Altered neural processing of the need to stop in young adults at risk for stimulant dependence.
Identification of neurocognitive predictors of substance dependence is an important step in developing approaches to prevent addiction. Given evidence of inhibitory control deficits in substance abusers (Monterosso et al., 2005; Fu et al., 2008; Lawrence et al., 2009; Tabibnia et al., 2011), we examined neural processing characteristics in human occasional stimulant users (OSU), a population at risk for dependence. A total of 158 nondependent OSU and 47 stimulant-naive control subjects (CS) were recruited and completed a stop signal task while undergoing functional magnetic resonance imaging (fMRI). A Bayesian ideal observer model was used to predict probabilistic expectations of inhibitory demand, P(stop), on a trial-to-trial basis, based on experienced trial history. Compared with CS, OSU showed attenuated neural activation related to P(stop) magnitude in several areas, including left prefrontal cortex and left caudate. OSU also showed reduced neural activation in the dorsal anterior cingulate cortex (dACC) and right insula in response to an unsigned Bayesian prediction error representing the discrepancy between stimulus outcome and the predicted probability of a stop trial. These results indicate that, despite minimal overt behavioral manifestations, OSU use fewer brain processing resources to predict and update the need for response inhibition, processes that are critical for adjusting and optimizing behavioral performance, which may provide a biomarker for the development of substance dependence.


The effect of finishing and polishing on the decision to replace existing amalgam restorations.
The purpose of this investigation was to evaluate the influence of finishing and polishing procedures on the decision to replace existing amalgam restorations. Twenty Class I and Class II amalgam restorations, free from obvious defects, were selected in 6 patients. The restorations were photographed before and after being submitted to a standard finishing and polishing procedure. In the first phase, the preoperative slides were examined by 27 clinicians and senior dental students, who were instructed to inspect each restoration and answer a questionnaire indicating if and why the restoration needed to be replaced. Two weeks later, the postoperative slides were presented to the same examiners, who were asked to answer the same questionnaire as before. At the first phase, there were 236 decisions (44%) to replace existing amalgam restorations. Following the finishing and polishing procedures, 114 decisions (21%) were made to replace existing amalgam restorations. This difference was statistically significant. Secondary caries was the most common reason for replacement. The finishing and polishing procedure reversed the decision to replace old amalgam restorations.


Trends and district variations in the hospital care of childhood asthma: results of a regional study 1970-85.
Trends and district variations in the pre-hospital and hospital care of children aged 0-14 years admitted with acute asthma were surveyed in all 13 districts of a health region by examining case notes for 1970, 1978, and 1985. From 1970 to 1985 there was a substantial increase in admissions and some reduction of hospital stay. Over this time adrenergic drugs remained the most frequently used treatment with a large shift towards selective beta2 agonists administered by nebulisation. Use of corticosteroids fell in the under 5s with a decrease in the parenteral route of administration but rose in the 5-14 age group with an increase in the oral route of administration. There was an increase the use of oral xanthines but this was outweighed by falls in the use of suppositories and in parenteral administration. The use of antibiotics became less frequent and that of sedatives and antihistamines fell to almost nil. There were also important changes in other aspects of management, notably an increase in the use of lung function tests (from 3% to 70%) and falls in the use of chest radiographs, blood tests, bacteriology, and physiotherapy. In nearly all aspects of management there were significant and often very extreme variations in practice between districts, which were unlikely to be explained by differences in morbidity. These variations would be a suitable focus for medical audit, with the aim of establishing which treatment regimens have the best outcome and avoiding unnecessary cost and discomfort. Because early hospital drug treatment is closely related to the type of treatment given before admission such audit activities would need to include general practitioners.


Orexin neurons express a functional pancreatic polypeptide Y4 receptor.
The receptor subtypes that mediate the effects of neuropeptide Y (NPY) on food intake have not been clearly defined. The NPY Y4 receptor has been identified recently as a potential mediator of the regulation of food intake. The purpose of the present study was to characterize the central site of action of the Y4 receptor using a combination of neuroanatomical and physiological approaches. Using immunocytochemistry, Y4-like immunoreactivity was found to be colocalized with orexin cell bodies in the lateral hypothalamic area (LHA) and orexin fibers throughout the brain. In situ hybridization confirmed the expression of Y4 mRNA in orexin neurons. To determine the functional interaction between Y4 receptors and orexin neurons, we examined the effects of rat pancreatic polypeptide (rPP), a Y4-selective ligand, or NPY, a nonselective ligand, administered directly into the LHA on the stimulation of food and water intake and c-Fos expression. Both rPP and NPY significantly increased food and water intake when they were administered into the LHA, although NPY was a more potent stimulator of food intake. Furthermore, both NPY and rPP significantly stimulated c-Fos expression in the LHA. However, whereas rPP stimulated c-Fos expression in orexin neurons, NPY did not. Neither rPP nor NPY stimulated c-Fos in melanin-concentrating hormone neurons, but both activated neurons of an unknown phenotype in the LHA. These results suggest that a functional Y4 receptor is expressed on orexin neurons and that these neurons are activated in response to a ligand with high affinity for the Y4 receptor (rPP). Although these data suggest a role for central Y4 receptors, the endogenous ligand for this receptor has yet to be clearly established.


Beyond reminders: a conceptual framework for using short message service to promote prevention and improve healthcare quality and clinical outcomes for people living with HIV.
The availability of effective antiretroviral therapy has altered HIV from being an acute disease to being a chronic, manageable condition for many people living with HIV (PLWH). Because of their ubiquity and flexibility, mobile phones with short message service (SMS) offer a unique opportunity to enhance treatment and prevention for people managing HIV. To date, very few US studies using SMS for HIV self-management have been published. In this article, we review the published SMS-based intervention research that aimed to improve healthcare quality and outcomes for PLWH and other chronic health conditions, and propose a conceptual model that integrates the communication functionality of SMS with important psychosocial factors that could mediate the impact of SMS on health outcomes. We posit that an SMS-based intervention that incorporates the elements of interactivity, frequency, timing, and tailoring of messages could be implemented to encourage greater medication adherence as well as impact other mutually reinforcing behaviors and factors (e.g., increasing patient involvement and social support, reducing risk behaviors, and promoting general health and well-being) to support better healthcare quality and clinical outcomes for PLWH. We recommend that future studies explore the potential linkages between variations in SMS characteristics and these mediating factors to determine if and how they influence the larger outcomes.


Understanding jumping to conclusions in patients with persecutory delusions: working memory and intolerance of uncertainty.
Persecutory delusions are a key psychotic experience. A reasoning style known as 'jumping to conclusions' (JTC) - limited information gathering before reaching certainty in decision making - has been identified as a contributory factor in the occurrence of delusions. The cognitive processes that underpin JTC need to be determined in order to develop effective interventions for delusions. In the current study two alternative perspectives were tested: that JTC partially results from impairment in information-processing capabilities and that JTC is a motivated strategy to avoid uncertainty. A group of 123 patients with persistent persecutory delusions completed assessments of JTC (the 60:40 beads task), IQ, working memory, intolerance of uncertainty, and psychiatric symptoms. Patients showing JTC were compared with patients not showing JTC. A total of 30 (24%) patients with delusions showed JTC. There were no differences between patients who did and did not jump to conclusions in overall psychopathology. Patients who jumped to conclusions had poorer working memory performance, lower IQ, lower intolerance of uncertainty and lower levels of worry. Working memory and worry independently predicted the presence of JTC. Hasty decision making in patients with delusions may partly arise from difficulties in keeping information in mind. Interventions for JTC are likely to benefit from addressing working memory performance, while in vivo techniques for patients with delusions will benefit from limiting the demands on working memory. The study provides little evidence for a contribution to JTC from top-down motivational beliefs about uncertainty.


Prevalence and Associated Factors of Depressive Disorder in Caregivers of Individuals With Parkinson Disease.
Parkinson disease (PD) is a debilitating neurodegenerative disease. Caring for an individual with PD can have a variety of negative physical and psychological effects on caregivers which may challenge their ability to continue in their caretaking role. The aim of this study was to assess the prevalence and associated factors of depressive disorders in caregivers of individuals with PD using standardized instruments. This study used a cross-sectional design with consecutive sampling. Study participants were recruited from the neurological ward or neurological outpatient clinic of a medical center from August 2018 to July 2019. Caregivers of persons with PD were enrolled and assessed using the Mini International Neuropsychiatric Interview, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Beck Hopelessness Scale, Brief Fatigue Inventory, Connor-Davidson Resilience Scale, and Big Five Inventory-10. Of the 162 caregivers that completed the study, 67.3% (n = 109) were females. The most common psychiatric diagnosis was depressive disorder (11.1%), followed by insomnia disorder (7.4%) and anxiety disorder not otherwise specified (4.3%); 28% of the caregivers had a psychiatric diagnosis. Using logistic regression analysis, it was found that duration of caregiving (odds ratio [OR] = 1.28; 95% CI, 1.05-1.58), severity of anxiety (OR = 1.86; 95% CI, 1.36-2.53), and severity of fatigue (OR = 1.08; 95% CI, 1.01-1.16) were 3 significant associated factors for the development of depression. Depression was the most prevalent psychiatric diagnosis in caregivers of people with PD. Early diagnosis of these caregivers is crucial to the offering of suitable support and treatment and might improve caregivers' quality of life.


