Genetic predisposition to adverse drug reactions in the intensive care unit.
Adverse drug reactions are a significant public health problem that leads to mortality, hospital admissions, an increased length of stay, increasing healthcare costs, and withdrawal of drugs from market. Intensive care unit patients are particularly vulnerable and are at an elevated risk. Critical care practitioners, regulatory agencies, and the pharmaceutical industry aggressively seek biomarkers to mitigate patient risk. The rapidly expanding field of pharmacogenomics focuses on the genetic contributions to the variability in drug response. Polymorphisms may explain why some groups of patients have the expected response to pharmacotherapy whereas others experience adverse drug reactions. Historically, genetic association studies have focused on characterizing the effects of variation in drug metabolizing enzymes on pharmacokinetics. Recent work has investigated drug transporters and the variants of genes encoding drug targets, both intended and unintended, that comprise pharmacodynamics. This has led to an appreciation of the role that genetics plays in adverse drug reactions that are either predictable extensions of a drug's known therapeutic effect or idiosyncratic.This review presents the evidence for a genetic predisposition to adverse drug reactions, focusing on gene variants producing alterations in drug pharmacokinetics and pharmacodynamics in intensive care unit patients. Genetic biomarkers with the strongest associations to adverse drug reaction risk in the intensive care unit are presented along with the medications involved. Variant genotypes and phenotypes, allelic frequencies in different populations, and clinical studies are discussed. The article also presents the current recommendations for pharmacogenetic testing in clinical practice and explores the drug, patient, research study design, regulatory, and practical issues that presently limit more widespread implementation.


Reducing sick leave, improving work ability, and quality of life in patients with mild to moderate Long COVID through psychosocial, physiotherapeutic, and nutritive supportive digital intervention (MiLoCoDaS): study protocol for a randomized controlled trial.
Following SARS-CoV-2 infection, a relevant proportion of patients suffer from persistent or recurring sequela, even after initially mild primary illness. Many patients experience exhaustion and fatigue, rendering them incapable of working. Long COVID exerts a substantial burden on society and the healthcare system: at least 65 million people are currently affected worldwide. The underlying pathobiology is a complex derangement in several organ systems. To date, causal pharmaceutical therapies remain elusive. Waiting lists for specialist care are long. Rapidly scalable digital interventions offering support for the frequent subgroup of patients with mild to moderate impairment from Long COVID are urgently needed. The MiLoCoDaS study compares three intensities of a potentially rapidly scalable digital intervention aiming to accelerate recovery. The overall objective is to figure out if there is a difference in the effect sizes between these modalities. The online intervention uses a learning platform (LMS, TYPO3 framework) comprising 12 sessions of medical, psychological, physiotherapeutic, and nutritional content. The three modalities differ as follows: patient information only (sham intervention, control), information plus interactive digital workbook including practical exercises (digital intervention), and the digital workbook augmented by once-weekly online seminars and discussion groups (person and peer-contact). Eligible patients are 18-67 years old satisfying Long COVID diagnostic criteria. Patients are recruited through primary care physicians and randomly allocated. The primary endpoint is the number of sick leave days during the 6-month observation period; secondary endpoints are patient-reported symptoms, quality of life, and work ability. The study size provides a power of 80% at a type I error of < 0.05 to show an effect size of Cohen = 0.3 between the augmented and the sham intervention (N = 152 per arm, total accounting for attrition N = 600). If one of the two interventions is superior to providing information alone, MiLoCoDaS would provide the starting point for a rapidly scalable digital intervention for the frequent and currently underserved patient group with mild to moderate impairment from Long COVID. Several caveats pertain to the heterogeneity of Long COVID manifestation and duration prior to inclusion. It is conceivable that the possible effect of the intervention may differ across subgroups. Therefore, a priori defined secondary analysis will be conducted. German Clinical Trials Register (DRKS) DRKS00028964. Registered on 24 August 2022.


Alterations in gut virome are associated with cognitive function and minimal hepatic encephalopathy cross-sectionally and longitudinally in cirrhosis.
Cognitive dysfunction due to minimal hepatic encephalopathy (MHE) adversely impacts patients with cirrhosis and more precise therapies are needed. Gut-brain axis changes are therapeutic targets, but prior studies have largely focused on bacterial changes. Our aim was to determine linkages between individual cognitive testing results and bacteria with the virome using a cross-sectional and longitudinal approach. We included cross-sectional (n = 138) and longitudinal analyses (n = 36) of patients with cirrhosis tested using three cognitive modalities, which were psychometric hepatic encephalopathy score (PHES), inhibitory control test (ICT), Stroop, and all three. Stool metagenomics with virome and bacteriome were analyzed studied cross-sectionally and in a subset followed for development/reversal of MHE repeated at 6 months (longitudinally only using PHES). Cross-sectional: We found no significant changes in α/β diversity in viruses or bacteria regardless of cognitive testing. Cognitively impaired patients were more likely to have higher relative abundance of bacteriophages linked with Streptococcus, Faecalibacterium, and Lactobacillus, which were distinct based on modality. These were also linked with cognition on correlation networks. Longitudinally, 27 patients remained stable while 9 changed their MHE status. Similar changes in phages that are linked with Streptococcus, Faecalibacterium, and Lactobacillus were seen. These phages can influence ammonia, lactate, and short-chain fatty acid generation, which are neuro-active. In conclusion, we found linkages between bacteriophages and cognitive function likely due to impact on bacteria that produce neuroactive metabolites cross-sectionally and longitudinally. These findings could help explore bacteriophages as options to influence treatment for MHE in cirrhosis.


