 0.29) or median duration of chest tube drainage (3 vs 4 days; P = 0.10). There was a statistically nonsignificant trend for higher rate of pathogen identification in cohort 2 (cohort 1, 33% vs cohort 2, 54.1%; P = 0.12); Streptococcus pneumonia was the most commonly identified pathogen in both cohorts (37.5% vs 27%; P = 0.23). Implementation of an institutional complicated pneumonia management algorithm reduced CT scan use/radiation exposure, VATS procedures, and readmission rate in children with a diagnosis of pleural infection, without associated increases in length of stay or vancomycin use. This algorithm provides the framework for future prospective quality improvement studies in pediatric patients with complicated pneumonia.


Acoustic Screening for Obstructive Sleep Apnea in Home Environments Based on Deep Neural Networks.
Obstructive sleep apnea (OSA) is a chronic and prevalent condition with well-established comorbidities. However, many severe cases remain undiagnosed due to poor access to polysomnography (PSG), the gold standard for Obstructive sleep apnea (OSA) diagnosis. Accurate home-based methods to screen for OSA are needed, which can be applied inexpensively to high-risk subjects to identify those that require PSG to fully assess their condition. A number of methods that analyse speech or breathing sounds to screen for OSA have been previously investigated. However, these methods have constraints that limit their use in home environments (e.g., they require specialised equipment, are not robust to background noise, are obtrusive or depend on tightly controlled conditions). This paper proposes a novel method to screen for OSA, which analyses sleep breathing sounds recorded with a smartphone at home. Audio recordings made over a whole night are divided into segments, each of which is classified for the presence or absence of OSA by a deep neural network. The apnea-hypopnea index estimated from the segments predicted as containing evidence of OSA is then used to screen for the condition. Audio recordings made during home sleep apnea testing from 103 participants for 1 or 2 nights were used to develop and evaluate the proposed system. When screening for moderate OSA the acoustics based system achieved a sensitivity of 0.79 and a specificity of 0.80. The sensitivity and specificity when screening for severe OSA were 0.78 and 0.93, respectively. The system is suitable for implementation on consumer smartphones.


Development and validation a simple model for identify malignant ascites.
The differential diagnosis of benign ascites and malignant ascites is incredibly challenging for clinicians. This research aimed to develop a user-friendly predictive model to discriminate malignant ascites from non-malignant ascites through easy-to-obtain clinical parameters. All patients with new-onset ascites fluid were recruited from January 2014 to December 2018. The medical records of 317 patients with ascites for various reasons in Renmin Hospital of Wuhan University were collected and reviewed retrospectively. Thirty-six parameters were included and selected using univariate logistic regression, multivariate logistic regression, and receiver operating characteristic (ROC) curve analyses to establish a mathematical model for differential diagnosis, and its diagnostic performance was validated in the other groups. Age, cholesterol, hypersensitivity C-reactive protein (hs-CRP) in serum, ascitic fluid adenosine deaminase (AF ADA), ascitic fluid lactate dehydrogenase (AF LDH) involvement in a 5-marker model. With a cut-off level of 0.83, the sensitivity, specificity, accuracy, and area under the ROC of the model for identifying malignant ascites in the development dataset were 84.7%, 88.8%, 87.6%, and 0.874 (95% confidence interval [CI], 0.822-0.926), respectively, and 80.9%, 82.6%, 81.5%, and 0.863 (95% CI,0.817-0.913) in the validation dataset, respectively. The diagnostic model has a similar high diagnostic performance in both the development and validation datasets. The mathematical diagnostic model based on the five markers is a user-friendly method to differentiate malignant ascites from benign ascites with high efficiency.


Recent guidelines and recommendations for laboratory assessment of the direct oral anticoagulants (DOACs): is there consensus?
A new generation of antithrombotic agents, which are conventionally known as direct oral anticoagulants (DOACs), have recently emerged and are continuing to be developed. These provide direct inhibition of either thrombin (factor IIa; FIIa) or activated factor X (FXa) and currently include dabigatran (FIIa inhibitor) and rivaroxaban, apixaban, and edoxaban (FXa inhibitors). The dogma that DOACs do not require laboratory monitoring is countered by ongoing recognition that laboratory testing for drug effects is needed in many situations. In this review, we summarize the background to establishment of DOACs, assess which tests were found to be useful to screen for or quantitate drug effects/levels, and then review published guidelines/recommendations to assess concordance. In brief, (a) for the anti-FIIa agent dabigatran, the recommended screening assays are activated partial thromboplastin time (APTT) and/or thrombin time (TT), and the quantitative assays (using a dabigatran standard) are dilute TT/direct thrombin inhibitor assay (Hemoclot thrombin inhibitor) or an ecarin-based assay such as the ecarin clot time (ECT); (b) for the anti-FXa agent rivaroxaban, the recommended screening assay is the prothrombin time (PT), but this was not endorsed by all guidelines, and the quantitative assay (using a specific rivaroxaban standard) is an anti-FXa assay; (c) for the anti-FXa agent apixaban, the general insensitivity of PT and APTT prevented most groups from providing recommendation, and instead there was generalized support for direct quantitative assessment using anti-FXa assays and specific apixaban standard; (d) there is insufficient data for other direct anti-FXa agents and limited guidance in the literature.


