Single- vs. multiple-set resistance training: recent developments in the controversy.
The number of sets in a resistance training program remains a major point of discussion and controversy. Studies prior to 1998 demonstrated inconsistent findings between single-set and multiple-set programs; however, recent evidence suggests that multiple sets promote additional benefits following short- and long-term training. The rationale supporting multiple sets is that the number of sets is part of the exercise volume equation, and the volume of exercise is crucial in producing the stimulus necessary to elicit specific physiological adaptations. The purpose of this paper is to present an overview of recent resistance training studies comparing single and multiple sets. However, it should be noted that studies to date have been conducted in young and middle-aged adults, and it remains to be determined if the additional benefits accrued with multiple-set training also occurs for older adults, especially the frail elderly.


Development of an occupational advice intervention for patients undergoing lower limb arthroplasty (the OPAL study).
There are an increasing number of patients of working age undergoing hip and knee replacements. Currently there is variation in the advice and support given about sickness absence, recovery to usual activities and return to work after these procedures. Earlier, sustainable, return to work improves the health of patients and benefits their employers and society. An intervention that encourages and supports early recovery to usual activities, including work, has the potential to reduce the health and socioeconomic burden of hip and knee replacements. A two-phase research programme delivered over 27 months will be used to develop and subsequently test the feasibility of an occupational advice intervention to facilitate return to work and usual activities in patients undergoing lower limb arthroplasty. The 2 phases will incorporate a six-stage intervention mapping process: Phase 1: Intervention mapping stages 1-3: 1 Needs assessment (including rapid evidence synthesis, prospective cohort analysis and structured stakeholder interviews) 2 Identification of intended outcomes and performance objectives 3 Selection of theory-based methods and practical strategies Phase 2: Intervention mapping stages 4-6: 4 Development of components and materials for the occupational advice intervention using a modified Delphi process 5 Adoption and implementation of the intervention 6 Evaluation and feasibility testing The study will be undertaken in four National Health Service (NHS) hospitals in the United Kingdom and two Higher Education Institutions. OPAL (Occupational advice for Patients undergoing Arthroplasty of the Lower limb) aims to develop an occupational advice intervention to support early recovery to usual activities including work, which is tailored to the requirements of patients undergoing hip and knee replacements. The developed intervention will then be assessed with a specific focus on evaluating its feasibility as a potential trial intervention to improve speed of recovery to usual activities including work. The study was registered retrospectively with the International Standard Randomised Controlled Trials Number (ISRCTN): 27426982 (Date 20/12/2016) and the International prospective register of systematic reviews (PROSPERO): CRD42016045235 (Date 04/08/2016).


Characterization of the maize gene sugary1, a determinant of starch composition in kernels.
In maize kernels, mutations in the gene sugary1 (su1) result in (1) increased sucrose concentration; (2) decreased concentration of amylopectin, the branched component of starch; and (3) accumulation of the highly branched glucopolysaccharide phytoglycogen. To investigate further the mechanisms of storage carbohydrate synthesis in maize, part of the su1 gene locus and a cDNA copy of the su1 transcript were characterized. Five new su1 mutations were isolated in a Mutator background, and the mutant allele su1-R4582::Mu1 was isolated by transposon tagging. The identity of the cloned element as the su1 gene locus was confirmed by the cosegregation of restriction fragment length polymorphisms in the same or nearby genomic intervals with three additional, independent su1 mutations. Pedigree analysis was also used to confirm the identity of su1. A 2.8-kb mRNA that is homologous to the cloned gene was detected in maize kernels, and a 2.7-kb cDNA clone was isolated based on hybridization to the genomic DNA. Specific portions of the cDNA hybridized with multiple segments of the maize genome, suggesting that su1 is part of a multigene family. The cDNA sequence specified a polypeptide of at least 742 amino acids, which is highly similar in amino acid sequence to bacterial enzymes that hydrolyze alpha-(1-->6) glucosyl linkages of starch. Therefore, debranching of glucopolysaccharides is seemingly part of the normal process of starch biosynthesis, and the final degree of branch linkages in starch most likely arises from the combined actions of branching and debranching enzymes.


Myocardial smad4 is essential for cardiogenesis in mouse embryos.
Congenital heart diseases are the most commonly observed human birth defects and are the leading cause of infant morbidity and mortality. Accumulating evidence indicates that transforming growth factor-beta/bone morphogenetic protein signaling pathways play critical roles during cardiogenesis. Smad4 encodes the only common Smad protein in mammals, which is a critical nuclear mediator of transforming growth factor-beta/bone morphogenetic protein signaling. The aim of this work was to investigate the roles of Smad4 during heart development. To overcome the early embryonic lethality of Smad4(-/-) mice, we specifically disrupted Smad4 in the myocardium using a Cre/loxP system. We show that myocardial-specific inactivation of Smad4 caused heart failure and embryonic lethality at midgestation. Histological analysis revealed that mutant mice displayed a hypocellular myocardial wall defect, which is likely the primary cause for heart failure. Both decreased cell proliferation and increased apoptosis contributed to the myocardial wall defect in mutant mice. Data presented in this article contradict a previous report showing that Smad4 is dispensable for heart development. Our further molecular characterization showed that expression of Nmyc and its downstream targets, including cyclin D1, cyclin D2, and Id2, were downregulated in mutant embryos. Reporter analysis indicated that the transcriptional activity of the 351-bp Nmyc promoter can be positively regulated by bone morphogenetic protein stimulation and negatively regulated by transforming growth factor-beta stimulation. Chromatin immunoprecipitation analysis revealed that the Nmyc promoter can form a complex with Smad4, suggesting that Nmyc is a direct downstream target of Smad4. In conclusion, this study provides the first mouse model showing that Smad4 plays essential roles during cardiogenesis.


Toward a Comprehensive Treatment of Tautomerism in Chemoinformatics Including in InChI V2.
We have collected 86 different transforms of tautomeric interconversions. Out of those, 54 are for prototropic (non-ring-chain) tautomerism, 21 for ring-chain tautomerism, and 11 for valence tautomerism. The majority of these rules have been extracted from experimental literature. Twenty rules, covering the most well-known types of tautomerism such as keto-enol tautomerism, were taken from the default handling of tautomerism by the chemoinformatics toolkit CACTVS. The rules were analyzed against nine differerent databases totaling over 400 million (non-unique) structures as to their occurrence rates, mutual overlap in coverage, and recapitulation of the rules' enumerated tautomer sets by InChI V.1.05, both in InChI's Standard and a Nonstandard version with the increased tautomer-handling options 15T and KET turned on. These results and the background of this study are discussed in the context of the IUPAC InChI Project tasked with the redesign of handling of tautomerism for an InChI version 2. Applying the rules presented in this paper would approximately triple the number of compounds in typical small-molecule databases that would be affected by tautomeric interconversion by InChI V2. A web tool has been created to test these rules at https://cactus.nci.nih.gov/tautomerizer.


A function for EHD family proteins in unidirectional retrograde dendritic transport of BACE1 and Alzheimer's disease Aβ production.
Abnormal accumulation of β-secretase (BACE1) in dystrophic neurites and presynaptic β-amyloid (Aβ) production contribute to Alzheimer's disease pathogenesis. Little, however, is known about BACE1 sorting and dynamic transport in neurons. We investigated BACE1 trafficking in hippocampal neurons using live-cell imaging and selective labeling. We report that transport vesicles containing internalized BACE1 in dendrites undergo exclusive retrograde transport toward the soma, whereas they undergo bidirectional transport in axons. Unidirectional dendritic transport requires Eps15-homology-domain-containing (EHD) 1 and 3 protein function. Furthermore, loss of EHD function compromises dynamic axonal transport and overall BACE1 levels in axons. EHD1/3 colocalize with BACE1 and APP β-C-terminal fragments in hippocampal mossy fiber terminals, and their depletion in neurons significantly attenuates Aβ levels. These results demonstrate unidirectional endocytic transport of a dendritic cargo and reveal a role for EHD proteins in neuronal BACE1 transcytosis and Aβ production, processes that are highly relevant for Alzheimer's disease.


Neuroendocrine and oxidoreductive mechanisms of stress-induced cardiovascular diseases.
The review concerns a number of basic molecular pathways that play a crucial role in perception, transmission, and modulation of the stress signals, and mediate the adaptation of the vital processes in the cardiovascular system (CVS). These highly complex systems for intracellular transfer of information include stress hormones and their receptors, stress-activated phosphoprotein kinases, stress-activated heat shock proteins, and antioxidant enzymes maintaining oxidoreductive homeostasis of the CVS. Failure to compensate for the deleterious effects of stress may result in the development of different pathophysiological states of the CVS, such as ischemia, hypertension, atherosclerosis and infarction. Stress-induced dysbalance in each of the CVS molecular signaling systems and their contribution to the CVS malfunctioning is reviewed. The general picture of the molecular mechanisms of the stress-induced pathophysiology in the CVS pointed out the importance of stress duration and intensity as etiological factors, and suggested that future studies should be complemented by the careful insights into the individual factors of susceptibility to stress, prophylactic effects of 'healthy' life styles and beneficial action of antioxidant-rich nutrition.