A comprehensive review of current treatments for granulomatous cheilitis.
Granulomatous cheilitis (GC) is a poorly understood disease process belonging to the larger group of orofacial granulomatosis. The treatment of GC has proven exceedingly difficult. While various treatments have been applied to GC, there has been no uniform or predictably successful model demonstrated in the literature. Poor understanding of the aetiological mechanisms underpinning GC has significantly hampered the development of an effective approach to treatment. Those therapies that have shown promise principally consist of agents with anti-inflammatory activity such as corticosteroids and immunomodulatory medications. On a careful review of the literature, we have found no systematic review and assessment of current treatments. We seek to address this absence in the available literature by providing a consolidated overview of current treatment for GC.


Identification of TPIT and other novel autoantigens in lymphocytic hypophysitis: immunoscreening of a pituitary cDNA library and development of immunoprecipitation assays.
Lymphocytic hypophysitis is an organ-specific autoimmune disease of the pituitary gland. A specific and sensitive serological test currently does not exist to aid in the diagnosis. To identify target autoantigens in lymphocytic hypophysitis and develop a diagnostic assay for these proteins. A pituitary cDNA expression library was immunoscreened using sera from four patients with lymphocytic hypophysitis. Relevant cDNA clones from screening, along with previously identified autoantigens pituitary gland-specific factor 1a and 2 (PGSF1a and PGSF2) and neuron-specific enolase (NSE) were tested in an in vitro transcription and translation immunoprecipitation assay. The corticotroph-specific transcription factor, TPIT, was investigated separately as a candidate autoantigen. Significantly positive autoantibody reactivity against TPIT was found in 9/86 hypophysitis patients vs 1/90 controls (P = 0.018). The reactivity against TPIT was not specific for lymphocytic hypophysitis with autoantibodies detectable in the sera from patients with other autoimmune endocrine diseases. Autoantibodies were also detected against chromodomain-helicase-DNA binding protein 8, presynaptic cytomatrix protein (piccolo), Ca(2+)-dependent secretion activator, PGSF2 and NSE in serum samples from patients with lymphocytic hypophysitis, but at a frequency that did not differ from healthy controls. Importantly, 8/86 patients with lymphocytic hypophysitis had autoantibodies against any two autoantigens in comparison with 0/90 controls (P = 0.0093). TPIT, a corticotroph-specific transcription factor, was identified as a target autoantigen in 10.5% of patients with lymphocytic hypophysitis. Further autoantigens related to vesicle processing were also identified as potential autoantigens with different immunoreactivity patterns in patients and controls.


Assessing Self-concept as a Mediator Between Anger and Resilience in Adolescents With Cancer in Taiwan.
Anger is considered a common method used by patients to relieve emotional frustrations. However, this emotional response is not a common research focus for adolescents with cancer. The aim of this study was to determine whether self-concept mediated the relationship between anger and resilience for adolescent patients currently being treated for cancer. A cross-sectional study of 40 adolescents with cancer was conducted. The instruments included the Chinese Beck Self-Concept Inventory, the Chinese Beck Anger Inventory, and the Chinese Resilience Scale. Mediation analysis was also conducted. The results indicate that (1) variations in anger significantly account for 6.86% of observed variations in self-concept, (2) variations in self-concept significantly account for 52.83% of observed variations in resilience, (3) variations in anger significantly account for 10.96% of observed variations in resilience, and (4) when paths in conditions 1 and 2 were controlled, variations in anger through self-concept significantly account for 54.04% of observed variations in resilience, and variations in anger did not significantly account for observed variations in resilience. Gender and age might affect anger control. Despite worse physical functioning and an impacted appearance, participants had normative-to-positive self-concept levels, suggesting that their self-concept might not be affected by cancer. Self-concept might play a mediating role between anger and resilience, thus helping to bridge this knowledge gap. The current gap in knowledge regarding the mediating relationship necessitates the implementation of a large-scale study designed to verify the mediating role of self-concept between anger and resilience.


Production and characterization of monoclonal antibodies against the novel neutrophil activating peptide NAP/IL-8.
LPS-stimulated human mononuclear cells have recently been shown to produce large amounts of a novel neutrophil-activating cytokine termed neutrophil-activating peptide NAP/IL-8. This chemotactic factor has in the meantime been biochemically and functionally well characterized. We now report on four distinct murine mAb directed against this peptide. All four mAb are different in respect to isotype and IEF pattern. The cross-reactivity with partially homologous peptides like beta-thromboglobulin and platelet factor 4 showed defined differences. With the use of these antibodies we were able to detect solid phase as well as soluble NAP/IL-8 as tested in a sandwich-ELISA. Also dose-dependent neutralization of NAP/IL-8 chemotactic activity in the Boyden chamber chemotaxis assay was observed. Immunoaffinity columns prepared with these four mAb bound NAP/IL-8 from supernatants of LPS-stimulated mononuclear cells. Furthermore, Western immunoblots showed a single protein band in the expected region of Mr of 10 kDa with all four mAb presented.