New insight into the functions of the interleukin-17 receptor adaptor protein Act1 in psoriatic arthritis.
Recent genome-wide association studies have implicated the tumor necrosis factor receptor-associated factor 3-interacting protein 2 (TRAF3IP2) gene and its product, nuclear factor-kappa-B activator 1 (Act1), in the development of psoriatic arthritis (PsA). The high level of sequence homology of the TRAF3IP2 (Act1) gene across the animal kingdom and the presence of the Act1 protein in multiple cell types strongly suggest that the protein is of importance in normal cellular function. Act1 is an adaptor protein for the interleukin-17 (IL-17) receptor, and recent observations have highlighted the significance of IL-17 signaling and localized inflammation in autoimmune diseases. This review summarizes data from recent genome-wide association studies as well as immunological and molecular investigations of Act1. Together, these studies provide new insight into the role of IL-17 signaling in PsA. It is well established that IL-17 activation of tumor necrosis factor receptor-associated factor 6 (TRAF6) signaling pathways normally leads to nuclear factor-kappa-B-mediated inflammation. However, the dominant PsA-associated TRAF3IP2 (Act1) gene single-nucleotide polymorphism (rs33980500) results in decreased binding of Act1 to TRAF6. This key mutation in Act1 could lead to a greater association of the IL-17 receptor with TRAF2/TRAF5 and this in turn suggests an alternative function for IL-17 in PsA. The recent observations described and discussed in this review raise the clinically significant possibility of redefining the immunological role of IL-17 in PsA and provide a basis for defining future studies to elucidate the molecular and cellular functions of Act1.


Distinctive immunological properties of cultured murine thymic epithelial cells.
Skin painting with chemically reactive haptens induces a hapten-specific state of hypersensitivity that is long lasting and can be transferred to unirradiated recipient mice. A similar state of hapten-specific contact sensitivity can be induced by intravenous immunization with hapten-conjugated cells. Thus far, only two cell types have been described that can perform this function: Langerhans cells of the skin, and splenic dendritic cells. All other types, coupled with hapten, induce either tolerance or a short-lived state of contact hypersensitivity that is readily suppressed, and cannot be transferred to normal recipients. In the present experiments, it was demonstrated that culture-enriched, hapten-coupled thymic epithelial cells can also induce a state of stable contact hypersensitivity identical to that induced by skin painting. This provides evidence that thymic epithelial cells have distinctive properties as antigen-presenting cells in vivo. The relationship of this finding to the postulated role of thymic epithelium in T-cell development is discussed.


Conditional deletion of cytochrome P450 oxidoreductase in the liver and gastrointestinal tract: a new model for studying the functions of the P450 system.
We have previously described a mouse model, where hepatic cytochrome P450 oxidoreductase (POR) expression has been deleted, resulting in almost complete ablation of hepatic P450 function [Hepatic P450 Reductase Null (HRN)]. HRN mice grow normally but develop fatty livers, and they have increased cytochrome P450 levels. Associated with the hepatic lipid accumulation are significant changes in the expression of genes controlling lipid homeostasis. We have characterized this model extensively and demonstrated its value in drug efficiency testing, in toxicokinetics, and in evaluating the role of the hepatic P450 system in drug pharmacokinetics. To extend the deletion of POR, and P450 inactivation, to other tissues, and to develop the utility of this model, we have generated a mouse where POR can be deleted conditionally in the liver and gastrointestinal tract using the rat cytochrome P450 CYP1A1 promoter to drive Cre recombinase expression. Administration of the CYP1A1 inducers tetrachlorodibenzo-p-dioxin or beta-naphthoflavone resulted in both hepatic and gastrointestinal deletion of POR, whereas administration of 3-methylcholanthrene resulted specifically in loss of hepatic POR expression. In all cases, the resulting hepatic phenotype seemed identical to that of the HRN model, including increased cytochrome P450 expression. Hepatic deletion of POR and the subsequent increase in P450 expression were dependent on inducer dose, with maximal POR deletion occurring at a single dose of 3-methylcholanthrene of 40 mg/kg. This model provides a powerful approach for studying the functions of POR as well as in the evaluation of the role of hepatic and gastrointestinal P450s in drug deposition and chemical toxicity.


[Suicide: a medico-historical exploration].
The recent rise of suicide rates internationally clearly indicates that the medical profession needs to give more attention to suicidality. To construct a medico-historical framework for the concepts of suicide and suicidality. The study is based on articles referred to in PubMed and on the historical literature. Throughout history, the legal, stoic, medical, and sociological perspectives have all left their own unique stamp on the conceptualisation of suicide and suicidality. Recent initiatives in the Netherlands such as 113Online and the Multi-disciplinary guideline for diagnosis and treatment of suicidal behaviour constitute apt responses to the alarming rise of suicide rates, but it is not clear to what extent these initiatives will be able to counterbalance the interpersonal and social-economic mechanisms which appear to have determined suicide rates in the course of history.


Cyclic Peptides Incorporating Phosphotyrosine Mimetics as Potent and Specific Inhibitors of the Grb7 Breast Cancer Target.
The Grb7 adaptor protein is a therapeutic target for both TNBC and HER2+ breast cancer. A nonphosphorylated cyclic peptide 1 (known as G7-18NATE) inhibits Grb7 via targeting the Grb7-SH2 domain, but requires the presence of phosphate ions for both affinity and specificity. Here we report the discovery of malonate bound in the phosphotyrosine binding pocket of the apo-Grb7-SH2 structure. Based on this, we carried out the rational design and synthesis of two analogues of peptide 1 that incorporate carboxymethylphenylalanine (cmF) and carboxyphenylalanine (cF) as mimics of phosphotyrosine (pY). Binding studies using SPR confirmed that affinity for Grb7-SH2 domain is improved up to 9-fold over peptide 1 under physiological phosphate conditions (KD = 2.1-5.7 μM) and that binding is specific for Grb7-SH2 over closely related domains (low or no detectable binding to Grb2-SH2 and Grb10-SH2). X-ray crystallographic structural analysis of the analogue bearing a cmF moiety in complex with Grb7-SH2 has identified the precise contacts conferred by the pY mimic that underpin this improved molecular interaction. Together this study identifies and characterizes the tightest specific inhibitor of Grb7 to date, representing a significant development toward a new Grb7-targeted therapeutic.