A qualitative study exploring women's beliefs about physical activity after stillbirth.
Research provides strong evidence for improvements in depressive symptoms as a result of physical activity participation in many populations including pregnant and post-partum women. Little is known about how women who have experienced stillbirth (defined as fetal death at 20 or more weeks of gestation) feel about physical activity or use physical activity following this experience. The purpose of this study was to qualitatively explore women's beliefs about physical activity following a stillbirth. This was an exploratory qualitative research study. Participants were English-speaking women between the ages of 19 and 44 years who experienced a stillbirth in the past year from their recruitment date. Interviews were conducted over the phone or in-person based on participants' preferences and location of residence and approximately 30-45 minutes in length. Twenty-four women participated in the study (M age = 33 ± 3.68 years; M time since stillbirth = 6.33 ± 3.06 months). Women's beliefs about physical activity after stillbirth were coded into the following major themes: barriers to physical activity (emotional symptoms and lack of motivation, tired, lack of time, guilt, letting go of a pregnant body, and seeing other babies), benefits to physical activity (feeling better emotionally/mentally, helping women to cope or be therapeutic), importance of physical activity (working through grief, time for self), motivators for physical activity (body shape/weight, health, more children, be a role model, already an exerciser). Health care providers and their role in physical activity participation was also a major theme. This is the first study to qualitatively explore beliefs about physical activity in women after a stillbirth. Women who have experienced stillbirth have unique beliefs about physical activity related to their experience with stillbirth. Findings from this study may help to improve the health and quality of life for women who have experienced stillbirth by utilizing physical activity as a strategy for improving depressive symptoms associated with experiencing a stillbirth. Future research in this area is highly warranted.


miRNA in the regulation of ion channel/transporter expression.
Ion channels and transporters are expressed in every living cell, where they participate in controlling a plethora of biological processes and physiological functions, such as excitation of cells in response to stimulation, electrical activities of cells, excitation-contraction coupling, cellular osmolarity, and even cell growth and death. Alterations of ion channels/transporters can have profound impacts on the cellular physiology associated with these proteins. Expression of ion channels/transporters is tightly regulated and expression deregulation can trigger abnormal processes, leading to pathogenesis, the channelopathies. While transcription factors play a critical role in controlling the transcriptome of ion channels/transporters at the transcriptional level by acting on the 5'-flanking region of the genes, microribonucleic acids (miRNAs), a newly discovered class of regulators in the gene network, are also crucial for expression regulation at the posttranscriptional level through binding to the 3'untranslated region of the genes. These small noncoding RNAs fine tune expression of genes involved in a wide variety of cellular processes. Recent studies revealed the role of miRNAs in regulating expression of ion channels/transporters and the associated physiological functions. miRNAs can target ion channel genes to alter cardiac excitability (conduction, repolarization, and automaticity) and affect arrhythmogenic potential of heart. They can modulate circadian rhythm, pain threshold, neuroadaptation to alcohol, brain edema, etc., through targeting ion channel genes in the neuronal systems. miRNAs can also control cell growth and tumorigenesis by acting on the relevant ion channel genes. Future studies are expected to rapidly increase to unravel a new repertoire of ion channels/transporters for miRNA regulation.


Gut Peptide Agonism in the Treatment of Obesity and Diabetes.
Obesity is a global healthcare challenge that gives rise to devastating diseases such as the metabolic syndrome, type-2 diabetes (T2D), and a variety of cardiovascular diseases. The escalating prevalence of obesity has led to an increased interest in pharmacological options to counteract excess weight gain. Gastrointestinal hormones such as glucagon, amylin, and glucagon-like peptide-1 (GLP-1) are well recognized for influencing food intake and satiety, but the therapeutic potential of these native peptides is overall limited by a short half-life and an often dose-dependent appearance of unwanted effects. Recent clinical success of chemically optimized GLP-1 mimetics with improved pharmacokinetics and sustained action has propelled pharmacological interest in using bioengineered gut hormones to treat obesity and diabetes. In this article, we summarize the basic biology and signaling mechanisms of selected gut peptides and discuss how they regulate systemic energy and glucose metabolism. Subsequently, we focus on the design and evaluation of unimolecular drugs that combine the beneficial effects of selected gut hormones into a single entity to optimize the beneficial impact on systems metabolism. © 2020 American Physiological Society. Compr Physiol 10:99-124, 2020.


Activation and perceived expectancies: correlations with health outcomes among veterans with inflammatory bowel disease.
Inflammatory bowel disease imposes psychosocial stress on the patient. Patients' adaptive capacities may predict quality of life. We examined two adaptive capacity measures and their association with quality of life. Cross-sectional mail survey of patients with inflammatory bowel disease. The Patient Activation Measure (PAM) assesses knowledge, skill, and confidence in self-health management. The Perceived Expectancies Index (PEI) measures perceived competence and dispositional optimism. Four hundred and seventy-seven veterans at VA-Tennessee Valley Healthcare System. Primary outcome was health-related quality of life (measured by the Short Inflammatory Bowel Disease Questionnaire). Bivariate analysis assessed unadjusted correlations. Sequential multivariate linear regression tested theoretical model relationships by calculating the variation in each dependent variable accounted for by independent variables (R-squared statistic). Two hundred and sixty surveys were returned with usable data (54.5%). Median age was 63 years (range 19-91); 90.8% were men and 86.9% self-identified as white. Fifty percent reported having ulcerative colitis, 36.5% Crohn's disease, and 12.3% uncertain type. Unadjusted bivariate analysis revealed positive correlations between the PAM and PEI and the Short Inflammatory Bowel Disease Questionnaire (correlation coefficient = 0.35 and 0.60, respectively; p < 0.0001). Multivariate model including the PAM accounted for 26% of the variation in Short Inflammatory Bowel Disease Questionnaire scores, while the model including the PEI accounted for 50% (p < 0.0001). There are positive, highly significant correlations between adaptive capacities and health-related quality of life in patients with inflammatory bowel disease.


Anxiolytic Treatment Impairs Helping Behavior in Rats.
Despite decades of research with humans, the biological mechanisms that motivate an individual to help others remain poorly understood. In order to investigate the roots of pro-sociality in mammals, we established the helping behavior test, a paradigm in which rats are faced with a conspecific trapped in a restrainer that can only be opened from the outside. Over the course of repeated test sessions, rats exposed to a trapped cagemate learn to open the door to the restrainer, thereby helping the trapped rat to escape (Ben-Ami Bartal et al., 2011). The discovery of this natural behavior provides a unique opportunity to probe the motivation of rodent helping behavior, leading to a deeper understanding of biological influences on human pro-sociality. To determine if an affective response motivates door-opening, rats receiving midazolam, a benzodiazepine anxiolytic, were tested in the helping behavior test. Midazolam-treated rats showed less helping behavior than saline-treated rats or rats receiving no injection. Yet, midazolam-treated rats opened a restrainer containing chocolate, highlighting the socially specific effects of the anxiolytic. To determine if midazolam interferes with helping through a sympatholytic effect, the peripherally restricted beta-adrenergic receptor antagonist nadolol was administered; nadolol did not interfere with helping. The corticosterone response of rats exposed to a trapped cagemate was measured and compared to the rats' subsequent helping behavior. Rats with the greatest corticosterone responses showed the least helping behavior and those with the smallest responses showed the most consistent helping at the shortest latency. These results are discussed in terms of their implications for the interaction between stress and pro-social behavior. Finally, we observed that door-opening appeared to be reinforcing. A novel analytical tool was designed to interrogate the pattern of door-opening for signs that a rat's behavior on one session influenced his behavior on the next session. Results suggest that helping a trapped rat has a greater motivational value than does chocolate. In sum, this series of experiments clearly demonstrates the fundamental role of affect in motivating pro-social behavior in rodents and the need for a helper to resonate with the affect of a victim.


Factors affecting the documentation of spoken safety-netting advice in routine GP consultations: a cross-sectional study.
Previous studies have reported how often safety-netting is documented in medical records, but it is not known how this compares with what is verbalised and what factors might influence the consistency of documentation. To compare spoken and documented safety-netting advice and to explore factors associated with documentation. A cross-sectional study, using an existing GP consultations archive. Observational coding involving classifying and quantifying medical record entries and comparison with spoken safety-netting advice in 295 video-/audio-recorded consultations. Associations were tested using logistic regression. Two-thirds of consultations (192/295) contained spoken safety-netting advice that applied to less than half of the problems assessed (242/516). Only one-third of consultations (94/295) had documented safety-netting advice, which covered 20.3% of problems (105/516). The practice of GPs varied widely, from those that did not document their safety-netting advice to those that nearly always did so (86.7%). GPs were more likely to document their safety-netting advice for new problems (P = 0.030), when only a single problem was discussed in a consultation (P = 0.040), and when they gave specific rather than generic safety-netting advice (P = 0.007). In consultations where multiple problems were assessed (n = 139), the frequency of spoken and documented safety-netting advice decreased the later a problem was assessed. GPs frequently do not document the safety-netting advice they have given to patients, which may have medicolegal implications in the event of an untoward incident. GPs should consider how safely they can assess and document more than one problem in a single consultation and this risk should be shared with patients to help manage expectations.


Comparative efficacy and safety of the artemisinin derivatives compared to quinine for treating severe malaria in children and adults: A systematic update of literature and network meta-analysis.
The artemisinin derivatives are the preferred antimalaria drugs for treating severe Plasmodium falciparum malaria. However, their clinical effectiveness compared to each other is unknown. Our objective, therefore, was to evaluate the efficacy and safety of the artemisinin derivatives and quinine for treating severe P. falciparum malaria in children and adults using a network meta-analysis. Review protocol was registered with PROSPERO, CRD42020218190. We updated the search strategies of three Cochrane systematic reviews which included published and unpublished randomised control trials (RCTs) that have compared specific artemisinin derivatives to quinine in treating severe malaria. Search included CENTRAL, MEDLINE, Embase, LILACS, ISI Web of Science and trial registries up to February 2021. We screened studies, extracted data, assessed risk of bias, and quality of evidence in duplicate. Separate network meta-analyses in the frequentist framework, using a random effects model, with quinine as reference, were conducted for adults and children, and rankings were produced using p-scores to assess mortality, parasite clearance, coma recovery, fever clearance, neurological sequela and adverse events. Searches identified 818 citations, 33 RCTs were eligible. We pooled 7795 children and 3182 adults. The networks involved artesunate, artemether, rectal artemisinin, arteether and quinine. Compared to quinine, artesunate reduced mortality in children (risk ratio (RR), 0.76; 95%CI [0.65 to 0.89], moderate quality), adults (RR, 0.55; 95%CI [0.40 to 0.75], moderate quality) and in cerebral malaria (RR, 0.72; 95%CI [0.55 to 0.94], moderate quality). Compared to rectal artemisinin and intramuscular arteether, the efficacy and safety of parenteral artesunate, and intramuscular artemether in treating severe malaria are not clear. Rankings showed that none of the artemisinin drugs were consistently superior in all the outcomes assessed. Indirect evidence produced were of very low ratings due to suspected publication bias and imprecision. Artesunate reduces mortality compared to quinine for both adults and children in Asia and Africa including cerebral malaria. The artemisinin derivatives remain the best treatment for severe malaria but their comparative clinical effectiveness is yet to be fully explored.