Unhealthy Diet Is Associated With Poor Sleep in Preschool-Aged Children.
Unhealthy dietary choices are associated with poor sleep in children through adults. Yet, how diet and sleep are related in early childhood, when diet is reliant on parent choices around food availability, is unknown. The authors aimed to explore how frequency of fruit, vegetable, fast food, and soda consumption are associated with preschool children's sleep quality. They also considered how parenting factors may impact the relationship between children's sleep and diet. Actigraphy data were collected from 383 children 33-70 months old. Caregivers reported on child food and beverage frequency, demographics, and health items. Parenting strategies were assessed using the Parenting Scale. Multiple linear regression was used to examine associations between sleep and dietary measures with socioeconomic status, race-ethnicity, physical activity, and body mass index as covariates. Shorter nap duration was associated with more frequent consumption of fruits and vegetables (B = -3.6, p = .03). Shorter nighttime and 24-hr sleep durations were associated with more frequent consumption of fast food (B = -6.5, p = .01; B = -5.8, p = .01). Shorter nighttime sleep and later sleep onset were associated with more frequent soda consumption (B = -9.2, p = .01; B = 0.23, p = .001). Use of ineffective parenting strategies was negatively associated with fruit and vegetable consumption (r = -.29, p = .01) and positively associated with soda consumption (r = .25, p = .02) but was unrelated to sleep measures. Thus, ineffective parenting strategies may underlie child access to unhealthy foods, which, in turn, contributes to poor sleep. Encouraging healthier dietary habits and educating caregivers on how to reinforce such practices may lead to better sleep outcomes in early childhood.


MRI of human hair.
Hair care for humans is a major world industry with specialised tools, chemicals and techniques. Studying the effect of hair care products has become a considerable field of research, and besides mechanical and optical testing numerous advanced analytical techniques have been employed in this area. In the present work, another means of studying the properties of hair is added by demonstrating the feasibility of magnetic resonance imaging (MRI) of the human hair. Established dedicated nuclear magnetic resonance microscopy hardware (solenoidal radiofrequency microcoils and planar field gradients) and methods (constant time imaging) were adapted to the specific needs of hair MRI. Images were produced at a spatial resolution high enough to resolve the inner structure of the hair, showing contrast between cortex and medulla. Quantitative evaluation of a scan series with different echo times provided a T*(2) value of 2.6 ms for the cortex and a water content of about 90% for hairs saturated with water. The demonstration of the feasibility of hair MRI potentially adds a new tool to the large variety of analytical methods used nowadays in the development of hair care products.


Tris (2-butoxyethyl) phosphate affects motor behavior and axonal growth in zebrafish (Danio rerio) larvae.
Tris (2-butoxyethyl) phosphate (TBOEP) is an environmental contaminant that poses serious risks to aquatic organisms and their associated ecosystem. Recently, the reproductive and developmental toxicology of TBOEP has been reported. However, fewer studies have assessed the neurotoxic effects in zebrafish (Danio rerio) larvae. In this study, zebrafish embryos were subjected to waterborne exposure of TBOEP at 0, 50, 500, 1500 and 2500 μg/L from 2 to 144-h post-fertilization (hpf). Behavioral measurements showed that TBOEP exposure reduced embryonic spontaneous movement and decreased swimming speed of larvae in response to dark stimulation. In accordance with these motor effects, TBOEP treatment reduced neuron-specific GFP expression in transgenic Tg (HuC-GFP) zebrafish larvae and inhibited the growth of secondary motoneurons, as well as decreased expression of marker genes related to central nervous system development in TBOEP treated group. Furthermore, increased concentrations of reactive oxygen species (ROS) and malondialdehyde (MDA), as well as reduction of SOD activity were detected in TBOEP exposure group. The present results showed that the alteration in motor neuron and oxidative stress could together lead to the motor behavior alterations induced by TBOEP.


Identification of patient information corruption in the intensive care unit: using a scoring tool to direct quality improvements in handover.
To use a handover assessment tool for identifying patient information corruption and objectively evaluating interventions designed to reduce handover errors and improve medical decision making. The continuous monitoring, intervention, and evaluation of the patient in modern intensive care unit practice generates large quantities of information, the platform on which medical decisions are made. Information corruption, defined as errors of distortion/omission compared with the medical record, may result in medical judgment errors. Identifying these errors may lead to quality improvements in intensive care unit care delivery and safety. Handover assessment instrument development study divided into two phases by the introduction of a handover intervention. Closed, 17-bed, university-affiliated mixed surgical/medical intensive care unit. Senior and junior medical members of the intensive care unit team. Electronic handover page. Study subjects were asked to recall clinical information commonly discussed at handover on individual patients. The handover score measured the percentage of information correctly retained for each individual doctor-patient interaction. The clinical intention score, a subjective measure of medical judgment, was graded (1-5) by three blinded intensive care unit experts. A total of 137 interactions were scored. Median (interquartile range) handover scores for phases 1 and 2 were 79.07% (67.44-84.50) and 83.72% (76.16-88.37), respectively. Score variance was reduced by the handover intervention (p < .05). Increasing median handover scores, 68.60 to 83.72, were associated with increases in clinical intention scores from 1 to 5 (chi-square = 23.59, df = 4, p < .0001). When asked to recall clinical information discussed at handover, medical members of the intensive care unit team provide data that are significantly corrupted compared with the medical record. Low subjective clinical judgment scores are significant associated with low handover scores. The handover/clinical intention scores may, therefore, be useful screening tools for intensive care unit system vulnerability to medical error. Additionally, handover instruments can identify interventions that reduce system vulnerability to error and may be used to guide quality improvements in handover practice.


From virus evolution to vector revolution: use of naturally occurring serotypes of adeno-associated virus (AAV) as novel vectors for human gene therapy.
Gene transfer vectors based on the human adeno-associated virus serotype 2 (AAV-2) have been developed and tested in pre-clinical studies for almost 20 years, and are currently being evaluated in clinical trials. So far, all these studies have provided evidence that AAV-2 vectors possess many properties making them very attractive for therapeutic gene delivery to humans, such as a lack of pathogenicity or toxicity, and the ability to confer long-term gene expression. However, there is concern that two restrictions of AAV-2 vectors might limit their clinical use in humans. First, these vectors are rather inefficient at transducing some cells of therapeutic interest, such as liver and muscle cells. Second, gene transfer might be hampered by neutralizing anti-AAV-2 antibodies, which are highly prevalent in the human population. In efforts to overcome both limitations, an increasing number of researchers are now focusing on the seven other naturally occurring serotypes of AAV (AAV-1 and AAV-3 to -8), which are structurally and functionally different from AAV-2. To this end, several strategies have been devised to cross-package an AAV-2 vector genome into the capsids of the other AAV serotypes, resulting in a new generation of "pseudotyped" AAV vectors. In vitro and in vivo, these novel vectors were shown to have a host range different from AAV-2, and to escape the anti-AAV-2 immune response, thus underscoring the great potential of this approach. Here the biology of the eight AAV serotypes is summarized, existing technology for pseudotyped AAV vector production is described, initial results from pre-clinical evaluation of the vectors are reviewed, and finally, the prospects of these promising novel tools for human gene therapy are discussed.


Clinical features of the reactive positive contraction stress test.
During a five-year period, 2815 patients undergoing 5685 fetal heart rate (FHR) tests produced 147 positive contraction stress tests. Baseline FHR patterns were considered reactive if three or more accelerations occurred during 30 minutes of the contraction stress test and nonreactive if fewer or no accelerations were noted. There were 75 reactive positive contraction stress tests and 72 nonreactive positive contraction stress tests. Both groups were promptly delivered, generally (91%) within 24 hours of the last test. Fetuses producing reactive positive patterns tended to be more mature, larger, and most frequently tested for postmaturity. Fetuses with nonreactive positive patterns had significantly higher rates of perinatal mortality and morbidity, growth retardation, and cesarean deliveries; they were frequently carried by hypertensive mothers. Each group was analyzed according to deceleration: contraction ratio, and deceleration: contraction ratio deciles from 30 to 100% were examined. Perinatal complications increased progressively with higher deceleration: contraction ratios, irrespective of baseline reactivity; however, nonreactive fetuses in any deceleration: contraction ratio decile had more frequent perinatal compromise than their reactive counterparts. The lack of specificity (26 poor outcomes in 75 cases) associated with the reactive positive contraction stress tests encourages more frequent attempts at vaginal delivery; in this group, 64 of 71 patients had successful vaginal deliveries. Furthermore, the high incidence of good fetal outcome in the reactive positive group suggests that the urgency of delivery in such circumstances be reassessed and that other fetal-maternal indicators be considered in delivery decisions.


Cross-infection of virulent Dichelobacter nodosus between sheep and co-grazing cattle.
Dichelobacter nodosus is the main aetiological agent of ovine footrot and the bacterium has also been associated with interdigital dermatitis is cattle. The aim of this study was to investigate possible cross-infection of virulent D. nodosus between sheep and co-grazing cattle. Five farms, where sheep previously diagnosed with virulent D. nodosus were co-grazing with cattle for different periods of time, were included. The study sample consisted of 200 cows and 50 sheep. All cows were examined for the presence of interdigital dermatitis, and ten ewes, preferably with symptoms of footrot, had the footrot scores recorded. On each farm, the same ten ewes and ten cows were chosen for bacterial analyses. Swabs were analysed for D. nodosus by PCR and culturing. D. nodosus isolates were virulence-tested and assigned to serogroups by fimA variant determination. Biopsies were evaluated histopathologically and analysed by fluorescent in situ hybridization for D. nodosus, Treponema spp. and Fusobacterium necrophorum. D. nodosus defined as virulent by the gelatin gel test were isolated from 16 sheep from four farms and from five cows from two of the same farms. All five cows had interdigital dermatitis. Two of the cows stayed infected for at least eight months. By pulsed-field gel electrophoresis (PFGE), the isolates from the five cows were found to be genetically indistinguishable or closely related to isolates from sheep from the same farm. This indicates that cross-infection between sheep and cows have occurred.


Identification of Avramr1 from Phytophthora infestans using long read and cDNA pathogen-enrichment sequencing (PenSeq).
Potato late blight, caused by the oomycete pathogen Phytophthora infestans, significantly hampers potato production. Recently, a new Resistance to Phytophthora infestans (Rpi) gene, Rpi-amr1, was cloned from a wild Solanum species, Solanum americanum. Identification of the corresponding recognized effector (Avirulence or Avr) genes from P. infestans is key to elucidating their naturally occurring sequence variation, which in turn informs the potential durability of the cognate late blight resistance. To identify the P. infestans effector recognized by Rpi-amr1, we screened available RXLR effector libraries and used long read and cDNA pathogen-enrichment sequencing (PenSeq) on four P. infestans isolates to explore the untested effectors. Using single-molecule real-time sequencing (SMRT) and cDNA PenSeq, we identified 47 highly expressed effectors from P. infestans, including PITG_07569, which triggers a highly specific cell death response when transiently coexpressed with Rpi-amr1 in Nicotiana benthamiana, suggesting that PITG_07569 is Avramr1. Here we demonstrate that long read and cDNA PenSeq enables the identification of full-length RXLR effector families and their expression profile. This study has revealed key insights into the evolution and polymorphism of a complex RXLR effector family that is associated with the recognition by Rpi-amr1.