Long working hours and change in body weight: analysis of individual-participant data from 19 cohort studies.
To examine the relation between long working hours and change in body mass index (BMI). We performed random effects meta-analyses using individual-participant data from 19 cohort studies from Europe, US and Australia (n = 122,078), with a mean of 4.4-year follow-up. Working hours were measured at baseline and categorised as part time (<35 h/week), standard weekly hours (35-40 h, reference), 41-48 h, 49-54 h and ≥55 h/week (long working hours). There were four outcomes at follow-up: (1) overweight/obesity (BMI ≥ 25 kg/m2) or (2) overweight (BMI 25-29.9 kg/m2) among participants without overweight/obesity at baseline; (3) obesity (BMI ≥ 30 kg/m2) among participants with overweight at baseline, and (4) weight loss among participants with obesity at baseline. Of the 61,143 participants without overweight/obesity at baseline, 20.2% had overweight/obesity at follow-up. Compared with standard weekly working hours, the age-, sex- and socioeconomic status-adjusted relative risk (RR) of overweight/obesity was 0.95 (95% CI 0.90-1.00) for part-time work, 1.07 (1.02-1.12) for 41-48 weekly working hours, 1.09 (1.03-1.16) for 49-54 h and 1.17 (1.08-1.27) for long working hours (P for trend <0.0001). The findings were similar after multivariable adjustment and in subgroup analyses. Long working hours were associated with an excess risk of shift from normal weight to overweight rather than from overweight to obesity. Long working hours were not associated with weight loss among participants with obesity. This analysis of large individual-participant data suggests a small excess risk of overweight among the healthy-weight people who work long hours.


St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor.
St. John's wort (Hypericum perforatum) is an herbal remedy used widely for the treatment of depression. Recent clinical studies demonstrate that hypericum extracts increase the metabolism of various drugs, including combined oral contraceptives, cyclosporin, and indinavir. In this report, we show that hyperforin, a constituent of St. John's wort with antidepressant activity, is a potent ligand (K(i) = 27 nM) for the pregnane X receptor, an orphan nuclear receptor that regulates expression of the cytochrome P450 (CYP) 3A4 monooxygenase. Treatment of primary human hepatocytes with hypericum extracts or hyperforin results in a marked induction of CYP3A4 expression. Because CYP3A4 is involved in the oxidative metabolism of >50% of all drugs, our findings provide a molecular mechanism for the interaction of St. John's wort with drugs and suggest that hypericum extracts are likely to interact with many more drugs than previously had been realized.


A mesocosm study of fate and effects of CuO nanoparticles on endobenthic species (Scrobicularia plana, Hediste diversicolor).
The fate and effects of CuO nanoparticles (CuO NPs) were examined in endobenthic species (Scrobicularia plana , Hediste diversicolor), under environmentally realistic conditions in outdoor mesocosms (exposure to Cu at 10 μg L(-1) in particulate (CuO NPs) or soluble salt (CuNO(3)) forms) for 21 days. Labile Cu was determined in water and sediment by using diffusive gradient in thin films. No labile Cu being detected from CuO NPs; the observed effects in invertebrates exposed to CuO NPs were mainly attributed to the toxicity of nanoparticulate rather than dissolved Cu toxicity. Bioaccumulation of CuO NPs was observed in both species. Biomarkers were examined at different levels of biological organization: biochemical markers of defense and damage, biomarkers of genotoxicity (comet assay), and behavioral biomarkers (feeding and burrowing). Behavioral biomarkers, antioxidant defenses (catalase, glutathion S-transferase, metallothionein), and genotoxicity are the most sensitive tools to highlight the effect of soluble or nanoparticulate metal forms. Concerning other biomarkers of defense (superoxide dismutase, lactate dehydrogenase, laccase) and damage (thiobarbituric acid reactive substances, acetylcholinesterase, acid phosphatase), no significant effects were detected. This experiment shows the suitability of mesocosms for studying the environmental effects of nanoparticles.


Filter-well technology for advanced three-dimensional cell culture: perspectives for respiratory research.
Cell culture has long been a valuable tool for studying cell behaviour. Classical plastic substrates are two-dimensional, and usually promote cellular proliferation and inhibit differentiation. Understanding cell behaviour within complex multicellular tissues requires the systematic study of cells within the context of specific model microenvironments. A model system must mimic, to a certain degree, the in vivo situation, but, at the same time, can significantly reduce its complexity. There is increasing agreement that moving up to the third dimension provides a more physiologically-relevant and predictive model system. Moreover, many cellular processes (morphogenesis, organogenesis and pathogenesis) have been confirmed to occur exclusively when cells are ordered in a three-dimensional (3-D) manner. In order to achieve the desired in vivo phenotype, researchers can use microporous membranes for improved in vitro cell culture experiments. In the present review, we discuss the applications of filter-well technology for the advanced 3-D cell culture of human pulmonary cells.