Pharmacological and physiological growth hormone stimulation tests to predict successful GH therapy in children.
Although the current use of growth hormone (GH) stimulation tests (GHSTs) is still subject to debate, the tests are widely used to diagnose GH deficiency. This literature review evaluates primarily the sensitivity, specificity and reliability of GHSTs and secondarily their convenience. Single pharmacological tests typically address only a single pathway in the complex physiological regulation of GH secretion and are therefore characterized by lower sensitivity, specificity and reliability than combined pharmacological tests or physiological tests. In spite of the high levels of sensitivity, specificity and reliability, physiological tests require considerably more effort to perform, from the physician as well as from the child. Therefore, a need for an alternative, convenient, physiological GHST still remains. Oral ingestion of dietary protein is convenient in practice and may induce more physiological stimulation of GH secretion, hence may be a promising valuable addition to the existing GHSTs in GH deficiency.


Prospective study to determine accuracy of rapid serological assays for diagnosis of acute dengue virus infection in Laos.
There is an urgent need for accurate and simple dengue virus infection diagnostic assays in limited-resource settings of dengue endemicity, to assist patient management. Using a panel of reference samples (S. D. Blacksell, P. N. Newton, D. Bell, J. Kelley, M. P. Mammen, D. W. Vaughn, V. Wuthiekanun, A. Sungkakum, A. Nisalak, and N. P. Day, Clin. Infect. Dis. 42:1127-1134, 2006), we recently evaluated eihgt commercially available immunochromatographic rapid diagnostic tests (RDTs) designed to detect dengue virus-specific immunoglobulin M (IgM) and/or IgG. We found that 6/8 RDTs had sensitivities of less than 50% (range, 6 to 65%), but specificities were generally high. Here, in conjuction with dengue virus serotyping by reverse transcriptase PCR and in the limited-resource setting of Laos, where dengue virus is endemic, we evaluated the same eight RDTs against a previously validated dengue IgM/IgG enzyme-linked immunosorbent assay for diagnosis of acute dengue virus infection. Paired serum samples were collected from 87 patients, of whom 38 had confirmed dengue virus infections (4 had primary infections, 33 had secondary infections, and 1 had an infection of indeterminate status). RDT sensitivity was low, with 7/8 RDTs having admission sample sensitivities of less than 20% (range, 4 to 26%). The majority (6/8) of the RDTs, demonstrated high specificity (>95%). Kappa statistic values ranged from 6 to 54% for the RDTs, demonstrating poor to moderate variation between three operators. No RDT adequately differentiated between primary and secondary dengue virus infections. The findings of this study suggest that currently available RDTs based on the detection of IgM antibodies for the diagnosis of acute dengue virus infections are unlikely to be useful for patient management.


Cytoprotection by melatonin and growth hormone in early rat myocardial infarction as revealed by Feulgen DNA staining.
To examine the cytoprotective effect of melatonin or recombinant human growth hormone (hGH) on the early phase of a running myocardial infarction in rats by using the Feulgen staining. Rats were subjected to surgical ligature of the left coronary artery or its sham-operation and were studied 1.5 3 h later. Melatonin was administered in the drinking water (100 microg/ml water) for 7 days before surgery. Recombinant hGH (2 IU/kg) was given ip at the time of surgery. Feulgen-stained histological cardiac sections were examined by light microscopy and image analysis. Infarcted rats receiving vehicle exhibited large, diffuse cardiac lesions with a marked positivity for Feulgen reaction. About 18 20% of the total area recorded became injured 1.5 or 3 h after infarction, respectively. Infarcted rats treated with melatonin or hGH, or the combination of both, and killed 3 h after surgery, showed cardiac sections with scattered lesions and only a few isolated injured muscle fibers. A similar effectiveness of melatonin and hGH, alone or in combination, to decrease injured area by 86 87% and the number of cardiac lesions by 75 80% was observed. A significant cytoprotective effect of melatonin or hGH is demonstrable in an early phase of myocardial infarction in rats.


Examining the relationship between clinical decision support and performance measurement.
In concept and practice, clinical decision support (CDS) and performance measurement represent distinct approaches to organizational change, yet these two organizational processes are interrelated. We set out to better understand how the relationship between the two is perceived, as well as how they jointly influence clinical practice. To understand the use of CDS at benchmark institutions, we conducted semistructured interviews with key managers, information technology personnel, and clinical leaders during a qualitative field study. Improved performance was frequently cited as a rationale for the use of clinical reminders. Pay-for-performance efforts also appeared to provide motivation for the use of clinical reminders. Shared performance measures were associated with shared clinical reminders. The close link between clinical reminders and performance measurement causes these tools to have many of the same implementation challenges.


Illuminating the impact of habitual behaviors in depression.
Researchers have hypothesized that habitual behaviors are zeitgebers for the circadian clock. However, few studies have examined the relationship between habitual behaviors and light, the strongest zeitgeber. Depression is an ideal model in which to explore this relationship because depression is a disorder associated with disruptions in circadian biological activity, sleep, and social rhythms (or patterns of habitual behaviors). We hypothesized that individuals with fewer habitual behaviors have less average exposure to light from morning rise time to evening bedtime and that a reduction in light exposure increases the likelihood of depression. Thirty-nine depressed and 39 never-depressed participants wore an ambulatory light monitor and completed the Social Rhythm Metric over the course of 2 weeks. Linear and logistic regression techniques were used to calculate regression coefficients, and confidence limits based on the distribution of the product of two normal random variables were computed to test the significance of the mediation effect. Infrequent habitual behaviors were associated with a decrease in average levels of light exposure, and low levels of light increased the likelihood of depression. This mediation effect was partial; the overall number of habitual behaviors had a direct relationship with depression above and beyond the association with light exposure. Longitudinal studies are needed to empirically demonstrate the direction of relationships between each of the variables tested.


Recombinant Mycobacterium bovis bacillus Calmette-Guérin vectors prime for strong cellular responses to simian immunodeficiency virus gag in rhesus macaques.
Live attenuated nonpathogenic Mycobacterium bovis bacillus Calmette-Guérin (BCG) mediates long-lasting immune responses, has been safely administered as a tuberculosis vaccine to billions of humans, and is affordable to produce as a vaccine vector. These characteristics make it very attractive as a human immunodeficiency virus (HIV) vaccine vector candidate. Here, we assessed the immunogenicity of recombinant BCG (rBCG) constructs with different simian immunodeficiency virus (SIV)gag expression cassettes as priming agents followed by a recombinant replication-incompetent New York vaccinia virus (NYVAC) boost in rhesus macaques. Unmutated rBCG constructs were used in comparison to mutants with gene deletions identified in an in vitro screen for augmented immunogenicity. We demonstrated that BCG-SIVgag is able to elicit robust transgene-specific priming responses, resulting in strong SIV epitope-specific cellular immune responses. While enhanced immunogenicity was sustained at moderate levels for >1 year following the heterologous boost vaccination, we were unable to demonstrate a protective effect after repeated rectal mucosal challenges with pathogenic SIVmac251. Our findings highlight the potential for rBCG vaccines to stimulate effective cross-priming and enhanced major histocompatibility complex class I presentation, suggesting that combining this approach with other immunogens may contribute to the development of effective vaccine regimens against HIV.


Connective tissue disease and autoantibodies in the kindreds of 63 patients with systemic sclerosis. The United Kingdom Systemic Sclerosis Study Group.
Systemic sclerosis (SSc) tends to occur in a sporadic fashion and familial occurrence of the disease is unusual. Nevertheless, reports of related connective tissue diseases (CTD), autoantibodies, or both in family members together with associations of certain HLA class II phenotypes with SSc suggest that genetic factors might play a part in susceptibility to the disease. Because of the relative rarity of SSc only a small number of family pedigrees have been studied previously. This report represents the largest study to date, to our knowledge, of family members of patients with scleroderma, and provides the opportunity to investigate the relative importance of genetic and environmental factors operating in the disease. The family pedigrees of 63 patients with systemic sclerosis were examined with respect to clinical, serologic, and immunogenetic features. Multiple cases of SSc were seen only in 1 family, in which the disease affected a father and daughter. Disease expression in these 2 individuals was very similar both clinically and serologically; relatives with other connective tissue diseases were found in 9 families, and nonspecific features of CTD such as Raynaud phenomenon, and arthralgia or arthritis, occurred commonly, especially in female relatives. Antinuclear antibodies (ANA) were also detected more frequently in relatives than in controls. However, antibodies previously demonstrated to have a high degree of specificity for SSc were confined to patients with this disease. Probands had an increase in the frequency of HLA-DR3, DR5, and C4AQO. Patients with diffuse scleroderma had an increased frequency of HLA-DR3, while those with the limited form of the disease had an increased frequency of HLA-DR5.(ABSTRACT TRUNCATED AT 250 WORDS)


Mechanistic Investigations of Green mEos4b Reveal a Dynamic Long-Lived Dark State.
Green-to-red photoconvertible fluorescent proteins (PCFPs) are key players in advanced microscopy schemes such as photoactivated localization microscopy (PALM). Whereas photoconversion and red-state blinking in PCFPs have been studied intensively, their green-state photophysical behavior has received less attention. Yet dark states in green PCFPs can become strongly populated in PALM schemes and exert an indirect but considerable influence on the quality of data recorded in the red channel. Furthermore, green-state photoswitching in PCFPs can be used directly for PALM and has been engineered to design highly efficient reversibly switchable fluorescent proteins (RSFPs) amenable to various nanoscopy schemes. Here, we demonstrate that green mEos4b efficiently switches to a long-lived dark state through cis-trans isomerization of its chromophore, as do most RSFPs. However, by combining kinetic crystallography, molecular dynamics simulations, and Raman spectroscopy, we find that the dark state in green mEos4b is much more dynamic than that seen in switched-off green IrisFP, a biphotochromic PCFP engineered from the common EosFP parent. Our data suggest that H-bonding patterns maintained by the chromophore in green PCFPs and RSFPs in both their on- and off-states collectively control photoswitching quantum yields. The reduced number of H-bonds maintained by the dynamic dark chromophore in green mEos4b thus largely accounts for the observed lower switching contrast as compared to that of IrisFP. We also compare the long-lived dark states reached from green and red mEos4b, on the basis of their X-ray structures and Raman signatures. Altogether, these data provide a unifying picture of the complex photophysics of PCFPs and RSFPs.