Evaluation of CogSport for acute concussion diagnosis in cricket.
The diagnosis of sport-related concussion is a challenge for practitioners given the variable presentation and lack of a universal clinical indicator. The aim of this study was to describe the CogSport findings associated with concussion in elite Australian cricket players, and to evaluate the diagnostic ability of CogSport for this cohort. A retrospective study design was used to evaluate CogSport performance of 45 concussed (male n=27, mean age 24.5±4.5 years; female n=18, 23.5±3.5 years) compared with 45 matched non-concussed (male n=27, mean age 27.3±4.5 years; female n=18, 24.1±4.5 years) elite Australian cricket players who sustained a head impact during cricket specific activity between July 2015 and December 2019. Median number of reported symptoms on the day of injury for concussed players was 7 out of 24, with a median symptom severity of 10 out of 120. CogSport performance deteriorated significantly in concussed cricket players' Detection speed (p<0.001), Identification speed (p<0.001), One Back speed (p=0.001) and One Back accuracy (p=0.022) components. These components, when considered independently and together, had good diagnostic utility. This study demonstrated good clinical utility of CogSport for identifying concussed cricket players, particularly symptoms and Detection, Identification and One Back components. Therefore, CogSport may be considered a useful tool to assist concussion diagnosis in this cohort, and the clinician may place greater weight on the components associated with concussion diagnosis.


Over-seasons analysis of quantitative trait loci affecting phenolic content and antioxidant capacity in raspberry.
This study examined the total phenol content (TPC) and total anthocyanin content (TAC) in ripe fruit of progeny of a mapping population generated from a cross between the European red raspberry cv. Glen Moy ( Rubus ideaus var. idaeus) and the North American red raspberry cv. Latham ( Rubus ideaus var. strigosus) over five seasons in two different growing environments. Measurements of antioxidant capacity (FRAP and TEAC) were also carried out. TPC was highly correlated with TEAC and FRAP across the entire data set. The subset of anthocyanin content was genotype-dependent but also correlated with TPC, although the proportion of anthocyanin compounds varied between progeny. Quantitative trait locus (QTL) analysis was carried out, and key markers were tested for consistency of effects over sites and years. Four regions, on linkage groups 2, 3, 5, and 6, were identified. These agree with QTLs from a previous study over a single season and indicate that QTL effects were robust over seasons.


Locus of control of behaviour: is high externality associated with substance misuse?
Personal control and responsibility are key themes in the therapeutic use of 'motivational interviewing'. This popular method of counselling has suggested that clients need to believe they have a significant degree of control over their behaviour if they are to make progress. Using a well validated psychological test on locus of control of behaviour, our research sought to establish whether active misusers really believed they had less personal control than non-misusers. To establish this a sample of misusers was tested and compared with three diverse, comparable groups. Possible confounding factors such as age, sex and class were controlled for. T tests established a significant difference between the active misusers and the other sampled groups. Further, a regression analysis of variance, calculated to explain the differing external scores offered no reasonable explanation as far as age, sex and class were concerned. Alternatively, self diagnosed substance misuse accounted for 23% of the variation in scores. We concluded, therefore, that high externality scores are a good indicator of active misusing behaviour and that beliefs about personal control are important to address, if one is to increase the chances of a positive client outcome.


Phage T7 DNA mimic protein Ocr is a potent inhibitor of BREX defence.
BREX (for BacteRiophage EXclusion) is a superfamily of common bacterial and archaeal defence systems active against diverse bacteriophages. While the mechanism of BREX defence is currently unknown, self versus non-self differentiation requires methylation of specific asymmetric sites in host DNA by BrxX (PglX) methyltransferase. Here, we report that T7 bacteriophage Ocr, a DNA mimic protein that protects the phage from the defensive action of type I restriction-modification systems, is also active against BREX. In contrast to the wild-type phage, which is resistant to BREX defence, T7 lacking Ocr is strongly inhibited by BREX, and its ability to overcome the defence could be complemented by Ocr provided in trans. We further show that Ocr physically associates with BrxX methyltransferase. Although BREX+ cells overproducing Ocr have partially methylated BREX sites, their viability is unaffected. The result suggests that, similar to its action against type I R-M systems, Ocr associates with as yet unidentified BREX system complexes containing BrxX and neutralizes their ability to both methylate and exclude incoming phage DNA.


Cathepsin L Helps to Defend Mice from Infection with Influenza A.
Host-derived proteases can augment or help to clear infections. This dichotomy is exemplified by cathepsin L (CTSL), which helps Hendra virus and SARS coronavirus to invade cells, but is essential for survival in mice with mycoplasma pneumonia. The present study tested the hypothesis that CTSL protects mice from serious consequences of infection by the orthomyxovirus influenza A, which is thought to be activated by host-supplied proteases other than CTSL. Ctsl-/- mice infected with influenza A/Puerto Rico/8/34(H1N1) had larger lung viral loads and higher mortality than infected Ctsl+/+ mice. Lung inflammation in surviving infected mice peaked 14 days after initial infection, accompanied marked focal distal airway bronchiolization and epithelial metaplasia followed by desquamation and fibrotic interstitial remodeling, and persisted for at least 6 weeks. Most deaths occurred during the second week of infection in both groups of mice. In contrast to mycoplasma pneumonia, infiltrating cells were predominantly mononuclear rather than polymorphonuclear. The histopathology of lung inflammation and remodeling in survivors was similar in Ctsl-/- and Ctsl+/+ mice, although Ctsl+/+ mice cleared immunoreactive virus sooner. Furthermore, Ctsl-/- mice had profound deficits in CD4+ lymphocytes before and after infection and weaker production of pathogen-specific IgG. Thus, CTSL appears to support innate as well as adaptive responses, which confer a survival advantage on mice infected with the orthomyxovirus influenza A.


A patient advocate's perspective on patient-centered comparative effectiveness research.
The Patient Protection and Affordable Care Act created a new phrase and concept: patient-centered outcomes research. The author of this commentary, who served as a member of the US House of Representatives from California, is also a patient with epilepsy and a patient advocate. He consulted with lawmakers in the passage of the health reform law. Here he draws on his varied experiences to provide perspective on how the law will provide the necessary policy framework for patient-centered comparative effectiveness research. Elements of that framework include the meaningful engagement of multiple stakeholders, most especially patients; acknowledgment of individual differences among patients and the importance of advancing personalized medicine; transparency and opportunities to participate; a broad, clinically focused research agenda; and the need to communicate results appropriately.


Design and development of a film-based intervention about teenage men and unintended pregnancy: applying the Medical Research Council framework in practice.
Following the UK Medical Research Council's (MRC) guidelines for the development and evaluation of complex interventions, this study aimed to design, develop and optimise an educational intervention about young men and unintended teenage pregnancy based around an interactive film. The process involved identification of the relevant evidence base, development of a theoretical understanding of the phenomenon of unintended teenage pregnancy in relation to young men, and exploratory mixed methods research. The result was an evidence-based, theory-informed, user-endorsed intervention designed to meet the much neglected pregnancy education needs of teenage men and intended to increase both boys' and girls' intentions to avoid an unplanned pregnancy during adolescence. In prioritising the development phase, this paper addresses a gap in the literature on the processes of research-informed intervention design. It illustrates the application of the MRC guidelines in practice while offering a critique and additional guidance to programme developers on the MRC prescribed processes of developing interventions. Key lessons learned were: (1) know and engage the target population and engage gatekeepers in addressing contextual complexities; (2) know the targeted behaviours and model a process of change; and (3) look beyond development to evaluation and implementation.


The Criminogenic Influence of Family on Substance Use During Reentry: A Life-Course Perspective on Between Individual Differences and Within Individual Changes.
A large body of prior research has demonstrated a clear link between family support and desistance from substance use during reentry. Emerging research also suggests that family conflict may play an independent role in this process. Accordingly, this study moves towards an understanding of how baseline between-individual differences in both family support and conflict prior to release interact with within-individual change in the respective constructs to affect substance use during the reentry time period. Results of cross-lagged dynamic panel models examining four waves of the Serious and Violent Offender Reentry Initiative data demonstrate baseline between-individual differences and within-individual changes in family conflict, but not support, significantly relate to polysubstance use. While these results suggest that families play a criminogenic role in reentry, a series of interaction terms demonstrates that within-individual increases in family support can help offset the negative influence of family conflict.


Complement-derived leukotactic factors in pathological fluids.
Leukotactic factors derived from the complement sequence consist of C5-related products, including the small cleavage product and the higher molecular weight complex (C567). A leukotactically active cleavage product (of low molecular weight) has also been described. The C5-related factors have been found in two conditions: soluble tissue extracts of immunologic vasculitis and in synovial fluids from patients with rheumatoid arthritis. The C3-related product has been found in synovial fluids from patients with inflammatory, nonrheumatoid arthritis and in extracts of experimentally infarcted myocardium. The presence of these factors may be causally related to the acute inflammatory nature of the cellular exudates.


One-Pot Synthesis of High-Flux b-Oriented MFI Zeolite Membranes for Xe Recovery.
We demonstrate that b-oriented MFI (Mobil Five) zeolite membranes can be manufactured by in situ crystallization using an intermediate amorphous SiO2 layer. The improved in-plane growth by using a zeolite growth modifier leads to fusion of independent crystals and eliminates boundary gaps, giving good selectivity in the separation of CO2/Xe mixtures. The fast diffusion of CO2 dominates the overall membrane selectivity toward the CO2/Xe mixture. Because of the straight and short [010] channels, the obtained CO2 permeation fluxes are several orders of magnitude higher than those of carbon molecular sieving membranes and polymeric membranes, opening opportunities for Xe recovery from waste anesthetic gas.