Hijacking of the host cell Golgi by Plasmodium berghei liver stage parasites.
The intracellular lifestyle represents a challenge for the rapidly proliferating liver stage Plasmodium parasite. In order to scavenge host resources, Plasmodium has evolved the ability to target and manipulate host cell organelles. Using dynamic fluorescence-based imaging, we here show an interplay between the pre-erythrocytic stages of Plasmodium berghei and the host cell Golgi during liver stage development. Liver stage schizonts fragment the host cell Golgi into miniaturized stacks, which increases surface interactions with the parasitophorous vacuolar membrane of the parasite. Expression of specific dominant-negative Arf1 and Rab GTPases, which interfere with the host cell Golgi-linked vesicular machinery, results in developmental delay and diminished survival of liver stage parasites. Moreover, functional Rab11a is critical for the ability of the parasites to induce Golgi fragmentation. Altogether, we demonstrate that the structural integrity of the host cell Golgi and Golgi-associated vesicular traffic is important for optimal pre-erythrocytic development of P. berghei. The parasite hijacks the Golgi structure of the hepatocyte to optimize its own intracellular development. This article has an associated First Person interview with the first author of the paper.


Alterations in gait resulting from deliberate changes of arm-swing amplitude and phase.
OBJECTIVE: The purpose of the study was to reach a better understanding of the influence of arm movement in human gait. DESIGN: The experiment involved the adoption of different arm-swing patterns by normal subjects who walked in a gait laboratory. BACKGROUND: The reciprocal swinging of the arms in walking plays an important role in gait, but the details require further research. More insight into the role of the arm-swing in gait could be obtained by adopting different arm-swing patterns while walking at different speeds. METHOD: Thirteen normal subjects were therefore requested to walk adopting different arm-swing patterns which included, one or both arms strapped to the body, full reciprocal excursion of both arms, pace walking and swinging the arms in parallel. From measurements made at different speeds of walking, regressions were calculated which made it possible to compare basal gait characteristics of the different arm patterns. RESULTS: Maximum velocity decreased in all cases. In the test conditions where the arms were strapped, the subjects increased velocity by increasing stride frequency more than stride length. In the other conditions the reverse was the case. CONCLUSION: The experiments show that the gait pattern is very much influenced by changes in arm-swing but the effects are related to the pattern of arm-swing and the speed of walking.


A review of numerical and experimental compensation techniques for skull-induced phase aberrations in transcranial focused ultrasound.
The development of phased array transducers and their integration with magnetic resonance (MR) guidance and thermal monitoring has established transcranial MR-guided focused ultrasound (tcMRgFUS) as an attractive non-invasive modality for neurosurgical interventions. The presence of the skull, however, compromises the efficiency of transcranial FUS (tcFUS) therapy, as its heterogeneous nature and acoustic characteristics induce significant phase aberrations and energy attenuation, especially at the higher acoustic frequencies employed in tcFUS thermal therapy. These aberrations may distort and shift the acoustic focus as well as induce heating at the patient's scalp and skull bone. Phased array transducers feature hundreds of elements that can be driven individually, each with its own phase and amplitude. This feature allows for compensation of skull-induced aberrations by calculation and application of appropriate phase and amplitude corrections. In this paper, we illustrate the importance of precise refocusing and provide a comprehensive review of the wide variety of numerical and experimental techniques that have been used to estimate these corrections.


Genomic and Physiological Characteristics of a Novel Nitrite-Oxidizing Nitrospira Strain Isolated From a Drinking Water Treatment Plant.
Nitrite-oxidizing bacteria (NOB) catalyze the second step of nitrification, which is an important process of the biogeochemical nitrogen cycle and is exploited extensively as a biological nitrogen removal process. Members of the genus Nitrospira are often identified as the dominant NOB in a diverse range of natural and artificial environments. Additionally, a number of studies examining the distribution, abundance, and characterization of complete ammonia oxidation (comammox) Nitrospira support the ecological importance of the genus Nitrospira. However, niche differentiation between nitrite-oxidizing Nitrospira and comammox Nitrospira remains unknown due to a lack of pure cultures. In this study, we report the isolation, physiology, and genome of a novel nitrite-oxidizing Nitrospira strain isolated from a fixed-bed column at a drinking water treatment plant. Continuous feeding of ammonia led to the enrichment of Nitrospira-like cells, as well as members of ammonia-oxidizing genus Nitrosomonas. Subsequently, a microcolony sorting technique was used to isolate a novel nitrite-oxidizing Nitrospira strain. Sequences of strains showing the growth of microcolonies in microtiter plates were checked. Consequently, the most abundant operational taxonomic unit (OTU) exhibited high sequence similarity with Nitrospira japonica (98%) at the 16S rRNA gene level. The two other Nitrospira OTUs shared over 99% sequence similarities with N. japonica and Nitrospira sp. strain GC86. Only one strain identified as Nitrospira was successfully subcultivated and designated as Nitrospira sp. strain KM1 with high sequence similarity with N. japonica (98%). The half saturation constant for nitrite and the maximum nitrite oxidation rate of strain KM1 were orders of magnitude lower than the published data of other known Nitrospira strains; moreover, strain KM1 was more sensitive to free ammonia compared with previously isolated Nitrospira strains. Therefore, the new Nitrospira strain appears to be better adapted to oligotrophic environments compared with other known non-marine nitrite oxidizers. The complete genome of strain KM1 was 4,509,223 bp in length and contained 4,318 predicted coding sequences. Average nucleotide identities between strain KM1 and known cultured Nitrospira genome sequences are 76.7-78.4%, suggesting at least species-level novelty of the strain in the Nitrospira lineage II. These findings broaden knowledge of the ecophysiological diversity of nitrite-oxidizing Nitrospira.