Imaging diagnosis-magnetic resonance imaging features of a cerebral hemangioblastoma in a dog.
The magnetic resonance (MR) imaging features of a cerebral hemangioblastoma in a 9-year-old dog are described. Imaging revealed a well-defined contrast-enhancing lesion of the rostral forebrain that appeared extraparenchymal. Histopathology of the excised mass showed clusters of small blood vessels interspersed with interstitial cells staining positive for neuronal specific enolase, features consistent with a cerebral hemangioblastoma; the mass also appeared intraparenchymal after further immunohistochemistry study. This neoplasm should be considered a rare differential diagnosis for intracranial masses in dogs.


Adaptive wavelet neural network control with hysteresis estimation for piezo-positioning mechanism.
An adaptive wavelet neural network (AWNN) control with hysteresis estimation is proposed in this study to improve the control performance of a piezo-positioning mechanism, which is always severely deteriorated due to hysteresis effect. First, the control system configuration of the piezo-positioning mechanism is introduced. Then, a new hysteretic model by integrating a modified hysteresis friction force function is proposed to represent the dynamics of the overall piezo-positioning mechanism. According to this developed dynamics, an AWNN controller with hysteresis estimation is proposed. In the proposed AWNN controller, a wavelet neural network (WNN) with accurate approximation capability is employed to approximate the part of the unknown function in the proposed dynamics of the piezo-positioning mechanism, and a robust compensator is proposed to confront the lumped uncertainty that comprises the inevitable approximation errors due to finite number of wavelet basis functions and disturbances, optimal parameter vectors, and higher order terms in Taylor series. Moreover, adaptive learning algorithms for the online learning of the parameters of the WNN are derived based on the Lyapunov stability theorem. Finally, the command tracking performance and the robustness to external load disturbance of the proposed AWNN control system are illustrated by some experimental results.


Synthetic control and empirical prediction of redox potentials for Co4O4 cubanes over a 1.4 V range: implications for catalyst design and evaluation of high-valent intermediates in water oxidation.
The oxo-cobalt cubane unit [Co4O4] is of interest as a homogeneous oxygen-evolution reaction (OER) catalyst, and as a functional mimic of heterogeneous cobalt oxide OER catalysts. The synthesis of several new cubanes allows evaluation of redox potentials for the [Co4O4] cluster, which are highly sensitive to the ligand environment and span a remarkable range of 1.42 V. The [CoIII4O4]4+/[CoIII3CoIVO4]5+ and [CoIII3CoIVO4]5+/[CoIII2CoIV2O4]6+ redox potentials are reliably predicted by the pKas of the ligands. Hydrogen bonding is also shown to significantly raise the redox potentials, by ∼500 mV. The potential-pKa correlation is used to evaluate the feasibility of various proposed OER catalytic intermediates, including high-valent Co-oxo species. The synthetic methods and structure-reactivity relationships developed by these studies should better guide the design of new cubane-based OER catalysts.


Impact of nurse staffing mandates on safety-net hospitals: lessons from California.
California is the first and only state to implement a patient-to-nurse ratio mandate for hospitals. Increasing nurse staffing is an important organizational intervention for improving patient outcomes. Evidence suggests that staffing improved in California hospitals after the mandate was enacted, but the outcome for hospitals bearing a disproportionate share of uncompensated care-safety-net hospitals-remains unclear. One concern was that California's mandate would burden safety-net hospitals without improving staffing or that hospitals would reduce their skill mix, that is, the proportion of registered nurses of all nursing staff. We examined the differential effect of California's staffing mandate on safety-net and non-safety-net hospitals. We used a time-series design with Annual Hospital Disclosure data files from the California Office of Statewide Health Planning and Development (OSHPD) for the years 1998 to 2007 to assess differences in the effect of California's mandate on staffing outcomes in safety-net and non-safety-net hospitals. The mandate resulted in significant staffing improvements, on average nearly a full patient per nurse fewer (-0.98) for all California hospitals. The greatest effect was in those hospitals with the lowest staffing levels at the outset, both safety-net and non-safety-net hospitals, as the legislation intended. The mandate led to significantly improved staffing levels for safety-net hospitals, although there was a small but significant difference in the effect on staffing levels of safety-net and non-safety-net hospitals. Regarding skill mix, a marginally higher proportion of registered nurses was seen in non-safety-net hospitals following the mandate, while the skill mix remained essentially unchanged for safety-net hospitals. The difference between the two groups of hospitals was not significant. California's mandate improved staffing for all hospitals, including safety-net hospitals. Furthermore, improvement did not come at the cost of a reduced skill mix, as was feared. Alternative and more targeted designs, however, might yield further improvement for safety-net hospitals and reduce potential disparities in the staffing and skill mix of safety-net and non-safety-net hospitals.


636,120 Ways to Have Posttraumatic Stress Disorder.
In an attempt to capture the variety of symptoms that emerge following traumatic stress, the revision of posttraumatic stress disorder (PTSD) criteria in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) has expanded to include additional symptom presentations. One consequence of this expansion is that it increases the amorphous nature of the classification. Using a binomial equation to elucidate possible symptom combinations, we demonstrate that the DSM-IV criteria listed for PTSD have a high level of symptom profile heterogeneity (79,794 combinations); the changes result in an eightfold expansion in the DSM-5, to 636,120 combinations. In this article, we use the example of PTSD to discuss the limitations of DSM-based diagnostic entities for classification in research by elucidating inherent flaws that are either specific artifacts from the history of the DSM or intrinsic to the underlying logic of the DSM's method of classification. We discuss new directions in research that can provide better information regarding both clinical and nonclinical behavioral heterogeneity in response to potentially traumatic and common stressful life events. These empirical alternatives to an a priori classification system hold promise for answering questions about why diversity occurs in response to stressors.


Clinical features and prognosis with Guillain-Barré syndrome.
Guillain-Barré syndrome (GBS) is an acute inflammatory polyneuropathy commonly characterized by rapidly progressive, symmetric weakness and areflexia. We retrospectively assessed the clinical manifestations, results of electrodiagnostic tests, functional status and prognosis of 36 children diagnosed with GBS. Based on clinical and electrophysiological findings, the patients were classified as having acute inflammatory demyelinating polyradiculoneuropathy (AIDP) (n = 25), acute motor axonal neuropathy (AMAN) (n = 10) and acute motor-sensory axonal neuropathy (AMSAN) (n = 1). Twenty (55.5%) patients were males and 16 (44.5%) patients were females. The mean age of the 36 patients was 68.1 ± 45.01 months (range, 6-180 months). Five (13.8%) patients were younger than 2 years. The most common initial symptoms were limb weakness, which was documented in 34 (94.4%) patients. In our study, 18 patients (51.4%) showed albuminocytological dissociation (raised protein concentration without pleocytosis) on cerebrospinal fluid (CSF) examination. Three patients (8.3%) required mechanical ventilation therapy during hospitalization. Unfortunately, three (8.3%) patients died; one patient had AIDP and two patients had axonal involvement (one case was AMAN and another case was AMSAN). When we compared the cases of residual sequel/dead and cases of complete recovery for neural involvement type including AIDP, AMAN and AMSAN, we did not find a statistically significant difference between the groups (P > 0.05). Our findings showed that cases of GBS was not uncommon in children younger than 2 years of age, and CSF protein level might be found high in the first week of the disease in about one half of the patients, with a higher rate of morbidity and mortality in patients with axonal involvement than in those with AIDP.


Urban Stormwater: An Overlooked Pathway of Extensive Mixed Contaminants to Surface and Groundwaters in the United States.
Increasing global reliance on stormwater control measures to reduce discharge to surface water, increase groundwater recharge, and minimize contaminant delivery to receiving waterbodies necessitates improved understanding of stormwater-contaminant profiles. A multiagency study of organic and inorganic chemicals in urban stormwater from 50 runoff events at 21 sites across the United States demonstrated that stormwater transports substantial mixtures of polycyclic aromatic hydrocarbons, bioactive contaminants (pesticides and pharmaceuticals), and other organic chemicals known or suspected to pose environmental health concern. Numerous organic-chemical detections per site (median number of chemicals detected = 73), individual concentrations exceeding 10 000 ng/L, and cumulative concentrations up to 263 000 ng/L suggested concern for potential environmental effects during runoff events. Organic concentrations, loads, and yields were positively correlated with impervious surfaces and highly developed urban catchments. Episodic storm-event organic concentrations and loads were comparable to and often exceeded those of daily wastewater plant discharges. Inorganic chemical concentrations were generally dilute in concentration and did not exceed chronic aquatic life criteria. Methylmercury was measured in 90% of samples with concentrations that ranged from 0.05 to 1.0 ng/L.