Survey on public awareness, attitudes, and barriers for herpes zoster vaccination in South Korea.
A cross-sectional study was performed to assess current public awareness of herpes zoster (HZ) and its vaccine, determine the factors that influence people's intention regarding HZ vaccination, and investigate the barriers for vaccination by changing decisions with sequential questions regarding knowledge, cost, and physician's recommendation in the Department of Infectious Diseases, Korea University Guro Hospital, in South Korea, between August 23 and September 15 of 2013. Among 603 subjects who completed the survey, 85.7% and 43.6% subjects were aware of HZ and HZ vaccination, respectively. Women, younger age group, those with higher income or higher education levels were more likely to be aware of HZ. Overall, 85.8% of subjects aware of HZ were willing to be vaccinated or vaccinate their parents. The main obstacles for the increased acceptance toward vaccination were the high cost and low perceived risk, which decreased acceptance to 60.2%. However, physician's recommendation reversed 69.5% of the refusal to accept HZ vaccine. These results indicate that expanding public education and physician's recommendations are important factors aimed at increasing HZ vaccine coverage rate.


Supramolecular Reorientation During Deposition Onto Metal Surfaces of Quasi-Two-Dimensional Langmuir Monolayers Composed of Bifunctional Amphiphilic, Twisted Perylenes.
Supramolecular dye structures, which are often ruled by π-π interactions between planar chromophores, crucially determine the optoelectronic properties of layers and interfaces. Here, we present the interfacial assembly of perylene monoanhydride and monoimide that do not feature a planar chromophore but contain chlorine substituents in the bay positions to yield twisted chromophores and hence modified π-stacking. The assembly of the twisted perylene monoanhydride and monoimide is driven by their amphiphilicity that ensures proper Langmuir layer formation. The shielding of the hydrophilic segment upon attaching an alkyl chain to the imide moiety yielded a more rigid Langmuir layer, even though the degrees of freedom were increased due to this modification. For the characterization of the Langmuir layer's supramolecular structure, the layers were deposited onto glass, silver, and gold substrates via Langmuir-Blodgett (LB) and Langmuir-Schaefer (LS) techniques and were investigated with atomic force microscopy and surface-enhanced resonance Raman spectroscopy (SERRS). From the similarity between all SERR spectra of the LS and LB layers, we concluded that the perylenes have changed their orientation upon LB deposition to bind to the silver surface of the SERRS substrate via sulfur atoms. In the Langmuir layer, the perylenes, which are π-stacked with half of the twisted chromophores, must already be inclined and cannot achieve full parallel alignment because of the twisting-induced steric hindrance. However, upon rotation, the energetically most favorable antiparallel aligned structures can be formed and bind to the SERRS substrate. Thus, we present, to the best of our knowledge, the first fabrication of quasi-two-dimensional films from twisted amphiphilic perylene monoimides and their reassembly during LB deposition. The relation between the molecular structure, supramolecular interfacial assembly, and its adoption during adsorption revealed here is crucial for the fabrication of defined functionalizations of metal surfaces, which is key to the development of organic (opto)electronic devices.


Encapsulation performance of proteins and traditional materials for spray dried flavors.
The objective of this study was to evaluate the potential of selected proteins as alternative materials for flavor encapsulation by spray drying. Two traditional materials (gum acacia and modified starch) and three proteins (sodium caseinate, whey and soy protein isolates) were used at different infeed solid levels; test compounds included (R)-(+)-limonene and three alpha,beta-unsaturated aldehydes ((E)-2-hexenal, (E)-cinnamaldehyde, citral). The primary criteria for performance were flavor retention during drying and protection against losses during storage. Limonene oxidation and nonenzymatic browning were investigated as two possible deterioration routes. Overall, higher infeed solids improved retention during drying and limited flavor losses (aldehydes and limonene) during storage in traditional materials only. The materials giving the highest flavor retention during drying were gum acacia (94%), modified starch (88%) and whey protein isolate (87%). Gum acacia provided the highest retention of aldehydes during storage (37 to 58%) after 28 days at 40 degrees C but did not afford good protection against limonene oxidation. Oppositely, protein materials effectively limited limonene oxidation (>70% retained). Nonenzymatic browning was observed for all powders prepared with proteins, especially whey protein isolate, whereas no browning occurred with traditional materials.


Tunable Multifunctional Thermal Metamaterials: Manipulation of Local Heat Flux via Assembly of Unit-Cell Thermal Shifters.
Thermal metamaterials, designed by transformation thermodynamics are artificial structures that can actively control heat flux at a continuum scale. However, fabrication of them is very challenging because it requires a continuous change of thermal properties in materials, for one specific function. Herein, we introduce tunable thermal metamaterials that use the assembly of unit-cell thermal shifters for a remarkable enhancement in multifunctionality as well as manufacturability. Similar to the digitization of a two-dimensional image, designed thermal metamaterials by transformation thermodynamics are disassembled as unit-cells thermal shifters in tiny areas, representing discretized heat flux lines in local spots. The programmed-reassembly of thermal shifters inspired by LEGO enable the four significant functions of thermal metamaterials-shield, concentrator, diffuser, and rotator-in both simulation and experimental verification using finite element method and fabricated structures made from copper and PDMS. This work paves the way for overcoming the structural and functional limitations of thermal metamaterials.


Proteinuria with fumaric acid ester treatment for psoriasis.
Fumaric acid esters (FAE) have been used in the treatment of psoriasis for many years. In general, they are regarded as relatively safe compared with other antipsoriatic systemic treatments, with the most notable adverse effects being gastrointestinal upset, lymphopenia and transient flushing. Renal toxicity has only rarely been reported, and was not found in two independent prospective trials nor in a large retrospective evaluation of almost 1000 patients treated for a median of 44 months. We report three patients developing reversible proteinuria during FAE treatment. One of these displayed the same pattern upon repeated drug administration, thereby clearly indicating FAE treatment to be the causal trigger. The presented cases highlight proteinuria as a clinical concern in FAE treatment. Furthermore, as the novel FAE agent dimethylfumaric (DMF) ester (contained in BG00012/Panaclar) has previously been shown to be effective in psoriasis in a phase III trial and not shown renal toxicity in a large trial for multiple sclerosis, the current report suggests that market introduction of DMF for psoriasis should be pursued.


Effect of cathepsin D and prostate specific antigen on latent transforming growth factor-beta in breast cancer cell lines.
Transforming growth factor-beta (TGFbeta) is present, predominantly in latent forms, in normal and malignant breast tissue. The mechanisms by which latent TGFbeta is activated physiologically remain largely an enigma. The objective of this study was to assess whether the proteases, cathepsin D and prostate specific antigen (PSA) could activate latent TGFbeta1 and TGFbeta2 in conditioned media of the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 human breast cancer cell lines, newly purchased from ATCC. Both of the cell lines were seeded in 6-well plates 2 days prior to treatment with varying concentrations of cathepsin D and PSA. Active TGFbeta1 and TGFbeta2 in the media were then measured by ELISA after 4, 8, 24 and 72 hours of treatment. TGFbeta1 and TGFbeta2 mRNA expression of both cell lines were measured by RT-PCR to determine whether any increase in level of active TGFbeta1 and TGFbeta2 was due to increased production. There was a significant increase in only active TGFbeta2 levels in the MDA-MB-231 cell line with both treatments. Cathepsin D and PSA did not have any effect on TGFbeta1 and TGFbeta2 mRNA expression. Cathepsin D and PSA were unable to activate latent TGFbeta1 and TGFbeta2 in these two breast cancer cell lines. A constant level of TGFbeta2 mRNA in the control and treated MDA-MB-231 cells suggests that the increase in level of active TGFbeta2 was not a result of increased production but was likely to be due to activation by a mechanism independent of cathepsin D and PSA.


Traction-assisted colonic endoscopic submucosal dissection using clip and line: a feasibility study.
Colonic endoscopic submucosal dissection (ESD) is a challenging procedure because it is often difficult to maintain good visualization of the submucosal layer. To facilitate colonic ESD, we designed a novel traction method, namely traction-assisted colonic ESD using clip and line (TAC), and investigated its feasibility. We retrospectively analyzed 23 patients with large colonic superficial lesions who had undergone TAC. The main outcome was the procedural success rate of TAC, which we defined as successful, sustained application of clip and line to the lesion until the end of the procedure. The procedural success rate of TAC was 87 % (20/23). In all three unsuccessful cases, the lesions were in the proximal colon and the procedure times over 100 minutes. The overall mean procedure time was 61 min (95 % confidence interval, 18 - 172 min). We achieved en bloc resections of all lesions. There were no perforations or fatal adverse events. TAC is feasible and safe for colonic ESD and may improve the ease of performing this procedure.


Brain Herniation Through the Cribriform Plate: Review and Comparison to Encephaloceles in the Same Region.
Herniations of the brain and/or meninges through an opening of the skull often occur through the foramen magnum, e.g., Chiari malformations and encephaloceles. The herniation of brain matter through the cribriform plate is a rare incident and has not been reported frequently. The presence of such an occurrence still requires attention and anatomical understanding. This review will examine the potential causes of cribriform plate herniation and its distinguishability to nasal encephaloceles. The sloping of brain tissue toward potential space/opening in response to elevated pressures in the cranium to accommodate for the added pressure are features seen in herniation. The presence of a pedicle and stalk seen in an encephalocele define its characteristics, which are not visible in a 'classical' herniation. Cerebrospinal fluid (CSF) fistula commonly occurs at the cribriform plate, and due to the structural weakness, a pathway is formed. This is often seen in conjunction with meningoceles. Delineating between herniation and encephaloceles is important for both clinicians and neurosurgeons.