The Potential of Cannabidiol as a Treatment for Psychosis and Addiction: Who Benefits Most? A Systematic Review.
The endogenous cannabinoid (eCB) system plays an important role in the pathophysiology of both psychotic disorders and substance use disorders (SUDs). The non-psychoactive cannabinoid compound, cannabidiol (CBD) is a highly promising tool in the treatment of both disorders. Here we review human clinical studies that investigated the efficacy of CBD treatment for schizophrenia, substance use disorders, and their comorbidity. In particular, we examined possible profiles of patients who may benefit the most from CBD treatment. CBD, either as monotherapy or added to regular antipsychotic medication, improved symptoms in patients with schizophrenia, with particularly promising effects in the early stages of illness. A potential biomarker is the level of anandamide in blood. CBD and THC mixtures showed positive effects in reducing short-term withdrawal and craving in cannabis use disorders. Studies on schizophrenia and comorbid substance use are lacking. Future studies should focus on the effects of CBD on psychotic disorders in different stages of illness, together with the effects on comorbid substance use. These studies should use standardized measures to assess cannabis use. In addition, future efforts should be taken to study the relationship between the eCB system, GABA/glutamate, and the immune system to reveal the underlying neurobiology of the effects of CBD.


Perception of speech by individuals with Parkinson's disease: a review.
A few clinical reports and empirical studies have suggested a possible deficit in the perception of speech in individuals with Parkinson's disease. In this paper, these studies are reviewed in an attempt to support clinical anecdotal observations by relevant empirical research findings. The combined evidence suggests a possible deficit in patients' perception of their own speech loudness. Other research studies on the perception of speech in this population were reviewed, in a broader scope of the perception of emotional prosody. These studies confirm that Parkinson's disease specifically impairs patients' perception of verbal emotions. However, explanations of the nature and causes of this perceptual deficit are still limited. Future research directions are suggested.


The molecular mechanisms of coactivator utilization in ligand-dependent transactivation by the androgen receptor.
Androgens drive sex differentiation, bone and muscle development, and promote growth of hormone-dependent cancers by binding the nuclear androgen receptor (AR), which recruits coactivators to responsive genes. Most nuclear receptors recruit steroid receptor coactivators (SRCs) to their ligand binding domain (LBD) using a leucine-rich motif (LXXLL). AR is believed to recruit unique coactivators to its LBD using an aromatic-rich motif (FXXLF) while recruiting SRCs to its N-terminal domain (NTD) through an alternate mechanism. Here, we report that the AR-LBD interacts with both FXXLF motifs and a subset of LXXLL motifs and that contacts with these LXXLL motifs are both necessary and sufficient for SRC-mediated AR regulation of transcription. Crystal structures of the activated AR in complex with both recruitment motifs reveal that side chains unique to the AR-LBD rearrange to bind either the bulky FXXLF motifs or the more compact LXXLL motifs and that AR utilizes subsidiary contacts with LXXLL flanking sequences to discriminate between LXXLL motifs.


CoDiagnose: Interactive software to harness collaborative diagnoses and to increase diagnostic accuracy amongst junior physicians.
Many studies have been conducted that highlight the prevalence of misdiagnoses within the medical profession and the statistically poor diagnostic accuracy rates associated with junior clinicians. There is evidence that crowdsourcing and multiple medical opinions can improve the veracity of a diagnosis. This paper proposes a cloud based prototype that makes use of interactive web technologies along with the concepts of crowdsourcing and e-learning to improve diagnostic accuracy rates amongst junior doctors. Existing approaches in this field are analysed to identify potential gaps and opportunities. Sample representations of both junior and senior clinicians are surveyed to establish the feasibility of adopting collaborative diagnostics. It is theorised that the prototype developed in this work will harness the experience and knowledge of expert clinicians. The prototype is a fully responsive web-based and feature-rich interactive system that has been developed using the latest Internet technologies. It has been evaluated using usability tests and a one month long trial involving a sample of end-users. Crowdsourcing is an innovative process in its infancy but the results being produced indicate a promising future for its use within medicine. The results offer an inclination that the prototype's usage could be attributed to improved diagnostic ability. However the findings need to be replicated in larger, independent samples.


A cost effective hydrogel test kit for pre and post blast trinitrotoluene.
A cost effective hydrogel test kit was successfully developed for the detection of pre- and post-blast trinitrotoluene (TNT). A polyvinyl alcohol (PVA) hydrogel matrix was used to entrap the potassium hydroxide (KOH) colourimetric reagent. The easily portable test kit was fabricated in situ in a small tube to which the sample could be added directly. The test kit was used in conjunction with digital image colourimetry (DIC) to demonstrate the rapid quantitative analysis of TNT in a test soil sample. The built-in digital camera of an iPhone was used to capture digital images of the colourimetric products from the test kit. Red-Green-Blue (RGB) colour data from the digital images of TNT standard solutions were used to establish a calibration graph. The validation of the DIC method indicated excellent inter day precision (0.12-3.60%RSD) and accuracy (93-108% relative accuracy). Post-blast soil samples containing TNT were analysed using the test kit and were in good agreement with spectrophotometric analysis. The intensity of the RGB data from the TNT complex deviated by +6.3%, +5.1%, and -4.9% after storage of the test kits in a freezer for 3 months. The test kit was also reusable for up to 12 times with only -5.4%, +0.3%, and +4.0% deviations. The hydrogel test kit was applied in the detection of trace explosive residues at the scene of the recent Bangkok bombing at the Ratchaprasong intersection and produced positive results for TNT demonstrating its operational field application as a rapid and cost effective quantitative tool for explosive residue analysis.