An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients.
Diagnosis of immune heparin-induced thrombocytopenia (HIT) is usually based on a fall in platelet count below 150 x 109/L (standard definition of thrombocytopenia). However, this definition may be inappropriate for postoperative patients who often develop postoperative thrombocytosis. We sought to determine an improved definition of thrombocytopenia indicating HIT in postoperative orthopedic patients, including its impact on frequency and thrombotic risk of HIT. We performed a secondary analysis of a clinical trial of 665 patients who received unfractionated or low-molecular-weight heparin following elective hip arthroplasty. Daily platelet counts and objective studies for deep vein thrombosis were performed in all patients. Laboratory detection of HIT antibodies from a 362-patient subgroup was used to define sensitivity and specificity of various definitions of thrombocytopenia to indicate HIT. The improved definition of HIT was a 50% or greater platelet count fall from the postoperative peak, as this definition had greater sensitivity (50% vs 25%) and similar high specificity (99.1% vs 99.4%) for detecting HIT-IgG compared with the standard definition. Patients with HIT who were identified using the improved definition had a higher frequency of thrombosis than patients without HIT (72.2% vs 17.3%; P<.001). The improved definition showed an even greater absolute difference in frequency of HIT between unfractionated and low-molecular-weight heparin (4.8% vs 0.6%; P<.001) compared with the standard definition (2.7% vs 0%; P =.002). A 50% or greater fall in the platelet count from the postoperative peak is a sensitive definition indicating possible HIT that is associated with an increased risk of thrombosis.


Flexibility, muscle strength and running biomechanical adaptations in older runners.
The increased injury risk in older runners has been associated with alterations in muscle strength, flexibility, and gait biomechanics. This study investigated whether older runners exhibit changes in muscle strength, flexibility and running biomechanics compared to younger runners, and possible relationships between these changes. Thirty-five young (20-36yrs) and 35 older (55-71yrs) recreational runners participated in the study. Measures of three-dimensional biomechanical data during treadmill running at 2.7m/s and measures of muscle strength and flexibility were compared between groups. A correlation analysis between biomechanical and clinical variables was also performed. Older runners demonstrated an overall reduction in muscle strength and flexibility, and altered running patterns compared to young runners but correlations between clinical and biomechanical variables were scarce. Reduced hip, ankle and trunk excursions along with reduced knee and ankle positive work were found in older runners. Older runners also exhibited increased knee abduction impulse, ankle abduction impulse and vertical loading rates. In contrast, older runners did not present a distal-to-proximal lower extremity joint moment redistribution. We observed age-related reduced strength and flexibility concomitant with alterations in running biomechanics, but a lack of correlation between these variables. This finding hampers the use of single, or even a subset of characteristics to better understand age-related changes in runners. The observed changes are complex and multivariate in nature. Clinicians will most likely have to monitor both clinical and biomechanical characteristics to optimize care. However, future studies need to prospectively address what are biomechanical age-related risk factors in runners.


Identification of Ebsulfur Analogues with Broad-Spectrum Antifungal Activity.
Invasive fungal infections are on the rise due to an increased population of critically ill patients as a result of HIV infections, chemotherapies, and organ transplantations. Current antifungal drugs are helpful, but are insufficient in addressing the problem of drug-resistant fungal infections. Thus, there is a growing need for novel antimycotics that are safe and effective. The ebselen scaffold has been evaluated in clinical trials and has been shown to be safe in humans. This makes ebselen an attractive scaffold for facile translation from bench to bedside. We recently reported a library of ebselen-inspired ebsulfur analogues with antibacterial properties, but their antifungal activity has not been characterized. In this study, we repurposed ebselen, ebsulfur, and 32 additional ebsulfur analogues as antifungal agents by evaluating their antifungal activity against a panel of 13 clinically relevant fungal strains. The effect of induction of reactive oxygen species (ROS) by three of these compounds was evaluated. Their hemolytic and cytotoxicity activities were also determined using mouse erythrocytes and mammalian cells. The MIC values of these compounds were found to be in the range of 0.02-12.5 μg mL(-1) against the fungal strains tested. Notably, yeast cells treated with our compounds showed an accumulation of ROS, which may further contribute to the growth-inhibitory effect against fungi. This study provides new lead compounds for the development of antimycotic agents.


Erythromycin and the gut.
The commonly reported gastrointestinal side effects that occur with erythromycin are related to its prokinetic action on the gut, mediated, at least in part, by its motilin receptor stimulating activity. This action may be of clinical use in conditions associated with gastrointestinal hypomotility such as diabetic gastroparesis and intestinal pseudo-obstruction, although further work needs to be done to establish the long term therapeutic uses of erythromycin in these disorders. Macrolide compounds with no antibacterial properties but which have a pronounced prokinetic action on the gut have already been synthesised and are currently being developed for future use in man. These 'motilides' should provide a useful addition to our rather limited armamentarium of effective gastrointestinal prokinetic agents.


Prioritizing COVID-19 tests based on participatory surveillance and spatial scanning.
This study aimed to identify, describe and analyze priority areas for COVID-19 testing combining participatory surveillance and traditional surveillance. It was carried out a descriptive transversal study in the city of Caruaru, Pernambuco state, Brazil, within the period of 20/02/2020 to 05/05/2020. Data included all official reports for influenza-like illness notified by the municipality health department and the self-reports collected through the participatory surveillance platform Brasil Sem Corona. We used linear regression and loess regression to verify a correlation between Participatory Surveillance (PS) and Traditional Surveillance (TS). Also a spatial scanning approach was deployed in order to identify risk clusters for COVID-19. In Caruaru, the PS had 861 active users, presenting an average of 1.2 reports per user per week. The platform Brasil Sem Corona started on March 20th and since then, has been officially used by the Caruaru health authority to improve the quality of information from the traditional surveillance system. Regarding the respiratory syndrome cases from TS, 1588 individuals were positive for this clinical outcome. The spatial scanning analysis detected 18 clusters and 6 of them presented statistical significance (p-value < 0.1). Clusters 3 and 4 presented an overlapping area that was chosen by the local authority to deploy the COVID-19 serology, where 50 individuals were tested. From there, 32 % (n = 16) presented reagent results for antibodies related to COVID-19. Participatory surveillance is an effective epidemiological method to complement the traditional surveillance system in response to the COVID-19 pandemic by adding real-time spatial data to detect priority areas for COVID-19 testing.


Activating and inhibitory receptors on synovial fluid natural killer cells of arthritis patients: role of CD94/NKG2A in control of cytokine secretion.
Natural killer (NK) cells are activated early during inflammatory events and contribute to the shaping of the ensuing adaptive immune response. To further understand the role for NK cells in inflammation, we investigated the phenotype and function of synovial fluid (SF) NK cells from patients with chronic joint inflammation, as well as from patients with transient inflammation of the knee following trauma. We confirm that synovial NK cells are similar to the well-characterized CD56(bright) peripheral blood (PB) NK-cell subset present in healthy individuals. However, compared to this PB subset the synovial NK cells express a higher degree of activation markers including CD69 and NKp44, the latter being up-regulated also on CD56(bright) NK cells in the PB of patients. Activated synovial NK cells produced interferon-gamma and tumour necrosis factor, and the production was further up-regulated by antibody masking of CD94/NKG2A, and down-regulated by target cells expressing human leucocyte antigen-E in complex with peptides known to engage CD94/NKG2A. We conclude that synovial NK cells have an activated phenotype and that CD94/NKG2A is a key regulator of synovial NK-cell cytokine synthesis.


Nanoscale thermal cloaking in graphene via chemical functionalization.
Macro-thermal cloaking is typically produced by coordinate transformations, but this method is unsuitable for nanostructures. We designed a graphene-based nanoscale thermal cloak using a novel mechanism of phonon localization. The nanocloak in graphene was produced via the chemical functionalization of hydrogen, methyl and hydroxyl using molecular dynamics simulations. The cloaking performance was quantified by the ratio of thermal cloaking (RTC). We found that the RTC correlated with the functionalization fraction and it has a local maximum at a certain width, since the heat flux reduction in the exterior and the protected region reversed if the width was excessive. The atomic mass of the functional group also correlated with the RTC. Our simulations determined that phonon localization occurred due to sp2-to-sp3 bonding transitions, which caused the heat flux to avoid the transition region. Finally, the extent of phonon localization was related to the cloaking performance.


An algorithm for risk assessment and intervention of mother to child transmission of hepatitis B virus.
Despite immunoprophylaxis, mother to child transmission (MTCT) of hepatitis B virus (HBV) still occurs in infants born to hepatitis B surface antigen (HBsAg)-positive mothers. We analyzed methods of risk assessment and interventions for MTCT. We reviewed 63 articles and abstracts published from 1975-2011 that were relevant to MTCT; articles were identified using the PubMed bibliographic database. Administration of HB immunoglobulin and HB vaccine to infants at birth (within 12 hours), followed by 2 additional doses of vaccines within 6-12 months, prevented approximately 95% of HBV transmission from HBsAg-positive mothers to their infants. However, HBV was still transmitted from 8%-30% of mothers with high levels of viremia. It is important to assess the risk for MTCT and identify mothers who are the best candidates for intervention. The most important risk factor is maternal level of HBV DNA >200,000 IU (10(6) copies)/mL; other factors include a positive test result for the HB e antigen, pregnancy complications such as threatened preterm labor or prolonged labor, and failure of immunoprophylaxis in prior children. Antiviral therapy during late stages of pregnancy is the most effective method to reduce transmission from mothers with high levels of viremia, but elective cesarean section might also be effective. Antepartum administration of HB immunoglobulin, giving infants a double dose of HB vaccine, or avoiding breastfeeding had no impact on MTCT. HBsAg-positive mothers should be assessed for risk of MTCT, and infants should receive immunoprophylaxis. Pregnant women with levels of HBV DNA >200,000 IU/mL should be considered for strategies to reduce the risk for MTCT. We propose an algorithm for risk assessment and patient management that is based on a review of the literature and the opinion of a panel of physicians with expertise in preventing MTCT.