Neuropsychological effects of formaldehyde use.
This study compared five individuals who intentionally ingested formaldehyde (possibly laced with PCP) in marijuana cigarettes to a control group on measures of cognitive ability. Formaldehyde, a major component in embalming fluid, is legal to purchase and possess and has become popular due to its euphoric properties. In significant doses, the chemical is a neurotoxin. The effects of inadvertent exposure are fairly well known, but the effects of intentional ingestion have only recently been investigated. In addition, there has been little research on the effects of formaldehyde use specific to intellectual ability and cognitive intactness. The results of this study indicate intentional ingestion may cause a decline in neuropsychological intactness, as measured by performance on the Shipley Institute of Living Scale.


Herbal medicines in Hawaii from tradition to convention.
The stories of kava and chaulmoogra demonstrate the importance of herbal products in ancient and recent Hawaiian medicine. Kava is a psychoactive beverage that has been used ceremonially for millennia throughout the Pacific. It is a nonfermented depressant that causes tranquil intoxication in which thoughts and memory remain clear. Its broad pharmacologic activity led to use in Hawaii to treat skin disorders and later in Germany to treat gonorrhea. Kava is now available outside the Pacific basin as a relaxant, emerging as a popular, albeit deritualized, natural product. In the late 19th century, the main treatment for leprosy was chaulmoogra, extracted from Hydnocarpus seeds. Chaulmoogra had been a traditional treatment for skin diseases in Ayurvedic and Chinese medicine. Chaulmoogra from Asian markets was expensive and usually adulterated so the USDA decided to plant Hydnocarpus in Hawaii. Joseph Rock, a botanist at University of Hawaii, trekked through southeast Asia collecting fresh seeds to plant on Oahu. Rock's trees provided chaulmoogra for leprosy patients on Molokai and elsewhere until it was replaced by dapsone. Chaulmoogra, once the treatment for leprosy worldwide, is now nearly forgotten; kava, once poorly known outside the Pacific, is now a widely-used alternative medicine. Hawaii will probably continue its role in the transition of plants from traditional use to conventional use.


Fowlpox virus as a recombinant vaccine vector for use in mammals and poultry.
Live vaccines against fowlpox virus, which causes moderate pathology in poultry and is the type species of the Avipoxvirus genus, were developed in the 1920s. Development of recombinant fowlpox virus vector vaccines began in the 1980s, for use not only in poultry, but also in mammals including humans. In common with other avipoxviruses, such as canarypox virus, fowlpox virus enters mammalian cells and expresses proteins, but replicates abortively. The use of fowlpox virus as a safe vehicle for expression of foreign antigens and host immunomodulators, is being evaluated in numerous clinical trials of vaccines against cancer, malaria, tuberculosis and AIDS, notably in heterologous prime-boost regimens. In this article, technical approaches to, and issues surrounding, the use of fowlpox virus as a recombinant vaccine vector in poultry and mammals are reviewed.


Serum Metabolites Associated with Healthy Diets in African Americans and European Americans.
High diet quality is associated with a lower risk of chronic diseases. Metabolomics can be used to identify objective biomarkers of diet quality. We used metabolomics to identify serum metabolites associated with 4 diet indices and the components within these indices in 2 samples from African Americans and European Americans. We studied cross-sectional associations between known metabolites and Healthy Eating Index (HEI)-2015, Alternative Healthy Eating Index (AHEI)-2010, the Dietary Approaches to Stop Hypertension Trial (DASH) diet, alternate Mediterranean diet (aMED), and their components using untargeted metabolomics in 2 samples (n1 = 1,806, n2 = 2,056) of the Atherosclerosis Risk in Communities study (aged 45-64 y at baseline). Dietary intakes were assessed using an FFQ. We used multivariable linear regression models to examine associations between diet indices and serum metabolites in each sample, adjusting for participant characteristics. Metabolites significantly associated with diet indices were meta-analyzed across 2 samples. C-statistics were calculated to examine if these candidate biomarkers improved prediction of individuals in the highest compared with lowest quintile of diet scores beyond participant characteristics. Seventeen unique metabolites (HEI: n = 6; AHEI: n = 5; DASH: n = 14; aMED: n = 2) were significantly associated with higher diet scores after Bonferroni correction in sample 1 and sample 2. Six of 17 significant metabolites [glycerate, N-methylproline, stachydrine, threonate, pyridoxate, 3-(4-hydroxyphenyl)lactate)] were associated with ≥1 dietary pattern. Candidate biomarkers of HEI, AHEI, and DASH distinguished individuals with highest compared with lowest quintile of diet scores beyond participant characteristics in samples 1 and 2 (P value for difference in C-statistics <0.02 for all 3 diet indices). Candidate biomarkers of aMED did not improve C-statistics beyond participant characteristics (P value = 0.930). A considerable overlap of metabolites associated with HEI, AHEI, DASH, and aMED reflects the similar food components and similar metabolic pathways involved in the metabolism of healthy diets in African Americans and European Americans.