Perceptual learning of contrast discrimination in macaca mulatta.
Rhesus monkeys underwent training in a contrast discrimination task, in which grating stimuli were presented at parafoveal and peripheral visual field locations. Subjects had to compare a sample stimulus that had a fixed contrast of 30% to a test stimulus that varied in contrast from trial to trial. Extensive practice yielded improvements in contrast discrimination that were observed across the full range of test stimulus contrasts. These improvements occurred across multiple sessions, as well as across trials within individual sessions. The finer the contrast discriminations required, the longer it took for subjects to improve. Improvements in psychophysical performance resulted in the steepening of psychometric functions and/or shifts in the point of subjective equality towards the contrast of the sample stimulus. Enhancement in discrimination was especially pronounced around the contrast level of the sample stimulus, to which the subject was consistently exposed. The changes resulted in increased accuracy overall, lower discrimination thresholds, and faster response times. Partial transfer of learning, from vertically oriented training stimuli to horizontally oriented testing stimuli, was observed, while transfer to stimuli with different spatial frequencies was less pronounced. The results demonstrate the existence of perceptual learning in the contrast domain, whereby learning affects multiple performance-related psychophysical metrics.


Vagal modulation and symptomatology following a 6-month aerobic exercise program for women with fibromyalgia.
To examine the effects of a supervised aerobic exercise programme on heart rate variability (HRV) parameters and symptom severity in women with fibromyalgia (FM). Thirty-two women with FM were randomly allocated to one of two groups: aerobic exercise (AE) or usual care control for 24 weeks. Women allocated to AE performed two aerobic exercise sessions per week of 45-60 min duration including 15-20 min of steady-state aerobic exercise at 60-65% of predicted maximum heart rate (HRmax) and 15 min of interval training at 75-80% HRmax (six repetitions of 1.5 min, with 1 min interpolated rest intervals). Cardiac autonomic modulation was assessed using power spectral analysis of HRV. Symptom severity was assessed by a 10 cm visual analogue scale (VAS) for pain, sleep disturbances, stiffness, anxiety and depression. After 24 weeks, the women in the exercise group showed an increase (4.8 ± 0.2 to 5.2 ± 0.2) in total power (LnTP, p<0.001), low frequency power (LnLF, p<0.01), high frequency power (LnHF, p<0.001), and the root-mean-square of successive R-R intervals (rMSSD, p<0.001). In addition, significant group-by-time interaction effects were observed for LnHF (p=0.036) and LnLF/HF (p=0.014). Improvements in anxiety and depression were also observed in AE versus control patients. These results show that a programme of aerobic exercise training induced changes in cardiac autonomic nervous system modulation in FM and that these changes in HRV parameters were accompanied by changes in anxiety and depression.


Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis. Currently, there is no established treatment for this disease. We randomly assigned 247 adults with nonalcoholic steatohepatitis and without diabetes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 weeks. The primary outcome was an improvement in histologic features of nonalcoholic steatohepatitis, as assessed with the use of a composite of standardized scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indicate statistical significance. Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P=0.001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; P=0.04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone, as compared with placebo (P<0.001 for both comparisons), and both agents were associated with reductions in hepatic steatosis (P=0.005 for vitamin E and P<0.001 for pioglitazone) and lobular inflammation (P=0.02 for vitamin E and P=0.004 for pioglitazone) but not with improvement in fibrosis scores (P=0.24 for vitamin E and P=0.12 for pioglitazone). Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups. Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes. (ClinicalTrials.gov number, NCT00063622.)


Efficacy of bilateral repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: results of a multicenter double-blind randomized controlled trial.
Few studies have investigated the efficacy of repetitive transcranial magnetic stimulation (rTMS) treatment for negative symptoms of schizophrenia, reporting inconsistent results. We aimed to investigate whether 10 Hz stimulation of the bilateral dorsolateral prefrontal cortex during 3 weeks enhances treatment effects. A multicenter double-blind randomized controlled trial was performed in 32 patients with schizophrenia or schizo-affective disorder, and moderate to severe negative symptoms [Positive and Negative Syndrome Scale (PANSS) negative subscale ⩾15]. Patients were randomized to a 3-week course of active or sham rTMS. Primary outcome was severity of negative symptoms as measured with the Scale for the Assessment of Negative Symptoms (SANS) and the PANSS negative symptom score. Secondary outcome measures included cognition, insight, quality of life and mood. Subjects were followed up at 4 weeks and at 3 months. For analysis of the data a mixed-effects linear model was used. A significant improvement of the SANS in the active group compared with sham up to 3 months follow-up (p = 0.03) was found. The PANSS negative symptom scores did not show a significant change (p = 0.19). Of the cognitive tests, only one showed a significant improvement after rTMS as compared with sham. Finally, a significant change of insight was found with better scores in the treatment group. Bilateral 10 Hz prefrontal rTMS reduced negative symptoms, as measured with the SANS. More studies are needed to investigate optimal parameters for rTMS, the cognitive effects and the neural basis.


The structural stability of the endothelial glycocalyx after enzymatic removal of glycosaminoglycans.
It is widely believed that glycosaminoglycans (GAGs) and bound plasma proteins form an interconnected gel-like structure on the surface of endothelial cells (the endothelial glycocalyx layer-EGL) that is stabilized by the interaction of its components. However, the structural organization of GAGs and proteins and the contribution of individual components to the stability of the EGL are largely unknown. To evaluate the hypothesis that the interconnected gel-like glycocalyx would collapse when individual GAG components were almost completely removed by a specific enzyme. Using confocal microscopy, we observed that the coverage and thickness of heparan sulfate (HS), chondroitin sulfate (CS), hyaluronic acid (HA), and adsorbed albumin were similar, and that the thicknesses of individual GAGs were spatially nonuniform. The individual GAGs were degraded by specific enzymes in a dose-dependent manner, and decreased much more in coverage than in thickness. Removal of HS or HA did not result in cleavage or collapse of any of the remaining components. Simultaneous removal of CS and HA by chondroitinase did not affect HS, but did reduce adsorbed albumin, although the effect was not large. All GAGs and adsorbed proteins are well inter-mixed within the structure of the EGL, but the GAG components do not interact with one another. The GAG components do provide binding sites for albumin. Our results provide a new view of the organization of the endothelial glycocalyx layer and provide the first demonstration of the interaction between individual GAG components.


"There's more to life than just walking": older women's ways of staying healthy and happy.
This study assessed a range of activities reported by older women in Australia. Women between 75 and 81 years of age (N = 3,955) from the older cohort of the Australian Longitudinal Study on Women's Health responded to a request in a self-report survey for additional information concerning their health. Of these 3,955 women, 509 reported taking part in a variety of activities. Qualitative analysis of responses identified 55 coded categories of activities that were subsequently classified into four major themes: physical activities, creative pursuits, lifestyle, and social interaction. The data show that these older women are taking part in a wide range of activities.


Progesterone and estrogen receptor expression and activity in human non-small cell lung cancer.
Lung cancer is the most common cause of cancer mortality in male and female patients in the US. Although it is clear that tobacco smoking is a major cause of lung cancer, about half of all women with lung cancer worldwide are never-smokers. Despite a declining smoking population, the incidence of non-small cell lung cancer (NSCLC), the predominant form of lung cancer, has reached epidemic proportions particularly in women. Emerging data suggest that factors other than tobacco, namely endogenous and exogenous female sex hormones, have a role in stimulating NSCLC progression. Aromatase, a key enzyme for estrogen biosynthesis, is expressed in NSCLC. Clinical data show that women with high levels of tumor aromatase (and high intratumoral estrogen) have worse survival than those with low aromatase. The present and previous studies also reveal significant expression and activity of estrogen receptors (ERα, ERβ) in both extranuclear and nuclear sites in most NSCLC. We now report further on the expression of progesterone receptor (PR) transcripts and protein in NSCLC. PR transcripts were significantly lower in cancerous as compared to non-malignant tissue. Using immunohistochemistry, expression of PR was observed in the nucleus and/or extranuclear compartments in the majority of human tumor specimens examined. Combinations of estrogen and progestins administered in vitro cooperate in promoting tumor secretion of vascular endothelial growth factor and, consequently, support tumor-associated angiogenesis. Further, dual treatment with estradiol and progestin increased the numbers of putative tumor stem/progenitor cells. Thus, ER- and/or PR-targeted therapies may offer new approaches to manage NSCLC.


Computation of effective groove depth in an optical disk with vector diffraction theory.
Results of vector diffraction simulations pertaining to the effective groove depth for various disks with different groove parameters, different coatings, and different incident polarizations are presented. The effective depth deviates from the physical depth if the track pitch approaches the wavelength of the light source. Moreover, the difference of the effective depth for the two polarization states is demonstrated. The effective depth is usually shallower than the physical depth, especially for deeper grooves. The ray-bending mechanism associated with the objective lens and the different response to s- and p-polarized light on reflection from the disk surface impact the effective depth for objective lenses with different numerical apertures.


A Comparison of Bispectral Index and Entropy During Sevoflurane Anesthesia Induction in Children with and without Diplegic Cerebral Palsy.
This study compared the correlation of bispectral index (BIS) or entropy with different sevoflurane concentrations between children with and without cerebral palsy (CP) during induction. For eighty-two children (40 CP and 42 non-CP children), anesthesia was induced with sevoflurane. BIS and entropy (response entropy and state entropy (RE and SE)) were recorded before and after the induction of anesthesia at end-tidal sevoflurane concentrations of 1-3 vol%. The sedation status was assessed using an Observer's Assessment of Alertness/Sedation scale. The ability to predict awareness was estimated using the area under the receiver-operator characteristic curve (AUC) analysis. RE, SE and BIS values decreased continuously over the observed concentration range of sevoflurane in both groups. The SE values while awake and the RE, SE, BIS values at 3 vol% sevoflurane were lower in children with CP than in those without CP. The AUC of the BIS was significantly better than RE or SE in children without CP. The AUC of the BIS was not significantly higher than that of the RE or SE in children with CP. BIS seems better correlated than entropy with the clinical state of loss of response in children without CP, but not in those with CP.