Postoperative Hyperglycemia and 4-Year Neurodevelopmental Outcome in Children Operated for Congenital Heart Disease.
To study the long-term neurodevelopmental effects of hyperglycemia in infant bypass surgery for congenital heart disease (CHD). Prospective cohort study on neurodevelopmental outcome after infant cardiac bypass surgery. age older than 1 year at first surgery, genetic comorbidity, and birth weight <2000 g. Of 167 eligible infants, follow-up examination at 4 years was completed in 150 children (90%). Intraoperative and postoperative highest and lowest glucose levels within 24 hours after bypass surgery were prospectively collected. Neurodevelopmental outcome at 4 years of age was assessed using standardized IQ tests and the Movement Assessment Battery for Children-second version for motor outcome assessment. Mean age at surgery was 2.8 months (0.1-10.7 months), 33% of children had an acyanotic CHD and 67% a cyanotic CHD. Glucose levels were elevated (>8 mmol/L) in 21 (14%) children in the first 24 postoperative hours. Glucose levels normalized in all children within 48 hours, 7 children (4%) received insulin infusions. Mean total IQ was within the normal range, but significantly lower than the normal population (92.5 [SD 15.0], P < .001). Higher postoperative glucose levels were related to better cognitive performance in the univariate analysis (P < .03), but not when other risk factors were taken into account. Independent risk factors for adverse outcome were lower socioeconomic status, higher risk adjustment for congenital heart surgery score, and longer duration of intensive care stay. Hyperglycemia is common in the early postoperative course after infant bypass surgery for CHD and normalizes within 48 hours. Hyperglycemia has no adverse effect on long-term neurodevelopmental outcome.


Effect of aminophylline on respiratory muscle strength after upper abdominal surgery: a double blind study.
The effect of aminophylline on maximum respiratory muscle strength in patients undergoing upper abdominal surgery was investigated. An open pilot study was performed in which aminophylline was administered continuously for 48 hours after surgery (protocol I). In a second group of subjects aminophylline was given for 24 hours after cholecystectomy in a double blind placebo controlled trial (protocol II). Twelve patients participated in the pilot study (group A) and 25 in protocol II of which 14 received aminophylline (group B) and 11 placebo (control, group C). Respiratory muscle strength was assessed by measuring mouth pressures during maximum static inspiratory and expiratory efforts. Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), vital capacity (VC), inspiratory maximum pressures (PImax), expiratory maximum pressures (PEmax) were measured 24 hours preoperatively, PImax and serum theophylline 24 hours postoperatively, and FEV1, FVC, VC, PImax, PEmax, and serum theophylline 48 hours after surgery. FEV1, FVC, and VC decreased in all groups of patients at +48 hours. PImax fell at +24 hours and +48 hours but this decrease was significantly smaller in the two groups who received aminophylline than in the control group. PEmax showed a decrease at +48 hours but this reduction was similar in all three groups studied, independent of the treatment given. These data suggest that either aminophylline had a protective effect only on the inspiratory muscles or, most probably, that the effect of aminophylline was central, reducing the phrenic nerve inhibition induced by cholecystectomy and thus improving diaphragmatic function. Upper abdominal surgery decreases inspiratory and expiratory muscle strength and aminophylline has a protective effect only on inspiratory muscle function. This may have important clinical applications in minimising pulmonary complications after cholecystectomy.


X-ray structure of tRNA pseudouridine synthase TruD reveals an inserted domain with a novel fold.
Pseudouridine synthases catalyse the isomerisation of uridine to pseudouridine in structural RNA. The pseudouridine synthase TruD, that modifies U13 in tRNA, belongs to a recently identified and large family of pseudouridine synthases present in all kingdoms of life. We report here the crystal structure of Escherichia coli TruD at 2.0 A resolution. The structure reveals an overall V-shaped molecule with an RNA-binding cleft formed between two domains: a catalytic domain and an insertion domain. The catalytic domain has a fold similar to that of the catalytic domains of previously characterised pseudouridine synthases, whereas the insertion domain displays a novel fold.


Fatty acids intakes and serum lipid profiles: NIPPON DATA90 and the national nutrition monitoring.
The National Nutritional Survey in Japan (NNSJ) was initiated in 1946. Using the majority of the participants for NNSJ, the National Survey on Circulatory Disorders (NSCD) has been conducted every 10 year since 1960. We compared fatty acids intakes obtained from NNSJ and serum lipid profiles from NSCD conducted in 1990. A total of 8344 community residents (4856 women and 3488 men, age > or = 30) from 300 randomly selected districts participated in the both surveys in 1990. At baseline, history, physical, and blood biochemical measurement and a nutritional survey were performed. We estimated nutrient intakes of each household member by dividing household intake data proportionally using average intakes by sex and age groups calculated for NNSJ95. Total fat, saturated fatty acids (SFA), poly-unsaturated fatty acids (PUFA), dietary cholesterol, and Keys dietary lipid factor (KEYS) were inversely associated with age in both men and women (all Ps < 0.001). In women, age and body mass index (BMI) adjusted serum total cholesterol (TC), high-density lipoprotein cholesterol (HDLc), and low-density lipoprotein cholesterol (LDLc) were positively associated with SFA, total fat intakes (%kcal), and with KEYS (P < 0.001). In men, age-BMI adjusted HDLc was not associated with SFA, total fat intakes, and with KEYS factors unlike in women. Other associations were similar to those in women. The total fatty acids, SFA intakes, and KEYS lipid factor obtained from NNSJ were significantly associated with serum total and LDL cholesterol from the National Survey on Circulatory Disorders conducted in 1990.


Intraovarian excess of nerve growth factor increases androgen secretion and disrupts estrous cyclicity in the rat.
A single injection of estradiol valerate induces a form of cystic ovary resembling some aspects of the human polycystic ovarian syndrome. Preceding the development of follicular cysts, there is an increase in intraovarian synthesis of nerve growth factor (NGF) and the low affinity NGF receptor (p75 NGFR). Selective blockade of NGF actions and p75 NGFR synthesis in the ovary restored estrous cyclicity and ovulatory capacity in estradiol valerate-treated rats, suggesting that an increase in NGF-dependent, p75 NGFR-mediated actions within the ovary contributes to the development of cystic ovarian disease. We have tested this hypothesis by grafting NGF-producing neural progenitor cells into the ovary of juvenile rats that have been induced to ovulate precociously by a single injection of PMSG. The NGF-producing cells, detected by their content of immunoreactive p75 NGFR material, were found scattered throughout the ovary with some of them infiltrating the granulosa cell compartment of large, precystic follicles. Ovarian NGF content was 2-fold higher than in the ovary of rats receiving control cells. Estrous cyclicity was disrupted, with the animals showing prolonged periods of persistent estrus, and an almost continuous background of vaginal cornified cells at other phases of the estrous cycle. Morphometric analysis revealed that the presence of NGF-producing cells neither reduced the total number of corpora lutea per ovary nor significantly increased the formation of follicular cysts. However, the ovaries receiving these cells showed an increased incidence of precystic, type III follicles, accompanied by a reduced number of healthy antral follicles, and an increased size of both healthy and atretic follicles. These changes in follicular dynamics were accompanied by a selective increase in serum androstenedione levels. The results show that an abnormally elevated production of NGF within the ovary suffices to initiate several of the structural and functional alterations associated with the development of follicular cysts in the rat ovary.


Peripherally inserted central venous catheter safety in burn care: a single-center retrospective cohort review.
The use of peripherally inserted central catheter (PICC) line for central venous access in thermally injured patients has increased in recent years despite a lack of evidence regarding safety in this patient population. A recent survey of invasive catheter practices among 44 burn centers in the United States found that 37% of burn units use PICC lines as part of their treatment protocol. The goal of this study was to compare PICC-associated complication rates with the existing literature in both the critical care and burn settings. The methodology involved is a single institution retrospective cohort review of patients who received a PICC line during admission to a regional burn unit between 2008 and 2013. Fifty-three patients were identified with a total of seventy-three PICC lines. The primary outcome measurement for this study was indication for PICC line discontinuation. The most common reason for PICC line discontinuation was that the line was no longer indicated (45.2%). Four cases of symptomatic upper extremity deep vein thrombosis (5.5%) and three cases of central line-associated bloodstream infection (4.3%, 2.72 infections per 1000 line days) were identified. PICC lines were in situ an average of 15 days (range 1 to 49 days). We suggest that PICC line-associated complication rates are similar to those published in the critical care literature. Though these rates are higher than those published in the burn literature, they are similar to central venous catheter-associated complication rates. While PICC lines can be a useful resource in the treatment of the thermally injured patient, they are associated with significant and potentially fatal risks.


A single LipiFlow® Thermal Pulsation System treatment improves meibomian gland function and reduces dry eye symptoms for 9 months.
To evaluate the effect of a single treatment with the LipiFlow(®) Thermal Pulsation System on signs of meibomian gland dysfunction (MGD) and dry eye symptoms over a 9-month period. Patients (n = 42 eyes, 21 subjects) diagnosed with MGD and dry eye symptoms were recruited for a non-significant risk, prospective, open-label, 1-month clinical trial. Patients received a single 12-minute treatment using the LipiFlow(®) Thermal Pulsation System on each eye. The LipiFlow(®) device applies heat to the conjunctival surfaces of the upper and lower inner eyelids while simultaneously applying pulsatile pressure to the outer eyelid surfaces to express the meibomian glands. Patient symptoms were evaluated using the Ocular Surface Disease Index (OSDI) and Standard Patient Evaluation for Eye Dryness (SPEED) dry eye questionnaires; tear break-up time was measured with the dry eye test (DET™); and meibomian gland function was evaluated using a standardized diagnostic expression technique. Data are presented for patient's pre-treatment (baseline) and at 1-month and 9-month post-treatment. Meibomian gland secretion scores improved significantly from baseline (4.4 ± 4.0) to 1-month post-treatment (11.3 ± 6.2; p < 0.0001) and this improvement was maintained with no significant regression at 9 months (11.7 ± 5.9). Similarly, baseline tear break-up time (4.8 ± 3.2) was significantly increased at 1 month (9.6 ± 7.6; p < 0.001) and this increase was maintained with no significant regression at 9 months (7.1 ± 5.6). Symptom scores on both OSDI and SPEED questionnaires improved significantly at 1 month (p < 0.0001) and this improvement was maintained at 9 months. With such prolonged improvement in signs and symptoms of dry eye disease, the LipiFlow(®) Thermal Pulsation System offers a technological advancement for the treatment of dry eye disease secondary to meibomian gland dysfunction. A single 12-minute LipiFlow(®) treatment results in up to 9 months of sustained improvement of meibomian gland function, tear break-up time and dry eye symptoms that are unparalleled with current dry eye treatments.