When is the allele-sharing dissimilarity between two populations exceeded by the allele-sharing dissimilarity of a population with itself?
Allele-sharing statistics for a genetic locus measure the dissimilarity between two populations as a mean of the dissimilarity between random pairs of individuals, one from each population. Owing to within-population variation in genotype, allele-sharing dissimilarities can have the property that they have a nonzero value when computed between a population and itself. We consider the mathematical properties of allele-sharing dissimilarities in a pair of populations, treating the allele frequencies in the two populations parametrically. Examining two formulations of allele-sharing dissimilarity, we obtain the distributions of within-population and between-population dissimilarities for pairs of individuals. We then mathematically explore the scenarios in which, for certain allele-frequency distributions, the within-population dissimilarity - the mean dissimilarity between randomly chosen members of a population - can exceed the dissimilarity between two populations. Such scenarios assist in explaining observations in population-genetic data that members of a population can be empirically more genetically dissimilar from each other on average than they are from members of another population. For a population pair, however, the mathematical analysis finds that at least one of the two populations always possesses smaller within-population dissimilarity than the value of the between-population dissimilarity. We illustrate the mathematical results with an application to human population-genetic data.


Cholinergic dependence of gallbladder response to cholecystokinin in the guinea pig in vivo.
The physiological mechanism responsible for cholecystokinin (CCK)-induced gallbladder (GB) contraction is unclear. We investigated the relative roles of direct muscle stimulation and neural activation at physiological and supraphysiological levels of CCK-octapeptide (CCK-8) using an in vivo guinea pig model. GB pressure was measured by a pressure transducer inserted into the GB lumen. Infusion of CCK-8 (2.5-40 ng.kg-1.min-1) increased GB pressure in a dose-dependent fashion. Pretreatment with atropine or hexamethonium antagonized GB responses to low doses of CCK-8 (2.5-5 ng.kg-1.min-1) but had no effect on doses greater than 10 ng.kg-1.min-1. Bilateral truncal vagotomy also significantly reduced GB responses to low doses of CCK-8 (2.5-5 ng.kg-1.min-1) but did not affect responses to high doses (10-40 ng.kg-1.min-1). Atropine or hexamethonium had no further inhibitory effects on guinea pigs that had undergone truncal vagotomy. Fasted guinea pigs that were fed ad libitum produced a postprandial peak plasma CCK level of 7.8 +/- 1.8 pM. This level was most closely approximated by infusion of 5 ng.kg-1.min-1 of CCK-8 (8.4 +/- 2.6 pM). CCK-8 infusion at greater than or equal to 10 ng.kg-1.min-1 gave supraphysiological plasma CCK levels. These observations indicate that CCK stimulated GB contraction via both a neural and a direct smooth muscle effect. Doses of CCK-8 that produce physiological plasma CCK levels act via stimulation of presynaptic cholinergic neurons in a vagally mediated pathway, whereas doses of CCK-8 that produce supraphysiological CCK levels act directly on GB smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)


Unprecedented synthesis of 1,2,3-triazolo-cinnolinone via Sonogashira coupling and intramolecular cyclization.
An unprecedented copper mediated one-pot sequential synthesis of 1,2,3-triazolo cinnolinone derivatives from 2-halo-phenyl triazoles and terminal alkynes has been reported. Under the optimized reaction conditions, a broad range of substituted triazoles and alkynes were found to participate in this transformation, thus affording unknown 1,2,3-triazolo cinnolinone derivatives in moderate to excellent yields. This method proceeds through sequential C-C coupling followed by an annulation cascade sequence in the same vessel under atmospheric air as the sole oxidant, thus representing a simple, efficient and atom economical approach for the synthesis of aza-cinnolinones.


Measuring cardiac output at the bedside.
Bedside cardiac output (CO) measurement is an important part of routine hemodynamic monitoring in the differential diagnosis of circulatory shock and fluid management. Different choices of CO measurement devices are available. The purpose of this review is to review the importance of CO [or stroke volume (SV)] measurement and to discuss the various methods (devices) used in determination of CO. CO measurement devices can be classified into two types: those use simple physical principles with minimal assumptions, and those predicting CO via mathematical modelling with a number of assumptions. Both have pros and cons, with the former being more accurate but with limited continuous monitoring capability whereas the latter less accurate but usually equipped with continuous monitoring functionality. With frequent updates in mathematical models, research data constantly become outdated in this area. Recent data suggest devices based on mathematical modelling have limited accuracies and poor precisions. Measurement of CO or SV is important in critically ill patients. Most devices have accuracy and reliability issues. The choice of device should depend on the purpose of measurement. For diagnostic purposes, devices based on simple physical principles, especially thermodilution and transthoracic echocardiography are more reliable due to accuracy.


[Problem-based learning in cardiopulmonary resuscitation: basic life support].
Descriptive and exploratory study, aimed to develop an educational practice of Problem-Based Learning in CPR/BLS with 24 students in the third stage of the Nursing Undergraduate Course in a University in the Southern region of Brazil. The study used the PBL methodology, focused on problem situations of cardiopulmonary arrest, and was approved by the CONEP. The methodological strategies for data collection, such as participative observation and questionnaires to evaluate the learning, the educational practices and their methodology, allowed for grouping the results in: students' expectations; group activities; individual activities; practical activities; evaluation of the meetings and their methodology. The study showed that PBL allows the educator to evaluate the academic learning process in several dimensions, functioning as a motivating factor for both the educator and the student, because it allows the theoretical-practical integration in an integrated learning process.