Including aspects of climate change into water safety planning: Literature review of global experience and case studies from Ethiopian urban supplies.
In recent years, the water safety plan approach has been extended towards climate-resilient water safety planning. This happened in response to increasing insight into impacts of climate on drinking-water and required adaptation to anticipated climate change. Literature was reviewed for published guidance and case examples, documenting how to consider climate in water safety planning to support future uptake. Climate-resilient water safety plans were piloted within a project in the water supplies of Addis Ababa and Adama, Ethiopia. Case examples have been published in four of six WHO regions with a focus on urban supplies. Integration of climate aspects focused mostly on the steps of establishing the team, system description, hazard analysis and risk assessment, improvement planning and development of management procedures. While the traditional framework focuses on drinking-water quality, considering climate change augments aspects of water quantity. Therefore, other factors affecting water quantity such as population development and demand of other sectors need to be considered as well. Local climate information and tools should be employed as a significant success factor for future uptake. Such information should be incorporated as it becomes available, and may - depending on the setting - be incrementally integrated into existing water safety plans or used to develop new ones.


Ligand-based and e-pharmacophore modeling, 3D-QSAR and hierarchical virtual screening to identify dual inhibitors of spleen tyrosine kinase (Syk) and janus kinase 3 (JAK3).
The clinical efficacy of multiple kinase inhibitors has caught the interest of Pharmaceutical and Biotech researchers to develop potential drugs with multi-kinase inhibitory activity for complex diseases. In the present work, we attempted to identify dual inhibitors of spleen tyrosine kinase (Syk) and janus kinase 3 (JAK3), keys players in immune signaling, by developing ideal pharmacophores integrating Ligand-based pharmacophore models (LBPMs) and Structure-based pharmacophore models (SBPMs), thereby projecting the optimum pharmacophoric required for inhibition of both the kinases. The four point LBPM; ADPR.14 suggested the presence of one hydrogen bond acceptor, one hydrogen bond donor, one positive ionizable, and one ring aromatic feature for Syk inhibitory activity and AADH.54 proposed the necessity of two hydrogen bond acceptor, one hydrogen bond donor, and one hydrophobic feature for JAK3 inhibitory activity. To our interest, SBPMs identified additional ring aromatic features required for inhibition of both the kinases. For Syk inhibitory activity, the hydrogen bond acceptor feature indicated by LBPM was devoid of forming hydrogen bonding interaction with the hinge region amino acid residue (Ala451). Thus merging the information revealed by both LBPMs and SBPMs, ideal pharmacophore models i.e. ADPRR.14 (Syk) and AADHR.54 (JAK3) were generated. These models after rigorous statistical validation were used for screening of Asinex database. The systematic virtual screening protocol, including pharmacophore and docking-based screening, ADME property, and MM-GBSA energy calculations, retrieved final 10 hits as dual inhibitors of Syk and JAK3. Final 10 hits thus obtained can aid in the development of potential therapeutic agents for autoimmune disorders. Also the top two hits were evaluated against both the enzymes.


Assessing the Clinical Competence of Health Care Professionals Who Perform Airway Suctioning in Adults.
Airway suctioning is an important health care intervention that can be associated with serious adverse effects. Given the risks involved with suctioning, it is important to ensure the clinical competence of health care professionals who perform it. A scoping review was conducted to identify the nature and extent of research related to the assessment of airway-suctioning competence for health care professionals working with adults. This included an examination of the assessment context, the type of suctioning and health care professionals being assessed, and the methods used to assess competence. Four scientific electronic databases (MEDLINE, EMBASE, CINAHL, and the Cochrane Library) were searched from inception to March 9, 2018. A gray literature search was also performed. Two reviewers independently screened articles and resources for inclusion, and data were extracted using a form created by the authors. Seventy full text articles and resources were screened for eligibility, with 36 included in the review. Endotracheal suctioning was the most common type, and intensive or critical care units were the primary setting of interest (28 of 36, 78%). Competence or a component of competence for nurses, nursing students, nursing assistants, or nurse technicians was specifically addressed in 97% (35 of 36) of the included articles and resources; 4 of 36 (11%) also included physical therapists, 1 of 36 (3%) included respiratory therapists, and 1 of 36 (3%) was aimed toward all clinicians who perform suctioning. Nine (25%) used questionnaire-based assessments, 11 (31%) used checklists, audit forms, or other observational tools, and 16 (44%) used both. Directed content analysis revealed 3 major themes: consistency across overarching evaluation frameworks, inconsistency across detailed components, and inconsistency in the evaluation or reporting of assessment tool measurement properties. Additional gaps in the literature included limited consideration of health care professionals beyond nursing, limited consideration of settings beyond intensive and critical care, a lack of tools to assess nasotracheal and orotracheal suctioning, and limited detail regarding assessment tool development.


Organic Food in the Diet: Exposure and Health Implications.
The market for organic food products is growing rapidly worldwide. Such foods meet certified organic standards for production, handling, processing, and marketing. Most notably, the use of synthetic fertilizers, pesticides, and genetic modification is not allowed. One major reason for the increased demand is the perception that organic food is more environmentally friendly and healthier than conventionally produced food. This review provides an update on market data and consumer preferences for organic food and summarizes the scientific evidence for compositional differences and health benefits of organic compared with conventionally produced food. Studies indicate some differences in favor of organic food, including indications of beneficial health effects. Organic foods convey lower pesticide residue exposure than do conventionally produced foods, but the impact of this on human health is not clear. Comparisons are complicated by organic food consumption being strongly correlated with several indicators of a healthy lifestyle and by conventional agriculture "best practices" often being quite close to those of organic.


Ultrasonic Sensing and Actuation in Laminate Structures Using Bondline-Embedded d35 Piezoelectric Sensors.
Ultrasonic systems employing embedded piezoelectric transducers have seen increased interest in recent years. The ability to sense, actuate, and analyze the wave propagation modes in engineering structures has been fundamental to the advancement of ultrasonic structural health monitoring (SHM). This paper presents a study into the sensing and actuation properties of shear-mode (d35) piezoelectric transducers made of lead zirconate titanate (PZT) that are internally embedded in the bondline of laminate structures. The manuscript presents analytical analysis, finite element simulation, and experimental validation building from an individual piezoelectric element to a full laminate structure. The validated model was then used to perform a parametric study into the effects of d35 PZT transducer size on the strength of actuation and sensing output signal. The selectivity of d35 PZT sensors was also investigated by generating multiple wave modes in the laminate structure and inspecting the output signals. The d35 PZT sensors were found to selectively detect only certain modes of the wave propagation providing a fundamental hardware filter that could be employed to simplify signal analysis and processing. The results of this study indicate that d35 PZTs embedded in the bondline have multiple properties that can potentially be employed for ultrasonic SHM.


LSD1/CoREST is an allosteric nanoscale clamp regulated by H3-histone-tail molecular recognition.
The complex of lysine-specific demethylase-1 (LSD1/KDM1A) with its corepressor protein CoREST is an exceptionally relevant target for epigenetic drugs. Here, we provide insight into the local and global changes of LSD1/CoREST conformational dynamics that occur upon H3 binding on the basis of a total cumulative time of one microsecond molecular dynamics simulation. The LSD1/CoREST complex functions as an allosteric nanoscale-binding clamp, which is regulated by substrate binding. In the unbound state, LSD1/CoREST reversibly visits clamp states that are more open or significantly more closed compared with the available X-ray crystal structures. The Lys triad of residues Lys355, Lys357, and Lys359 gates the entrance of the H3 pocket. H3 binding shifts the pocket breathing dynamics toward open, higher-volume states while reducing the overall flexibility of the LSD1/CoREST nanoscale clamp. We show that the H3 pocket is an allosteric site for the regulation of the rotation of the amino oxidase domain with respect to the Tower domain. The allosteric mechanism relies on the specific reduction of nanoscale domain rotation upon local H3-tail binding. Instead, clamp opening/closing motions that do not involve domain rotation only reduce in amplitude yet are dominant in the bound state. Overall, our data suggest that the H3 binding pocket is a central target site to (i) switch off LSD1 amino oxidase activity, thus H3-tail demethylation; (ii) block the competitive binding of transcription factors; and (iii) prevent chromatin anchoring to LSD1/CoREST. This study underscores the importance of receptor flexibility for future epigenetic drug discovery.


Stomach antral endocrine cells in patients with irritable bowel syndrome.
To the best of our knowledge, stomach antral endocrine cells have not previously been investigated in patients with irritable bowel syndrome (IBS). Thus, in the present study, 76 patients with IBS were examined (designated as IBS-total). Diarrhoea was the predominant symptom in 26 of these patients (IBS-D), while in 21 patients, the predominant symptoms were both diarrhoea and constipation (IBS-M) and in 29 patients the predominant symptom was constipation (IBS-C). Forty-three healthy subjects were enrolled as the controls. Stomach antral biopsy samples obtained from all of the subjects were immunostained using the avidin-biotin-complex method for serotonin, gastrin, somatostatin and serotonin transporter (SERT). The immunopositive cell densities and immunoreactivity intensities were determined by computer-aided image analysis. The density of the serotonin-immunoreactive cells was significantly decreased in the IBS-M patients and increased in the IBS-C patients relative to the controls. The immunoreactivity intensity did not differ significantly between the controls and IBS-total. The density of the gastrin-immunoreactive cells was significantly greater in the IBS-D, IBS-M and IBS-C patients than in the controls. The immunoreactivity intensity of gastrin was significantly greater in the IBS-D patients than in the controls. The density of the somatostatin-immunoreactive cells cells was significantly lower in the IBS-total, IBS-D, IBS-M and IBS-C patients than in the controls. The immunoreactivity intensities of both somatostatin and SERT did not differ significantly between the controls and IBS-total. The increase in gastrin cell density and the decrease in somatostatin cell density in all IBS subtypes may cause high levels of gastric secretion, which may in turn contribute to the high incidence of dyspepsia and gastro-oesophageal reflux observed in patients with IBS.