Rod and cone function in patients with KCNV2 retinopathy.
To investigate rod and cone function and disease mechanisms in patients with KCNV2 retinopathy. Psychophysical examinations as well as detailed electrophysiological examinations with Ganzfeld and multifocal electroretinogram (ERG) were performed to study response dynamics. Additionally, fundus photography, autofluorescence imaging and spectral domain OCTs were carried out for morphological characterization. Molecular genetic analysis revealed compound heterozygosity in five patients and homozygosity for the KCNV2 gene in one patient. The mutations resulted in complete absence of Kv8.2 subunits in three patients (no protein group, NOP), while the other three patients expressed mutant Kv8.2 subunits resulting in altered Kv2.1/Kv8.2 heteromeric or residual Kv2.1 homomeric potassium channel function (altered protein group, ALP). Although more advanced morphological changes were visible in the NOP group, a clear functional difference between the two groups could not be observed. All patients showed characteristic dynamics of the b-wave intensity-response function, however, scotopic b-wave response amplitudes were within normal limits. We also observed severely reduced oscillatory potentials. A specific genotype-phenotype correlation in retinal function could not be demonstrated. KCNV2 mutations cause a unique form of retinal disorder illustrating the importance of K(+)-channels for the resting potential, activation and deactivation of photoreceptors, while phototransduction remains unchanged. The reduced oscillatory potentials further suggest an altered function of the inner retina. Besides the characteristically steep amplitude-versus-intensity relationship, flicker responses at intermediate frequencies (5-15 Hz) are significantly reduced and shifted in phase.


The colorectal surgeon's personality may influence the rectal anastomotic decision.
Colorectal surgeons regularly make the decision to anastomose, defunction or form an end colostomy when performing rectal surgery. This study aimed to define personality traits of colorectal surgeons and explore any influence of such traits on the decision to perform a rectal anastomosis. Fifty attendees of The Association of Coloproctology of Great Britain and Ireland 2016 Conference participated. After written consent, all underwent personality testing: alexithymia (inability to understand emotions), type of thinking process (intuitive versus rational) and personality traits (extraversion, agreeableness, openness, emotional stability, conscientiousness). Questions were answered regarding anastomotic decisions in various clinical scenarios and results analysed to reveal any influence of the surgeon's personality on anastomotic decision. Participants were: male (86%), consultants (84%) and based in England (68%). Alexithymia was low (4%) with 81% displaying intuitive thinking (reflex, fast). Participants scored higher in emotional stability (ability to remain calm) and conscientiousness (organized, methodical) compared with population norms. Personality traits influenced the next anastomotic decision if: surgeons had recently received criticism at a departmental audit meeting; were operating with an anaesthetist that was not their regular one; or there had been no anastomotic leaks in their patients for over 1 year. Colorectal surgeons have speciality relevant personalities that potentially influence the important decision to anastomose and could explain the variation in surgical practice across the UK. Future work should explore these findings in other countries and any link of personality traits to patient-related outcomes.


Porous polysulfone coated with platelet-derived growth factor-BB stimulates proliferation of human periodontal ligament fibroblasts.
The purpose of this study was to investigate if the treatment of porous polysulfone (PPSF) with various concentrations of platelet-derived growth factor-BB (PDGF-BB) would stimulate the proliferation of the adherent human periodontal ligament fibroblasts (HPDLF) in culture. Sterilized PPSF cylinders were immersed in an Eagle's minimum essential medium supplemented with 0.5% fetal bovine serum and 1% penicillin/streptomycin containing either 0, 10, 20, or 50 ng/ml of PDGF-BB for 24 hours. After 24 hours, the PPSF cylinders were removed and allowed to dry then placed in culture plates for each time point. Pooled HPDLF (8 x 10(4)) and 3H-thymidine in medium were pipetted into each well to cover the treated and control PPSF cylinders and plates were then incubated. At 1, 4, and 10 days the PPSF cylinders were removed and macromolecular precipitation was performed. Incorporation of 3H-thymidine was measured and a 2-way ANOVA with repeated measures was performed. In addition, determination of binding and release was performed using I125-PDGF-BB treated PPSF at 0, 2, 12, and 24 hours, and at 4 and 10 days. Results showed that the effects on HPDLF were significant for dose (P = 0.0012; F = 5.74) and time (P = 0.0001; F = 40.83). At 4 days, the percent increases above the control for the doses 10, 20, and 50 ng/ml were 192%, 310%, and 162% respectively. In conclusion, our findings suggest that treating PPSF with PDGF-BB results in a significant increase in the proliferation of HPDLF cells adherent to PPSF.


Functional convergence of hopanoids and sterols in membrane ordering.
Liquid-ordered phases are one of two biochemically active membrane states, which until now were thought to be a unique consequence of the interactions between eukaryotic membrane lipids. The formation of a liquid-ordered phase depends crucially on the ordering properties of sterols. However, it is not known whether this capacity exists in organisms that lack sterols, such as bacteria. We show that diplopterol, the simplest bacterial hopanoid, has similar properties and that hopanoids are bacterial "sterol surrogates" with the ability to order saturated lipids and to form a liquid-ordered phase in model membranes. These observations suggest that the evolution of an ordered biochemically active liquid membrane could have evolved before the oxygenation of Earth's surface and the emergence of sterols.


Optimal timing of referral for nerve transfer surgery for postoperative C5 palsy.
Cervical nerve 5 palsy can occur following surgery for cervical spine pathology. The prognosis of C5 palsy is generally favorable, and most patients recover useful function. However, some patients do not recover useful strength. Nerve transfers are a potential effective treatment of postoperative severe C5 palsy. This study aimed to further delineate the natural history of recovery from postoperative C5 palsy, determine whether lack of recovery at specific time points predicts poor recovery prognosis, and thereby determine a reasonable time point for referral to a complex peripheral nerve specialist. The authors conducted a retrospective review of 72 patients who underwent surgery for cervical spondylosis and stenosis complicated by C5 palsy. Medical Research Council (MRC) motor strength grades were recorded preoperatively; immediately postoperatively; at discharge; and at 2 weeks, 3 months, 6 months, and 12 months postoperatively. Univariate and multivariate logistic regression models were used to identify demographic and clinical risk factors associated with recovery of useful strength after severe C5 palsy. The mean patient age was 62.5 years, and 36.1% of patients were female. Thirty patients (41.7%) experienced severe C5 palsy with less than antigravity strength (MRC grade 2 or less) at discharge. Twenty-one (70%) of these patients recovered useful strength (MRC grade 3 or greater) at 12 months postoperatively, and 9 patients (30%) did not recover useful strength at 12 months. Of those patients with persistent severe C5 palsy at 3 months postoperatively, 50% recovered useful strength at 12 months. Of those patients with persistent severe C5 palsy at 6 months postoperatively, 25% recovered useful strength at 12 months. No patient with MRC grade 0 or 1 strength at 6 months postoperatively recovered useful strength. A history of diabetes was associated with the occurrence of severe C5 palsy. On multivariate analysis, female sex was associated with recovery of useful strength. Most patients with severe C5 palsy recover useful strength in their C5 myotome within 12 months of onset. However, at 3 months postoperatively, patients with persistent severe C5 palsy had only a 50% chance of recovering useful strength by 12 months. Lack of recovery of useful strength at 3 months postoperatively is a reasonable time point for referral to a complex peripheral nerve center to establish care and to determine candidacy for nerve transfer surgery if severe C5 palsy persists.


Gender inequality and sexual height dimorphism in Chile.
Chile has experienced significant improvements in its economy; thus, a secular trend in height has been observed in its population. Gender equality has also improved hand in hand with active policies addressing the gender gap in several dimensions (work, education, health) and overall economic improvement. This study examined changes in sexual height dimorphism in four samples of Chilean male and female working-age subjects and attempted to establish associations with gender equality and welfare. Sexual height dimorphism was calculated and compared with gender equality and overall welfare indicators between 1955 and 1995. Sexual height dimorphism reduction was seen to be strongly associated with greater gender equality and some general welfare indicators, such as the infant mortality rate. Gross domestic product per capita was not associated with sexual height dimorphism, but it showed significant associations with gender equality indicators. Overall, the gender gap has been reduced in Chile, which can be observed through improvements in gender equality indicators and a reduction in height dimorphism, mainly in areas associated with women's health. However, gender equality is still far behind in terms of female labour participation and women in political power, which require attention and further improvements.


"I am busy surviving" - Views about physical exercise in older adults scheduled for colorectal cancer surgery.
Seventy percent of patients with colorectal cancer (CRC) are aged 65 years or older. Netherlands Comprehensive Cancer Organization (n.d.) [1] Surgery is an important treatment modality, depending on cancer stage and the resectability of the tumor. Frail older patients are at an increased risk for complications and reduced self-care capacity after surgery. Increasing physical fitness preoperatively (prehabilitation) might improve treatment outcomes, but challenges remain with regard to uptake, attrition, and non-compliance. The objectives of this study were to investigate the barriers, facilitators, and preferences for preoperative exercise programs in older patients scheduled for CRC surgery. This was a qualitative study, using in-depth interviews of fifteen patients aged 65 years and older and surgically treated for CRC, thirteen informal care givers (ICs) and nine health care providers (HCPs) with experience in prehabilitation. Data analysis was done through thematic coding analysis. Limited time, not receiving or misunderstanding information, physical ailments, and emotional impact of the diagnosis are barriers to preoperative exercise. Not having physical complaints (Patients, ICs, HCPs), understandable information provided by a physician (Patients, ICs), and low cost programs (ICs, HCPs) facilitate exercise. Exercise should not be too intensive (Patients, ICs) and should be adjusted to personal preferences and be provided close to home (Patients, ICs, HCPs). To engage frail older adults with CRC in preoperative exercise programs information on exercise should improve. Exercise programs should be easily accessible and take personal preferences, needs and abilities into account.