Common nonsense mutations in RAD52.
RAD51, RAD52, and RAD54 encode proteins that are critical to the repair of double-strand DNA breaks by homologous recombination. The physical interactions among the products of RAD51, BRCA1, and BRCA2 have suggested that the BRCA1 and BRCA2 breast cancer susceptibility genes may function, at least in part, in this DNA damage repair pathway. Given the observation that different genes within a common functional pathway may be targeted by mutations in human cancers, we analyzed RAD51, RAD52, and RAD54 for the presence of germ-line mutations in 100 cases with early-onset breast cancer and for somatic mutations in 15 human breast cancer cell lines. Two premature stop codons, Ser346ter and Tyr415ter, were identified in germ-line RAD52 alleles from 5% of early-onset breast cancer cases. Together, these two heterozygous mutations were also found in 8% of a healthy control population, indicating that they do not confer an increased risk for breast cancer. A rare germ-line missense mutation was identified in RAD54, whereas no sequence variants were found in RAD51. None of the three RAD genes demonstrated somatic mutations in breast cancer cell lines. We conclude that, despite their potential functional association with the BRCA gene products, RAD51, RAD52, and RAD54 are not themselves targeted by mutations in human breast cancer. The presence of common nonsense mutations in RAD52 within the population may have significance for other conditions associated with potential alterations in DNA damage repair pathways.


Thrombus formation during intracranial aneurysm coil placement: treatment with intra-arterial abciximab.
The management of thrombus formation during coil placement in an intracranial aneurysm is important in minimizing periprocedural morbidity and mortality. We report on seven cases in which the primary treatment for thrombus formation during such coil placement was intra-arterial abciximab infusion. Clinical and radiologic records of 100 consecutive patients who underwent coil placement in intracranial aneurysms at our institution during a 1-year period were reviewed. We identified seven cases (four ruptured aneurysms, three unruptured aneurysms) in which thrombus formation occurred during the procedure. Intra-arterial abciximab infusion, up to 5 mg, completely dissolved the thrombus in four of seven patients and almost completely dissolved it in two. In one patient with distal emboli, recanalization was not achieved. In two patients, an intravenous bolus of abciximab without 12-hour infusion was also given adjunctively. In one patient, leakage of contrast material occurred; this was related to the intra-arterial infusion. Clinically, no new neurologic deficits were directly related to the intra-arterial abciximab infusion. Six patients had good clinical outcome, and one patient died. Relatively low-dose, intra-arterial abciximab infusion can immediately dissolve an acute thrombus that forms during intracranial aneurysm coil placement. Although neither the optimal dose of intra-arterial abciximab nor the need to supplement the intra-arterial infusion with intravenous administration was established, we preliminarily found that low-dose intra-arterial abciximab infusion may be relatively effective and safe in this setting, even in patients with acute subarachnoid hemorrhage.


Patterns of use and incidence of smokeless tobacco consumption in school-age children.
A sample of 5,392 students were surveyed using a 42-item, multiple-choice questionnaire from a population of 19,040 Texas school-age children. The geographic distribution was 70% urban and 30% rural, with a representative sampling of the various racial and ethnic groups within Texas. The results of the survey indicated that 486 (9%) of the students regularly used smokeless tobacco, 810 (15%) regularly smoked cigarettes, and 4,096 (76%) used no tobacco products. Further, 77% perceived cigarette smoking as very harmful, while only 40% perceived smokeless tobacco as very harmful. Age of initiating use indicated that 55% of smokeless tobacco users started before the age of 13 years, whereas only 36% of cigarette smokers began that early.


Vasa previa: prenatal diagnosis and management.
Vasa previa is a rare disorder of placentation associated with a high rate of perinatal morbidity and mortality when undetected before delivery. We have evaluated the recent evidence for prenatal diagnosis and management of vasa previa. Around 85% of cases of vasa previa have one or more identifiable risk factors including in-vitro fertilization, multiple gestations, bilobed, succenturiate or low-lying placentas, and velamentous cord insertion. The development of standardized prenatal targeted scanning protocols may improve perinatal outcomes. There is no clear consensus on the optimal surveillance strategy including the need for hospitalization, timing of corticosteroids administration and the value of transvaginal cervical length measurements. Outpatient management is possible if there is no evidence of cervical shortening on ultrasound and there are no symptoms of bleeding or uterine contractions. Recent national guidelines and expert reviews have recommended scheduled cesarean section of all asymptomatic women presenting with vasa previa between 34 and 36 weeks' gestation. Prenatal diagnosis of vasa previa is pivotal to prevent intrapartum fetal death. Although there is insufficient evidence to support the universal mid-gestation ultrasound screening for vasa previa, recent evidence indicates the need for standardized prenatal targeted screening protocols of pregnancies at high-risk of vasa previa.