One drop can be beneficial, one swig can be deadly: tetrahydrozoline intoxication.
Tetrahydrozoline is a commonly used imidazoline derivative with serious side effects and toxicity, particularly in small children. A one-year-old boy was admitted to the emergency department (ED) after he accidentally ingested about half a bottle of nasal decongestant solution containing tetrahydrozoline. He was unconscious, hypothermic and bradycardic on presentation. His respiration was irregular and superficial, and blood pressure was borderline hypotensive. His skin was pale and cold. Atropine was administered twice for symptomatic bradycardia, and the child was transferred to the pediatric intensive care unit (PICU). During the 12th hour of observation, vital signs returned to normal and there was no need for mechanical ventilation. Although suitable room temperature with passive warming was applied, hypothermia continued for approximately 24 hours. The patient was discharged on the second day of admission. There were no complaints one week later, and the physical examination was normal. We report a case of accidental tetrahydrozoline intoxication with life-threatening events accompanying hypothermia in a small infant.


Corticotropin-releasing hormone and mast cells in the regulation of mucosal barrier function in the human colon.
Corticotropin-releasing hormone (CRH) is an important neuro-endocrine mediator of the stress response. Local effects of CRH in the intestinal mucosa have become evident in recent years. We showed that CRH activates CRH receptor subtypes R1 and R2 on subepithelial mast cells, thereby inducing increased transcellular uptake of protein antigens in human colonic biopsies in Ussing chambers. Ongoing studies also implicate local cholinergic signaling in regulation of macromolecular permeability in the human colon. Since increased uptake of antigenic molecules is associated with mucosal inflammation, our findings may have implications for understanding stress-related intestinal disorders.


Occult head injury in high-risk abused children.
Head injury is the leading cause of death in abused children under 2 years of age. Evidence for establishing guidelines regarding screening for occult head injury in a neurologically asymptomatic child with other evidence of abuse is lacking. This is particularly important given that many children with acute inflicted head injury have evidence of old injury when they are diagnosed. The primary aim of this study was to estimate the prevalence of occult head injury in a high-risk sample of abused children with normal neurologic examinations. The secondary aim was to describe characteristics of this population. Children under 2 years of age admitted to an urban children's hospital between January 1998 and December 2001 with injuries suspicious for child abuse were eligible for this study if they had a normal neurologic examination on admission. Subjects were selected if they met 1 of the following "high-risk" criteria: rib fractures, multiple fractures, facial injury, or age <6 months. Subjects were excluded if they had a history of neurologic dysfunction, seizures, respiratory arrest, or if their initial physical examination revealed scalp injury. Of the 65 patients who met these criteria, 51 (78.5%) had a head computed tomography or magnetic resonance imaging in addition to skeletal survey. Of these 51 patients, 19 (37.3%, 95% confidence interval 24.2-50.4%) had an occult head injury. Injuries included scalp swelling (74%), skull fracture (74%), and intracranial injury (53%). All except 3 of the head-injured patients had at least a skull fracture or intracranial injury. Skeletal survey alone missed 26% (5/19) of the cases. Head-injured children were younger than non-head-injured children (median age 2.5 vs 5.1 months); all but 1 head-injured child was <1 year of age. Among the head-injured children, 72% came from single parent households, 37% had mothers whose age was <21 years, and 26% had a history of prior child welfare involvement in their families. Ophthalmologic examination was performed in 14 of the 19 cases; no retinal hemorrhages were noted. Our results support a recommendation for universal screening in neurologically asymptomatic abused children with any of the high-risk criteria used in this study, particularly if that child is under 1 year of age. Ophthalmologic examination is a poor screening method for occult head injury, and one should proceed directly to computed tomography or magnetic resonance imaging. Given the high prevalence of occult head injury detected in this study, further study is warranted to estimate the prevalence of occult head injury in lower risk populations of abused children.


Cytomegalovirus infection/disease after hematopoietic stem cell transplantation.
Cytomegalovirus (CMV) disease has historically been a main cause of death after allogeneic hematopoietic stem cell transplantation (HSCT). Since the introduction of prophylactic or preemptive therapy against CMV, the incidence of CMV disease has been successfully reduced. However, breakthrough CMV disease, particularly CMV gastrointestinal disease, remains one of the major infectious complications. Administration of an antiviral agent, ganciclovir, is often associated with myelotoxicity in HSCT recipients, and delayed immune reconstitution against CMV. Delayed immune reconstitution is a possible cause of the increasing incidence of late (more than 3 months after transplant) CMV disease after HSCT in this era of preemptive therapy. Foscarnet and valganciclovir are the available alternatives to intravenous ganciclovir. Foscarnet is not myelotoxic and has a toxicity profile different from ganciclovir. Valganciclovir, a prodrug of ganciclovir, has a higher bioavailability than oral ganciclovir and could be of clinical use, particularly in the outpatient setting or for patients requiring long-term antiviral therapy. Recent technological developments have enabled the visualization and isolation of CMV-specific T cells. Using these techniques, an individualized approach could be conducted based on each patient's immune reconstitution against CMV. In this review, we summarize the recent progress and current knowledge of CMV infection and disease after allogeneic HSCT.