Plasma surfactant protein-B: a novel biomarker in chronic heart failure.
In chronic heart failure (CHF), elevated pulmonary microvascular pressure (P(mv)) results in pulmonary edema. Because elevated P(mv) may alter the integrity of the alveolocapillary barrier, allowing leakage of surfactant protein-B (SP-B) from the alveoli into the circulation, we aimed to determine plasma levels of SP-B in CHF and their relation to clinical status. Fifty-three outpatients with CHF had plasma SP-B and N-terminal proBNP (NT-proBNP) assayed, in addition to a formalized clinical assessment at each clinic review over a period of 18 months. The control group comprised 19 normal volunteers. Plasma SP-B was elevated in CHF (P<0.001), and levels increased with New York Heart Association classification (P<0.001). SP-B correlated with objective clinical status parameters and NT-proBNP. During follow-up, major cardiovascular events occurred in patients with higher plasma SP-B (P<0.01) and NT-proBNP (P<0.05). Furthermore, on conditional logistic regression analysis, only SP-B was independently associated with CHF hospitalization (P=0.005). The 53 patients underwent a total of 210 outpatient visits. When the diuretic dosage was increased on clinical grounds, SP-B had increased 39% (P<0.001) and NT-proBNP had increased 32% (P<0.001). Conversely, at the next visit, SP-B fell 12% (P<0.001), whereas NT-proBNP fell 39% (P<0.001). Plasma SP-B is increased in CHF, and levels are related to clinical severity. Furthermore, within individual patients, SP-B levels vary with dynamic clinical status and NT-proBNP levels. Because plasma SP-B is independently associated with CHF hospitalization, it may, by virtue of its differing release mechanism to NT-proBNP, be a clinically useful biomarker of the pulmonary consequences of raised P(mv).


The N-acetylation of sulfamethazine and p-aminobenzoic acid by human liver slices in dynamic organ culture.
N-Acetyltransferase (NAT) polymorphism has been implicated in differences in the susceptibility of individuals to the toxicity of chemicals metabolized by this enzyme system. Investigation into the toxicological consequences of acetylator polymorphism and the mechanism of these effects in humans, however, has been greatly hindered due to the lack of a suitable human tissue culture system for determination of hepatic NAT activity and acetylator status of individuals. An in vitro system has been developed to study NAT activity using human liver slices in dynamic organ culture. Acetylation of para-aminobenzoic acid (PABA) and sulfamethazine (SMZ) by human liver slices was monitored by measuring the disappearance of the parent amine from the incubation medium using the colorimetric procedure of Bratton and Marshall. Presence of the acetyl conjugate was confirmed using HPLC. PABA acetylation rates varied from 0.72-2.52 nmol/hr/mg protein (N = 8). This small variation (less than 4-fold) is consistent with the classification of PABA as a monomorphic substrate. The variation in the rate of SMZ acetylation was greater than 20-fold (0.144-3.68 nmol/hr/mg protein; N = 9). This larger variation is characteristic of SMZ as a polymorphic substrate. A good correlation of N-acetylation activities for SMZ was also found between cytosol and slices prepared from the same human livers. The results obtained indicate that human liver slices in dynamic organ culture can be used for the determination of hepatic NAT activity in humans. These slices may be useful in toxicological studies that seek to relate N-acetylation of chemicals in the human liver with potential toxicity.


Microdroplet chain array for cell migration assays.
Establishing cell migration assays in multiple different microenvironments is important in the study of tissue repair and regeneration, cancer progression, atherosclerosis, and arthritis. In this work, we developed a miniaturized and massive parallel microfluidic platform for multiple cell migration assays combining the traditional membrane-based cell migration technique and the droplet-based microfluidic technique. Nanoliter-scale droplets are flexibly assembled as building blocks based on a porous membrane to form microdroplet chains with diverse configurations for different assay modes. Multiple operations including in-droplet 2D/3D cell culture, cell co-culture and cell migration induced by a chemoattractant concentration gradient in droplet chains could be flexibly performed with reagent consumption in the nanoliter range for each assay and an assay scale-up to 81 assays in parallel in one microchip. We have applied the present platform to multiple modes of cell migration assays including the accurate cell migration assay, competitive cell migration assay, biomimetic chemotaxis assay, and multifactor cell migration assay based on the organ-on-a-chip concept, for demonstrating its versatility, applicability, and potential in cell migration-related research.


Effectiveness of different types of motorcycle helmets and effects of their improper use on head injuries.
Differences among three helmet types and the ineffectiveness of improper helmet use in preventing head injuries are speculated about but are seldom explored with evidence. A case-control study was conducted to examine how different helmet types and improper helmet use affected protection against head injuries among motorcyclists in Taiwan. Case motorcyclists comprised 435 persons who sought emergency care due to head injuries at a medical centre in west-central Taiwan over an 8-month period and 23 motorcyclists who died from head injuries at the scene of the crash; 458 motorcyclists who had non-head injuries were used as the control group, and their crashes occurred within 1 hour earlier or later than the corresponding cases. Information on helmet type was validated by interviewing motorcyclists who were refuelling at petrol stations. A conditional logistic regression analysis showed that compared with helmeted motorcyclists, non-helmeted motorcyclists were more than four times as likely to have head injuries [odds ratio (OR) 4.54; 95% confidence interval (CI) 1.25-16.5] and ten times as likely to have brain injuries (OR 10.4; 95% CI 1.82-59.2). Compared with motorcyclists wearing full-face helmets, those wearing half-coverage helmets were more than twice as likely to have head injuries (OR 2.57; 95% CI 1.50-4.40) and brain injuries (OR 2.10; 95% CI 1.01-4.38). Compared with motorcyclists with firmly fastened helmets, those with loosely fastened helmets increased their risk of head injury (OR 1.94; 95% CI 1.33-2.82) and were more than twice as likely to have brain injuries (OR 2.50; 95% CI 1.47-4.25). Of the three helmet types, half-coverage helmets provided motorcyclists the least protection from head injuries. Furthermore, wearing a loosely fastened helmet may compromise any potential protection.


Genetic Structure across Broad Spatial and Temporal Scales: Rocky Mountain Tailed Frogs (Ascaphus montanus; Anura: Ascaphidae) in the Inland Temperate Rainforest.
Contemporary and historical processes interact to structure genetic variation, however discerning between these can be difficult. Here, we analyze range-wide variation at 13 microsatellite loci in 2098 Rocky Mountain tailed frogs, Ascaphus montanus, collected from 117 streams across the species distribution in the Inland Northwest (INW) and interpret that variation in light of historical phylogeography, contemporary landscape genetics, and the reconstructed paleodistribution of the species. Further, we project species distribution models (SDMs) to predict future changes in the range as a function of changing climate. Genetic structure has a strong spatial signature that is precisely congruent with a deep (~1.8 MY) phylogeographic split in mtDNA when we partition populations into 2 clusters (K = 2), and is congruent with refugia areas inferred from our paleorange reconstructions. There is a hierarchical pattern of geographic structure as we permit additional clusters, with populations clustering following mountain ranges. Nevertheless, genetic diversity is the highest in populations at the center of the range and is attenuated in populations closer to the range edges. Similarly, geographic distance is the single best predictor of pairwise genetic differentiation, but connectivity also is an important predictor. At intermediate and local geographic scales, deviations from isolation-by-distance are more apparent, at least in the northern portion of the distribution. These results indicate that both historical and landscape factors are contributing to the genetic structure and diversity of tailed frogs in the Inland Northwest.


Mast cells initiate early anti-Listeria host defences.
The Gram-positive bacterium Listeria monocytogenes (L. m.) is the aetiological agent of listeriosis. The early phase listeriosis is characterized by strong innate host responses that play a major role in bacterial clearance. This is emphasized by the fact that mice deficient in T and B cells have a remarkable ability to control infection. Mast cells, among the principal effectors of innate immunity, have largely been studied in the context of hyper-reactive conditions such as allergy and autoimmune diseases. In the present study, we evaluated the significance of mast cells during the early phase of listeriosis. Compared with controls, mice depleted of mast cells showed hundred-fold higher bacterial burden in spleen and liver and were significantly impaired in neutrophil mobilization. Although L. m. interacts with and triggers mast cell degranulation, bacteria were hardly found within such cells. Mainly neutrophils and macrophages phagozytosed L. m. Thus, mast cells control infection not via direct bacterial uptake, but by initiating neutrophils influx to the site of infection. We show that this is initiated by pre-synthesized TNF-alpha, rapidly secreted by mast cell upon activation by L. m. We also show that upon recruitment, neutrophils also become activated and additionally secrete TNF-alpha thus amplifying the anti-L. m. inflammatory response.


Modification and implementation of NCCN guidelines on lymphomas in the Middle East and North Africa region.
In the Middle East and North Africa (MENA) region, cancer has many epidemiologic and clinical features that are different from those in the rest of the world. Additionally, the region has a relatively young population and large disparities in the availability of resources at diagnostic and treatment levels. A critical need exists for regional guidelines on cancer care, including those for lymphoid malignancies. A panel of lymphoma experts from MENA reviewed the 2009 version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Non-Hodgkin's Lymphoma and Hodgkin Lymphoma and suggested modifications for the region that were discussed with the United States NCCN Lymphoma Panels. This article presents the consensus recommendations.


Polydopamine films change their physicochemical and antimicrobial properties with a change in reaction conditions.
The morphology and physicochemical properties of polydopamine are not totally inherent and undergo changes with differing reaction conditions like the choice of solvent used for polymerization. The polymerisation of dopamine to polydopamine carried out in different solvents like sodium hydroxide, sodium bicarbonate, PBS and Tris leads to polydopamine with exceptionally different morphological and physicochemical features with each solvent. Additionally, the different physicochemical characteristics and morphologies bestow the polymer films with different extents of antimicrobial activity. Moreover, the findings supported by chemical evidence from X-ray photoelectron spectroscopy reveal that higher antibacterial activities were obtained against E. coli and S. aureus with polydopamine films prepared by Tris and NaOH solvent induced polymerization. The antibacterial activity observed in saline was found to be higher than that in PBS medium for both E. coli and S. aureus. The higher antibacterial activity of polydopamine films prepared in Tris and NaOH solvents was attributed to the covalent incorporation of -OH groups on the surface provided by nucleophilic Tris and NaOH solvents during the polymerisation process. The distinct physicochemical and morphological changes were supported by the results from contact angle measurements, FE-SEM, EDAX, AFM, and XPS analysis. The present finding provides insight into the different chemistry, morphologies and properties of the designed polydopamine films with controlled antibacterial/antifouling properties. Additionally, new insights into the mechanism of formation, physicochemical changes in morphology and properties of polydopamine coatings were revealed.