Pharmacological Inhibition and Activation of the Ca2+ Activated Cl- Channel TMEM16A.
TMEM16A is a Ca2+ activated Cl- channel with important functions in airways, intestine, and other epithelial organs. Activation of TMEM16A is proposed as a therapy in cystic fibrosis (CF) to reinstall airway Cl- secretion and to enhance airway surface liquid (ASL). This CFTR-agnostic approach is thought to improve mucociliary clearance and lung function in CF. This could indeed improve ASL, however, mucus release and airway contraction may also be induced by activators of TMEM16A, particularly in inflamed airways of patients with asthma, COPD, or CF. Currently, both activators and inhibitors of TMEM16A are developed and examined in different types of tissues. Here we compare activation and inhibition of endogenous and overexpressed TMEM16A and analyze potential off-target effects. The three well-known blockers benzbromarone, niclosamide, and Ani9 inhibited both TMEM16A and ATP-induced Ca2+ increase by variable degrees, depending on the cell type. Niclosamide, while blocking Ca2+ activated TMEM16A, also induced a subtle but significant Ca2+ store release and inhibited store-operated Ca2+ influx. Niclosamide, benzbromarone and Ani9 also affected TMEM16F whole cell currents, indicating limited specificity for these inhibitors. The compounds Eact, cinnamaldehyde, and melittin, as well as the phosphatidylinositol diC8-PIP2 are the reported activators of TMEM16A. However, the compounds were unable to activate endogenous TMEM16A in HT29 colonic epithelial cells. In contrast, TMEM16A overexpressed in HEK293 cells was potently stimulated by these activators. We speculate that overexpressed TMEM16A might have a better accessibility to intracellular Ca2+, which causes spontaneous activity even at basal intracellular Ca2+ concentrations. Small molecules may therefore potentiate pre-stimulated TMEM16A currents, but may otherwise fail to activate silent endogenous TMEM16A.


Brilliant Blue as an alternative dye to Fast Green for in ovo electroporation.
Chick embryo electroporation is a powerful tool for the introduction of transgenes into tissues of interest for the study of developmental biology. This method often uses Fast Green to visualize the injected area by staining the solution containing DNA green. Here, we show that Fast Green fluoresces in a red color after electroporation, suggesting that researchers need to be cautious when detecting red fluorescence. Fast Green solution did not show any fluorescence before injection into chick embryos, but fluoresced red within 3 min post-injection into chick embryos. We identified Brilliant Blue as suitable alternative dye for use as an indicator of injection sites in ovo electroporation. We found that 0.2% of Brilliant Blue was sufficient to track the area of DNA injection. In addition, this chemical did not show red fluorescence after electroporation. Our findings demonstrate that Brilliant Blue can be used for detecting red fluorescent proteins introduced into chick embryos by electroporation. Our study also shows useful examples for the application of Brilliant Blue for the precise quantification of two fluorescence intensities after EGFP and mCherry co-electroporation.


Hemispheric asymmetries in reading Korean: task matters.
Native Korean readers were studied in a visual half-field paradigm. Subjects were to make speeded judgments on Hangul (syllabic) and Hanzza (logographic) scripts based on phonetic or visual properties of the stimuli. A task by visual field interaction was obtained indicating that, for both scripts, responses on the phonetic task were faster in the right visual field, whereas no visual field differences were found on the visual task. Script type did not interact with visual field. The results support a task-based account of hemispheric differences in verbal processing.


Ultra-high-field MR imaging in multiple sclerosis.
In multiple sclerosis (MS), MRI is the most important paraclinical tool used to inform diagnosis and for monitoring disease evolution, either natural or modified by treatment. The increased availability of ultra-high-field magnets (7 Tesla or higher) gives rise to questions about the main benefits of and challenges for their use in patients with MS. The main advantages of ultra-high-field MRI are the improved signal-to-noise ratio, greater chemical shift dispersion, and improved contrast due to magnetic susceptibility variations, which lead to increased sensitivity to the heterogeneous pathological substrates of the disease. At present, ultra-high-field MRI is mainly used to improve our understanding of MS pathogenesis. This review discusses the main achievements that have so far come from the use of these scanners, which are: better visualisation of white matter lesions and their morphological characteristics; an improvement in the ability to visualise grey matter lesions and their exact location; the quantification of 'novel' metabolites which may have a role in axonal degeneration; and greater sensitivity to iron accumulation. The application of ultra-high-field systems in standard clinical practice is still some way off since their role in the diagnostic work-up of patients at presentation with clinically isolated syndromes, or in monitoring disease progression or treatment response in patients with definite MS, needs to be established. Additional challenges remain in the development of morphological, quantitative and functional imaging methods at these field strengths, techniques which may ultimately lead to novel biomarkers for monitoring disease evolution and treatment response.