Identification of low molecular weight nuclear complexes containing integrase during the early stages of HIV-1 infection.
HIV-1 replication requires integration of its reverse transcribed viral cDNA into a host cell chromosome. The DNA cutting and joining reactions associated to this key step are catalyzed by the viral protein integrase (IN). In infected cells, IN binds the viral cDNA, together with viral and cellular proteins, to form large nucleoprotein complexes. However, the dynamics of IN complexes formation is still poorly understood. Here, we characterized IN complexes during the early stages of T-lymphocyte infection. We found that following viral entry into the host cell, IN was rapidly targeted to proteasome-mediated degradation. Interactions between IN and cellular cofactors LEDGF/p75 and TNPO3 were detected as early as 6 h post-infection. Size exclusion chromatography of infected cell extracts revealed distinct IN complexes in vivo. While at 2 h post-infection the majority of IN eluted within a high molecular weight complex competent for integration (IN complex I), IN was also detected in a low molecular weight complex devoid of full-length viral cDNA (IN complex II, ~440 KDa). At 6 h post-infection the relative proportion of IN complex II increased. Inhibition of reverse transcription or integration did not alter the elution profile of IN complex II in infected cells. However, in cells depleted for LEDGF/p75 IN complex II shifted to a lower molecular weight complex (IN complex III, ~150 KDa) containing multimers of IN. Notably, cell fractionation experiments indicated that both IN complex II and III were exclusively nuclear. Finally, IN complex II was not detected in cells infected with a virus harboring a mutated IN defective for LEDGF/p75 interaction and tetramerization. Our findings indicate that, shortly after viral entry, a significant portion of DNA-free IN that is distinct from active pre-integration complexes accumulates in the nucleus.


Herpes zoster and postherpetic neuralgia: diagnosis and therapeutic considerations.
Herpes zoster (HZ), also known as shingles, is a painful vesicular rash resulting from reactivation of the virus that also causes chickenpox - Varicella zoster virus (VZV). Typically, the rash runs its course in a matter of 4-5 weeks. The pain, however, may persist months, even years, after the skin heals. This phenomenon is known as postherpetic neuralgia (PHN). Often described as an intense burning, itching sensation, this pain can be significant to the point of being debilitating, and as such can greatly affect quality of life. Although shingles is generally regarded as a self-limited condition, the fact it can take several weeks to resolve and has the potential for development of complications such as PHN presents a challenge to clinicians. Many treatment options are available, each offering variable levels of efficacy. Conventional therapies include prescription antivirals, corticosteroids, and analgesics, both oral and topical. Other considerations include use of over-the-counter anti-inflammatory agents, physiotherapy, and nerve block injections. This article reviews herpes zoster and postherpetic neuralgia, and presents the most effective conventional treatment options currently available, as well as select botanical, nutritional, and other considerations that may be beneficial in the management of this condition.


Effects of inhibition of interleukin-6 signalling on insulin sensitivity and lipoprotein (a) levels in human subjects with rheumatoid diseases.
Interleukin-6 (IL-6) is a pro-inflammatory cytokine that has been found to be increased in type 2 diabetic subjects. However, it still remains unclear if these elevated IL-6 levels are co-incidental or if this cytokine is causally related to the development of insulin resistance and type 2 diabetes in humans. Therefore, in the present study we examined insulin sensitivity, serum adipokine levels and lipid parameters in human subjects before and after treatment with the IL-6 receptor antibody Tocilizumab. 11 non-diabetic patients with rheumatoid disease were included in the study. HOMA-IR was calculated and serum levels for leptin, adiponectin, triglycerides, LDL-cholesterol, HDL-cholesterol and lipoprotein (a) (Lp (a)) were measured before as well as one and three months after Tocilizumab treatment. The HOMA index for insulin resistance decreased significantly. While leptin concentrations were not altered by inhibition of IL-6 signalling, adiponectin concentrations significantly increased. Thus the leptin to adiponectin ratio, a novel marker for insulin resistance, exhibited a significant decrease. Serum triglycerides, LDL-cholesterol and HDL-cholesterol tended to be increased whereas Lp (a) levels significantly decreased. Inhibition of IL-6 signalling improves insulin sensitivity in humans with immunological disease suggesting that elevated IL-6 levels in type 2 diabetic subjects might be causally involved in the pathogenesis of insulin resistance. Furthermore, our data indicate that inhibition of IL-6 signalling decreases Lp (a) serum levels, which might reduce the cardiovascular risk of human subjects.