Malaria Four-year Epidemiological Trends in Sistan and Baluchistan Province, Iran.
Malaria is one of the foremost public health concerns in Iran, where more than 90% of malaria cases are reported in the southern and south-eastern areas of the country. The aim of this study was to assess the epidemiological trends of malaria over a four-year period in in the Sistan and Baluchistan province in south east of Iran. This descriptive epidemiological study examined malaria trends in Sistan and Baluchistan province from 2011 to 2014. The study used data collected in accordance with the Iranian Ministry of Health's malaria control and elimination protocol. This protocol has digitized the data reporting system for malaria, and all information were sent online to the Center of Disease Control in the Ministry of Health. In this manner, information on malaria cases in Sistan and Baluchistan were made available for the researchers to analyze. Descriptive and comparative analyses were conducted using the SPSS version 13. Annual incidence rates reported in 2011, 2012, 2013, and 2014 showed the prevalence of 89.9, 43.9, 38.3 and 36.6 (per 100,000 persons), respectively. Across all 4 years, the highest numbers of cases were found in persons 16-25 years old and among males. Most of the infected individuals were villagers and workers. In total, 64.8% of patients were Iranian and 29.5% were Pakistani. The highest number of cases was diagnosed in the cities of Sarbaz and Chabahar, with 1,742 and 1,707 cases, respectively. The results showed that over the last 4 years, 50.8% of cases have entered into Iran from foreign countries. The majority of cases involved parasites in the trophozoite stage of the life cycle. In terms of surveillance, passive care was reported in the majority of cases, and vivax malaria had the highest prevalence in comparison with other types. The findings are showing that the care, control and treatment system applied to Sistan and Baluchistan province has had a positive effect on decreasing the prevalence rate of Malaria disease. Meanwhile, it is recommended to policy makers to provide more health controls for border entries, stop irregular immigration and apply more precise case searches in order to have a complete and on time treatment in a way that the chain of transmission of the disease would be cut. Health education and knowledge-ability promotion programs are better to be set in order to develop self-protection and environment improvement among people.


Predicting deep venous thrombosis in pregnancy: out in "LEFt" field?
Clinicians' assessment of pretest probability, based on subjective criteria or prediction rules, is central to the diagnosis of deep venous thrombosis (DVT). Pretest probability assessment for DVT diagnosis has never been evaluated in pregnant women. To evaluate the accuracy of clinicians' subjective assessment of pretest probability for DVT diagnosis and identify prediction variables that could be used for pretest probability assessment in pregnant women with suspected DVT. A cross-sectional study conducted over 7 years (March 2000 to April 2007). 5 university-affiliated, tertiary care centers in Canada. 194 unselected pregnant women with suspected first DVT. Diagnosis of DVT was established with abnormal compression ultrasonography at presentation or on serial imaging. Pretest probability by subjective assessment was recorded by thrombosis experts for each patient before knowledge of results. The sensitivity, specificity, negative predictive value, and likelihood ratios of subjective pretest probability assessment and their corresponding 95% CIs were calculated on the basis of the diagnosis of DVT. Patients were DVT positive if they had diagnostic compression ultrasonography at initial or serial testing or symptomatic venous thromboembolism on follow-up. Patients were DVT negative if they had negative compression ultrasonography at presentation and no venous thromboembolism on follow-up. A prediction rule for assessing DVT was derived, and an internal validation study was done to explore its performance. The prevalence of DVT was 8.8%. Clinicians' subjective assessment of pretest probability categorized patients into 2 groups: low pretest probability (two thirds of patients) with a low prevalence of DVT (1.5% [95% CI, 0.4% to 5.4%]) and a negative predictive value of 98.5% (CI, 94.6% to 99.6%), and nonlow pretest probability with a higher prevalence of DVT (24.6% [CI, 15.5% to 36.7%]). Three variables (symptoms in the left leg [L], calf circumference difference > or = 2 cm [E], and first trimester presentation [Ft]) were highly predictive of DVT in pregnant patients. Few outcomes occurred. Altogether, 17 events were diagnosed during the study. The prediction rule derived should be validated on an independent sample before applying it to clinical practice. Subjective assessment of pretest probability seems to exclude DVT when the pretest probability is low. Moreover, 3 objective variables ("LEFt") may improve the accuracy of the diagnosis of DVT in pregnancy. Prospective validation studies are needed. Heart and Stroke Foundation of Ontario.


Crystal Structure of the Pre-fusion Nipah Virus Fusion Glycoprotein Reveals a Novel Hexamer-of-Trimers Assembly.
Nipah virus (NiV) is a paramyxovirus that infects host cells through the coordinated efforts of two envelope glycoproteins. The G glycoprotein attaches to cell receptors, triggering the fusion (F) glycoprotein to execute membrane fusion. Here we report the first crystal structure of the pre-fusion form of the NiV-F glycoprotein ectodomain. Interestingly this structure also revealed a hexamer-of-trimers encircling a central axis. Electron tomography of Nipah virus-like particles supported the hexameric pre-fusion model, and biochemical analyses supported the hexamer-of-trimers F assembly in solution. Importantly, structure-assisted site-directed mutagenesis of the interfaces between F trimers highlighted the functional relevance of the hexameric assembly. Shown here, in both cell-cell fusion and virus-cell fusion systems, our results suggested that this hexamer-of-trimers assembly was important during fusion pore formation. We propose that this assembly would stabilize the pre-fusion F conformation prior to cell attachment and facilitate the coordinated transition to a post-fusion conformation of all six F trimers upon triggering of a single trimer. Together, our data reveal a novel and functional pre-fusion architecture of a paramyxoviral fusion glycoprotein.


[Evidence-based therapeutic drug monitoring for saquinavir].
The human immunodeficiency virus (HIV) protease inhibitor saquinavir displays a large inter-individual variability in its pharmacokinetic parameters, related to a low absorption rate and an important hepatic metabolism. Based on literature, is the saquinavir therapeutic drug monitoring relevant? In naïve HIV-infected patients, the probability of achieving an undetectable HIV viral load at W48 was significantly associated with a saquinavir plasma trough concentration >100 ng/mL. Two studies in HIV-infected pre-treated patients reported that the genotypic inhibitory quotient was a predictive factor of virologic response with a threshold value around 40 ng/mL/mutation. Concerning the exposure-toxicity relationship, the risk of occurrence of grade 3-4 abdominal pains was more frequently associated with high concentrations of saquinavir, but without threshold value determination. Several studies, one of which was randomized, have reported the interest of saquinavir therapeutic drug monitoring to optimize the virologic response. Therefore, the level of evidence of the interest of saquinavir therapeutic drug monitoring is "recommended".


Yemeni families and child lead screening in Detroit.
This project was an exploratory effort to screen and treat immigrant Yemeni children who were at high risk for lead poisoning. The Detroit metropolitan area is home to the largest number of Arabic immigrants in the United States. In addition, Detroit has the largest rate of childhood lead poisoning in the state of Michigan. No published studies were found that explored the prevalence of lead poisoning among Yemeni children in Michigan. Immigrant children from countries where knowledge of lead poisoning is limited may be particularly vulnerable because of difficulties in language and accessing health care. Children's Hospital of Michigan CATCH School Mobile Health Center conducted this health-screening project. This article reports on the gender and health issues encountered during the community outreach lead testing effort within a Yemeni neighborhood in Detroit.


Deep learning with hierarchical convolutional factor analysis.
Unsupervised multilayered ("deep") models are considered for imagery. The model is represented using a hierarchical convolutional factor-analysis construction, with sparse factor loadings and scores. The computation of layer-dependent model parameters is implemented within a Bayesian setting, employing a Gibbs sampler and variational Bayesian (VB) analysis that explicitly exploit the convolutional nature of the expansion. To address large-scale and streaming data, an online version of VB is also developed. The number of dictionary elements at each layer is inferred from the data, based on a beta-Bernoulli implementation of the Indian buffet process. Example results are presented for several image-processing applications, with comparisons to related models in the literature.


Ezrin tunes T-cell activation by controlling Dlg1 and microtubule positioning at the immunological synapse.
T-cell receptor (TCR) signalling is triggered and tuned at immunological synapses by the generation of signalling complexes that associate into dynamic microclusters. Microcluster movement is necessary to tune TCR signalling, but the molecular mechanism involved remains poorly known. We show here that the membrane-microfilament linker ezrin has an important function in microcluster dynamics and in TCR signalling through its ability to set the microtubule network organization at the immunological synapse. Importantly, ezrin and microtubules are important to down-regulate signalling events leading to Erk1/2 activation. In addition, ezrin is required for appropriate NF-AT activation through p38 MAP kinase. Our data strongly support the notion that ezrin regulates immune synapse architecture and T-cell activation through its interaction with the scaffold protein Dlg1. These results uncover a crucial function for ezrin, Dlg1 and microtubules in the organization of the immune synapse and TCR signal down-regulation. Moreover, they underscore the importance of ezrin and Dlg1 in the regulation of NF-AT activation through p38.


Vascular endothelial growth factor expression correlates with serum CA125 and represents a useful tool in prediction of refractoriness to platinum-based chemotherapy and ascites formation in epithelial ovarian cancer.
There is an increasing need for the identification of novel biological markers and potential therapeutic targets in epithelial ovarian cancer (EOC). Given the critical role of growth factors in the biology of EOC, we aimed in the present study to evaluate the intratumoral expressions of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) proteins and their clinical relevance in a cohort of 100 patients with EOC. All patients received platinum-based chemotherapy after surgery. A comparative immunohistochemical study of normal ovarian and EOC tissues showed that both growth factors were expressed at higher levels in tumor samples. In our statistical analysis, while no association existed between the FGF expression status and the clinicopathological characteristics of patients, intratumoral VEGF was identified as a potential biomarker for the prediction of ascites formation. In addition, the expression status of VEGF appeared to independently predict overall survival and response to chemotherapy. Furthermore, a direct association was demonstrated between the pre-treatment VEGF expression and serum CA125 after three cycles of chemotherapy. In sum, we report for the first time to our knowledge the correlation between intratumoral VEGF and serum CA125 in EOC. Our data also shows the prognostic value of VEGF expression in EOC. These results suggest the potential value of intratumoral VEGF in patient stratification. Dual inhibition of VEGF and CA125 might bring about a better outcome for patients with EOC.