Second vascular access after failure of the first fistula in the elderly .
In patients with failure of an initial arteriovenous fistula (AVF), a subsequent vascular access is needed before hemodialysis (HD) initiation. To assess the optimal access strategy after a failed AVF, we linked data from the US Renal Data System with Medicare claims data identifying 21,436 patients ≥ 67 years old who started HD between January 1, 2005, and December 31, 2008, with an AVF placed as their first predialysis access. Of the 10,568 subjects whose AVF failed, 1,796 patients had an AVF placed as a second access predialysis (AVF2 group) and 399 patients had an arteriovenous graft placed as a second access predialysis (AVG2 group). Second access success was defined as HD initiation for the first HD session using this access avoiding need for a catheter. The mean age for AVF2 and AVG2 groups was 75.9 ± 6.0 and 75.9 ± 5.9 years with a significantly greater percentage of men and whites in the AVF2 group and women and blacks in the AVG2 group. Overall, 53% of AVF2 group initiated dialysis using AVF2, and 66% of AVG2 group started dialysis using AVG2 (p < 0.001). The following variables were found to be associated with AVF2 failure: female gender, peripheral vascular disease (PVD), interventional procedures, and the absence of pre-ESRD nephrology care. AVG2 failure was associated with white race, lower body mass index (BMI), and the absence of pre-ESRD (end-stage renal disease) nephrology care. Since the success rate to avoid the use of a catheter was significantly higher in the AVG2 group than in the AVF2 group, an AVG may be a preferable choice of second access in certain patients, especially in females, blacks and those with PVD. .


QALYs and carers.
When going 'beyond the patient', to measure QALYs for unpaid carers, a number of additional methodological considerations and value judgements must be made. While there is no theoretical reason to restrict the measurement of QALYs to patients, decisions have to be made about which carers to consider, what instruments to use and how to aggregate and present QALYs for carers and patients. Current, albeit limited, practice in measuring QALY gains to carers in economic evaluation varies, suggesting that there may be inconsistency in judgements about whether interventions are deemed cost effective. While conventional health-related quality-of-life tools can, in theory, be used to estimate QALYs, there are both theoretical and empirical concerns over the suitability of their use with carers. Measures that take a broader view of health or well-being may be more appropriate. Incorporating QALYs of carers in economic evaluations may have important distributional consequences and, therefore, greater normative discussion over the appropriateness of incorporating these impacts is required. In the longer term, more flexible forms of cost-per-QALY analysis may be required to take account of the broader impacts on carers and the weight these impacts should receive in decision making.


A common complement C3 variant is associated with protection against wet age-related macular degeneration in a Japanese population.
Genetic variants in the complement component 3 gene (C3) have been shown to be associated with age-related macular degeneration (AMD) in Caucasian populations of European descent. In particular, a nonsynonymous coding variant, rs2230199 (R102G), is presumed to be the most likely causal variant in the C3 locus based on strong statistical evidence for disease association and mechanistic functional evidence. However, the risk allele is absent or rare (<1%) in Japanese and Chinese populations, and the association of R102G with AMD has not been reported in Asian populations. Genetic heterogeneity of disease-associated variants among different ethnicities is common in complex diseases. Here, we sought to examine whether other common variants in C3 are associated with wet AMD, a common advanced-stage manifestation of AMD, in a Japanese population. We genotyped 13 tag single nucleotide polymorphisms (SNPs) that capture the majority of common variations in the C3 locus and tested for associations between these SNPs and wet AMD in a Japanese population comprising 420 case subjects and 197 controls. A noncoding variant in C3 (rs2241394) exhibited statistically significant evidence of association (allelic P = 8.32 × 10(-4); odds ratio = 0.48 [95% CI = 0.31-0.74] for the rs2241394 C allele). Multilocus logistic regression analysis confirmed that the effect of rs2241394 was independent of the previously described loci at ARMS2 and CFH, and that the model including variants in ARMS2 and CFH plus C3 rs2241394 provided a better fit than the model without rs2241394. We found no evidence of epistasis between variants in C3 and CFH, despite the fact that they are involved in the same biological pathway. Our study provides evidence that C3 is a common AMD-associated locus that transcends racial boundaries and provides an impetus for more detailed genetic characterization of the C3 locus in Asian populations.


Neferine inhibits growth and migration of gastrointestinal stromal tumor cell line GIST-T1 by up-regulation of miR-449a.
Gastrointestinal stromal tumor (GIST) threatens the health of middle-aged and older people with high recurrence rate and low survival rate. In this study, Neferin (Nef) was hoped to control growth and migration of GIST cell line GIST-T1. Cell viability, proliferation, apoptosis, and migration were determined by cell counting kit-8 (CCK-8) assay, bromodeoxyuridine (BrdU) assay, Annexin V-FITC/PI double staining method, and Transwell assay, respectively. The expression level of miR-449a was determined by qRT-PCR. Cell transfection was conducted to alter the expression level of miR-449a. Protein expression levels of key factors involved in cell cycle, cell apoptosis, cell migration, PI3K/AKT pathway and Notch pathways were analyzed by western boltting. Nef significantly inhibited GIST-T1 cell viability, proliferation, migration, but promoted cell apoptosis. The expression level of miR-449a was up-regulated in GIST-T1 cells after Nef treatment. Suppression of miR-449a reversed the Nef-induced GIST-T1 cell proliferation and migration inhibition, as well as cell apoptosis. Importantly, Nef inactivated PI3K/AKT and Notch pathways in GIST-T1 cells by up-regulating miR-449a. Inhibitors of PI3K/AKT and Notch pathways notably reversed the effects of Nef + miR-449a inhibitor on GIST-T1 cell proliferation, apoptosis and migration. Besides, Nef also suppressed human gastric cancer SGC7901 cell migration and induced cell apoptosis. Nef suppressed growth and migration of GIST-T1 cells possibly via up-regulation of miR-449a and then inactivation of PI3K/AKT and Notch pathways.