Bimetallic Nickel/Ruthenium Catalysts Synthesized by Atomic Layer Deposition for Low-Temperature Direct Methanol Solid Oxide Fuel Cells.
Nickel and ruthenium bimetallic catalysts were heterogeneously synthesized via atomic layer deposition (ALD) for use as the anode of direct methanol solid oxide fuel cells (DMSOFCs) operating in a low-temperature range. The presence of highly dispersed ALD Ru islands over a porous Ni mesh was confirmed, and the Ni/ALD Ru anode microstructure was observed. Fuel cell tests were conducted using Ni-only and Ni/ALD Ru anodes with approximately 350 μm thick gadolinium-doped ceria electrolytes and platinum cathodes. The performance of fuel cells was assessed using pure methanol at operating temperatures of 300-400 °C. Micromorphological changes of the anode after cell operation were investigated, and the content of adsorbed carbon on the anode side of the operated samples was measured. The difference in the maximum power density between samples utilizing Ni/ALD Ru and Pt/ALD Ru, the latter being the best catalyst for direct methanol fuel cells, was observed to be less than 7% at 300 °C and 30% at 350 °C. The improved electrochemical activity of the Ni/ALD Ru anode compared to that of the Ni-only anode, along with the reduction of the number of catalytically active sites due to agglomeration of Ni and carbon formation on the Ni surface as compared to Pt, explains this decent performance.


Women and hysteria in the history of mental health.
Hysteria is undoubtedly the first mental disorder attributable to women, accurately described in the second millennium BC, and until Freud considered an exclusively female disease. Over 4000 years of history, this disease was considered from two perspectives: scientific and demonological. It was cured with herbs, sex or sexual abstinence, punished and purified with fire for its association with sorcery and finally, clinically studied as a disease and treated with innovative therapies. However, even at the end of 19(th) century, scientific innovation had still not reached some places, where the only known therapies were those proposed by Galen. During the 20(th) century several studies postulated the decline of hysteria amongst occidental patients (both women and men) and the escalating of this disorder in non-Western countries. The concept of hysterical neurosis is deleted with the 1980 DSM-III. The evolution of these diseases seems to be a factor linked with social "westernization", and examining under what conditions the symptoms first became common in different societies became a priority for recent studies over risk factor.


Estimating the Natural History of Cervical Carcinogenesis Using Simulation Models: A CISNET Comparative Analysis.
The natural history of human papillomavirus (HPV)-induced cervical cancer (CC) is not directly observable, yet the age of HPV acquisition and duration of preclinical disease (dwell time) influences the effectiveness of alternative preventive policies. We performed a Cancer Intervention and Surveillance Modeling Network (CISNET) comparative modeling analysis to characterize the age of acquisition of cancer-causing HPV infections and implied dwell times for distinct phases of cervical carcinogenesis. Using four CISNET-cervical models with varying underlying structures but fit to common US epidemiological data, we estimated the age of acquisition of causal HPV infections and dwell times associated with three phases of cancer development: HPV, high-grade precancer, and cancer sojourn time. We stratified these estimates by HPV genotype under both natural history and CC screening scenarios, because screening prevents cancer development that affects the mix of detected cancers. The median time from HPV acquisition to cancer detection ranged from 17.5 to 26.0 years across the four models. Three models projected that 50% of unscreened women acquired their causal HPV infection between ages 19 and 23 years, whereas one model projected these infections occurred later (age 34 years). In the context of imperfect compliance with US screening guidelines, the median age of causal infection was 4.4-15.9 years later compared with model projections in the absence of screening. These validated CISNET-CC models, which reflect some uncertainty in the development of CC, elucidate important drivers of HPV vaccination and CC screening policies and emphasize the value of comparative modeling when evaluating public health policies.


Unmet health care need and income-Related horizontal equity in use of health care during the COVID-19 pandemic.
Using monthly data from the Understanding Society (UKHLS) COVID-19 Survey we analyse the evolution of unmet need and assess how the UK health care system performed against the principle of horizontal equity in health care use during the first wave of COVID-19 wave. Unmet need was most evident for hospital care, and less pronounced for primary health services (non-emergency medical helplines, GP consultations, community pharmacist advice, over the counter medications and prescriptions). Despite this, there is no evidence that horizontal equity, with respect to income, was violated for NHS hospital outpatient and inpatient care during the first wave of the pandemic. There is evidence of pro-rich inequities in use of GP consultations, prescriptions and medical helplines at the peak of the first wave, but these were eliminated as the pandemic progressed. There are persistent pro-rich inequities for services that may relate to individuals' ability to pay (over the counter medications and advice from community pharmacists).


Proteomic analysis of Oesophagostomum dentatum (Nematoda) during larval transition, and the effects of hydrolase inhibitors on development.
In this study, in vitro drug testing was combined with proteomic and bioinformatic analyses to identify and characterize proteins involved in larval development of Oesophagostomum dentatum, an economically important parasitic nematode. Four hydrolase inhibitors ο-phenanthroline, sodium fluoride, iodoacetamide and 1,2-epoxy-3-(pnitrophenoxy)-propane (EPNP) significantly inhibited (≥90%) larval development. Comparison of the proteomic profiles of the development-inhibited larvae with those of uninhibited control larvae using two-dimensional gel electrophoresis, and subsequent MALDI-TOF mass spectrometric analysis identified a down-regulation of 12 proteins inferred to be involved in various larval developmental processes, including post-embryonic development and growth. Furthermore, three proteins (i.e. intermediate filament protein B, tropomyosin and peptidyl-prolyl cis-trans isomerase) inferred to be involved in the moulting process were down-regulated in moulting- and development-inhibited O. dentatum larvae. This first proteomic map of O. dentatum larvae provides insights in the protein profile of larval development in this parasitic nematode, and significantly improves our understanding of the fundamental biology of its development. The results and the approach used might assist in developing new interventions against parasitic nematodes by blocking or disrupting their key biological pathways.


Chitosan-gold nanocomposite and its functionalized paper strips for reversible visual sensing and removal of trace Hg2+ in practice.
To eliminate mercury contamination in aqueous environment, chitosan-gold nanocomposite and its functionalized paper strips were designed and developed for visual sensing and removal of trace Hg2+. By simply immersing a common filter paper into the resultant composite dispersion, gold nanochromophores could be well dispersed with minor aggregation by virtue of the dual supporting roles of the chitosan and the filter paper. Under optimized conditions, the colour of both the chitosan-gold nanocomposite and its functionalized paper strips could change from dark red to yellow upon addition of Hg2+, with a detection limit of 3.2 × 10-9 mol L-1 and 5.0 × 10-8 mol L-1, respectively. Importantly, the chitosan-gold nanocomposite was non-toxic and could be utilized repeatedly for sensing trace Hg2+ in both environmental aqueous solutions and some fruit or vegetable juice samples, with satisfactory results. Furthermore, using the resulting functionalized filter-paper, more than 93.5% Hg2+ in aqueous solution with an initial concentration as high as 1.0 × 10-5 mol L-1 could be enriched and separated by a simple filtration process. The proposed operating mechanism is based on the reversible gold amalgam formation between the gold nanoparticles and Hg2+. This study will be the first report for paper-based sensing to visually detect, enrich and remove Hg2+ with minimal secondary pollution.


Risk factors for mortality and effect of correct fluid prescription in children with diarrhoea and dehydration without severe acute malnutrition admitted to Kenyan hospitals: an observational, association study.
Diarrhoea causes many deaths in children younger than 5 years and identification of risk factors for death is considered a global priority. The effectiveness of currently recommended fluid management for dehydration in routine settings has also not been examined. For this observational, association study, we analysed prospective clinical data on admission, immediate treatment, and discharge of children age 1-59 months with diarrhoea and dehydration, which were routinely collected from 13 Kenyan hospitals. We analysed participants with full datasets using multivariable mixed-effects logistic regression to assess risk factors for in-hospital death and effect of correct rehydration on early mortality (within 2 days). Between Oct 1, 2013, and Dec 1, 2016, 8562 children with diarrhoea and dehydration were admitted to hospital and eligible for inclusion in this analysis. Overall mortality was 9% (759 of 8562 participants) and case fatality was directly correlated with severity. Most children (7184 [84%] of 8562) with diarrhoea and dehydration had at least one additional diagnosis (comorbidity). Age of 12 months or younger (adjusted odds ratio [AOR] 1·71, 95% CI 1·42-2·06), female sex (1·41, 1·19-1·66), diarrhoea duration of more than 14 days (2·10, 1·42-3·12), abnormal respiratory signs (3·62, 2·95-4·44), abnormal circulatory signs (2·29, 1·89-2·77), pallor (2·15, 1·76-2·62), use of intravenous fluid (proxy for severity; 1·68, 1·41-2·00), and abnormal neurological signs (3·07, 2·54-3·70) were independently associated with in-hospital mortality across hospitals. Signs of dehydration alone were not associated with in-hospital deaths (AOR 1·08, 0·87-1·35). Correct fluid prescription significantly reduced the risk of early mortality (within 2 days) in all subgroups: abnormal respiratory signs (AOR 1·23, 0·68-2·24), abnormal circulatory signs (0·95, 0·53-1·73), pallor (1·70, 0·95-3·02), dehydration signs only (1·50, 0·79-2·88), and abnormal neurological signs (0·86, 0·51-1·48). Children at risk of in-hospital death are those with complex presentations rather than uncomplicated dehydration, and the prescription of recommended rehydration guidelines reduces risk of death. Strategies to optimise the delivery of recommended guidance should be accompanied by studies on the management of dehydration in children with comorbidities, the vulnerability of young girls, and the delivery of immediate care. The Wellcome Trust.