Exploring antibody recognition of sequence space through random-sequence peptide microarrays.
A universal platform for efficiently mapping antibody epitopes would be of great use for many applications, ranging from antibody therapeutic development to vaccine design. Here we tested the feasibility of using a random peptide microarray to map antibody epitopes. Although peptide microarrays are physically constrained to ∼10(4) peptides per array, compared with 10(8) permitted in library panning approaches such as phage display, they enable a much more high though put and direct measure of binding. Long (20 mer) random sequence peptides were chosen for this study to look at an unbiased sampling of sequence space. This sampling of sequence space is sparse, as an exact epitope sequence is unlikely to appear. Commercial monoclonal antibodies with known linear epitopes or polyclonal antibodies raised against engineered 20-mer peptides were used to evaluate this array as an epitope mapping platform. Remarkably, peptides with the most sequence similarity to known epitopes were only slightly more likely to be recognized by the antibody than other random peptides. We explored the ability of two methods singly and in combination to predict the actual epitope from the random sequence peptides bound. Though the epitopes were not directly evident, subtle motifs were found among the top binding peptides for each antibody. These motifs did have some predictive ability in searching for the known epitopes among a set of decoy sequences. The second approach using a windowing alignment strategy, was able to score known epitopes of monoclonal antibodies well within the test dataset, but did not perform as well on polyclonals. Random peptide microarrays of even limited diversity may serve as a useful tool to prioritize candidates for epitope mapping or antigen identification.


Children show adult-like facial appearance biases when trusting others.
A large research literature details the powerful behavioral consequences that a trustworthy appearance can have on adult behavior. Surprisingly, few studies have investigated how these biases operate among children, despite the theoretical importance of understanding when these biases emerge in development. Here, we used an economic trust game to systematically investigate trust behavior in young children (5-8 years), older children (9-12 years), and adults. Participants played the game with child and adult "partners" that varied in emotional expression (mild displays of happiness and anger, and a neutral baseline), which is known to modulate perceived trustworthiness. Strikingly, both groups of children showed adult-like facial appearance biases when trusting others, with no "own-age bias." There were no developmental differences in the magnitude of this effect, which supports adult-like overgeneralization of these transient emotion cues into enduring trait impressions that guide interpersonal behavior from as early as 5 years of age. Irrespective of whether or not they were explicitly directed to do so, all participants modulated their behavior in line with the emotion cues: more generous and trusting with happy partners, followed by neutral, and then angry. These findings speak to the impressive sophistication of children's early social cognition and provide key insights into the causal mechanisms driving trait impressions, suggesting they are not necessarily contingent upon protracted social experience. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Utility of emergency call centre, dispatch and ambulance data for syndromic surveillance of infectious diseases: a scoping review.
Syndromic surveillance can supplement conventional health surveillance by analyzing less-specific, near-real-time data for an indication of disease occurrence. Emergency medical call centre dispatch and ambulance data are examples of routinely and efficiently collected syndromic data that might assist in infectious disease surveillance. Scientific literature on the subject is scarce and an overview of results is lacking. A scoping review including (i) review of the peer-reviewed literature, (ii) review of grey literature and (iii) interviews with key informants. Forty-four records were selected: 20 peer reviewed and 24 grey publications describing 44 studies and systems. Most publications focused on detecting respiratory illnesses or on outbreak detection at mass gatherings. Most used retrospective data; some described outcomes of temporary systems; only two described continuously active dispatch- and ambulance-based syndromic surveillance. Key informants interviewed valued dispatch- and ambulance-based syndromic surveillance as a potentially useful addition to infectious disease surveillance. Perceived benefits were its potential timeliness, standardization of data and clinical value of the data. Various dispatch- and ambulance-based syndromic surveillance systems for infectious diseases have been reported, although only roughly half are documented in peer-reviewed literature and most concerned retrospective research instead of continuously active surveillance systems. Dispatch- and ambulance-based syndromic data were mostly assessed in relation to respiratory illnesses; reported use for other infectious disease syndromes is limited. They are perceived by experts in the field of emergency surveillance to achieve time gains in detection of infectious disease outbreaks and to provide a useful addition to traditional surveillance efforts.


Biofunctionalization of titanium implants with a biomimetic active peptide (P-15) promotes early osseointegration.
The early stages of peri-implant bone formation play an essential role in the osseointegration and long-term success of dental implants. By incorporating bioactive coatings, this biofunctionalization of implant surfaces may enhance the attachment of the implant to the surrounding bone and stimulate bone regeneration. To demonstrate faster osseointegration, the surfaces of dental implants were grit-blasted and acid-etched. They were then coated with hydroxyapatite (HA) and experimental implants were further coated with a biomimetic active peptide (P-15) in one of two concentrations. These biofunctionalized samples and controls with no peptide were placed in the forehead region of 12 adult pigs. Six animals were evaluated for a period of 14 or 30 days. Histomorphometric analysis demonstrated that the implants with the high concentration of P-15 had significantly higher percentage of bone-to-implant contact (BIC) at 14 (P=0.018) and 30 (P=0.015) days compared with the other groups. Both concentrations of P-15 showed increased peri-implant bone density compared to the control group at 30 days. Biofunctionalization of the implant surface with a biomimetic active peptide leads to significantly increased BIC rates at 14 and 30 days and higher peri-implant bone density at 30 days.


The acquisition of Cantonese classifiers by preschool children in Hong Kong.
The Cantonese language has a complex classifier system and young learners need to pay attention to both the semantics and syntax of classifiers. This study investigated the repertoire of classifiers produced by 492 Cantonese-speaking preschoolers in three age groups (3;0, 4;0 and 5;0). Spontaneous utterances produced in 30-minute toy-play contexts were collected and transcribed. Analyses identified a productive repertoire of 73 classifiers in the utterances, which could be appropriately classified into the typology proposed in the present study. An age-related increase in the number of classifier types per child as well as the repertoire size of each group was found. [symbol: see text] go3 (CL) was widely used as the general classifier by the young children. It was also discovered that the three-year-olds were already showing signs of grasping the basic syntax of classifiers. Cognitive, linguistic and contextual influences presumed to shape the evidence are discussed.