The impact of dosing interval in a novel tandem oral dosing strategy: enhancing the exposure of low solubility drug candidates in a preclinical setting.
In drug discovery, time and resource constraints necessitate increasingly early decision making to accelerate or stop preclinical programs. Early discovery drug candidates may be potent inhibitors of new targets, but all too often exhibit poor pharmaceutical or pharmacokinetic properties that limit the in vivo exposure. Low solubility of a drug candidate often leads to poor oral bioavailability and poor dose linearity. This issue is more significant for efficacy and target safety studies where high drug exposures are desired. When solubility issues are confronted, enabling formulations are often required to improve the exposure. However, this approach often requires a substantial and lengthy investment to develop the formulation. Previously, we introduced a gastrointestinal (GI) transit time-based novel oral tandem dosing strategy that enhanced in vivo exposures in rats. In this study, a refined time interval versus dose theory was tested. The resulting in vivo exposures based on altering frequency and doses were compared, and significant impacts were found.


Brain iron levels in attention-deficit/hyperactivity disorder: a pilot MRI study.
Brain iron deficiency has been supposed to be involved in the pathophysiology of ADHD. Available studies assessing iron in ADHD are based on serum ferritin, a peripheral marker of iron status. To what extent serum ferritin correlates with brain iron (BI) is unclear. The main aim of this study was to compare BI, estimated with magnetic resonance imaging (MRI) in the putamen, pallidum, caudate, and thalamus, between children with and without ADHD. The secondary aim was to assess the correlation between serum ferritin and BI levels. Thirty-six children (18 with and 18 without ADHD, the latter including nine healthy controls and nine psychiatric controls) completed MRI and blood sampling. Brain iron levels were estimated by imaging T2*. Children with ADHD showed significantly lower estimated BI in right and left thalamus compared to healthy controls. Estimated BI did not differ significantly between children with ADHD and psychiatric controls. Children with ADHD had significantly lower levels of serum ferritin than healthy as well as psychiatric controls. Serum ferritin and T2* values did not correlate significantly in most regions. Low iron in the thalamus may contribute to ADHD pathophysiology.


Conserving evolutionary history does not result in greater diversity over geological time scales.
Alternative prioritization strategies have been proposed to safeguard biodiversity over macroevolutionary time scales. The first prioritizes the most distantly related species-maximizing phylogenetic diversity (PD)-in the hopes of capturing at least some lineages that will successfully diversify into the future. The second prioritizes lineages that are currently speciating, in the hopes that successful lineages will continue to generate species into the future. These contrasting schemes also map onto contrasting predictions about the role of slow diversifiers in the production of biodiversity over palaeontological time scales. We consider the performance of the two schemes across 10 dated species-level palaeo-phylogenetic trees ranging from Foraminifera to dinosaurs. We find that prioritizing PD for conservation generally led to fewer subsequent lineages, while prioritizing diversifiers led to modestly more subsequent diversity, compared with random sets of lineages. Importantly for conservation, the tree shape when decisions are made cannot predict which scheme will be most successful. These patterns are inconsistent with the notion that long-lived lineages are the source of new species. While there may be sound reasons for prioritizing PD for conservation, long-term species production might not be one of them.


Improved measurement of erythrocyte volume distribution by aperture-counter signal analysis.
In aperture counters, particles in fluid suspension flow through a small orifice or aperture, causing a change in the electrical resistance of the aperture. This change is sensed by an external electronic circuit and translated into a voltage pulse, the signal height of which is proportional to the volume of the particle in the aperture. These signal pulses are collated into a spectrum of pulse heights by a multichannel pulse-height analyzer. The channel number (voltage increment) spectrum is proportional to the volume distribution of the particles sensed. A problem is that pulse height not only depends on cell volume, but also on the orientation and shape of the particle sensed and the current density along the path taken by the particle through the aperture. Uneven current density exists, primarily at the aperture entrance and exit, close to the wall. Orientation and shape of particles are altered near the wall by the unbalanced shear forces there. Toward the center of the aperture, the shear forces act so as not to induce continuous change in the orientation of the particles sensed. Thus introduction into the pulse-height spectrum of pulses that do not show a good proportionality to volume is primarily caused by particles that are traveling near the aperture wall. Residence time in the aperture for a particle traveling near the wall will be longer than that for a particle traveling down the center of the aperture, because of the smaller fluid velocity near the wall. Duration of the signal pulse created by a particle traveling near the wall will be correspondingly greater. We discuss an electronic filter to remove from the pulse-height spectrum those pulses that appear to result from particles traveling near the wall and the effect of the filter on the measured signal height and hence the volume distribution of erythrocytes. Use of this technique to characterize erythrocytes by volume distribution is described.


Structure/function correlation of spermine-analogue-induced modulation of peptidyltransferase activity.
In a cell-free system derived from Escherichia coli, various analogues of spermine were used to study their effect on the binding of AcPhe-tRNA to poly (U)-programmed ribosomes and on the puromycin reaction carried out at 6 mM Mg2+ (Ac, acetyl). In the absence of factors washable from ribosomes (FWR fraction), mono-acylated or di-acylated analogues of spermine stimulate the binding of AcPhe-tRNA to a lesser degree than spermine, in the order: N1-acetylspermine > N1,N12-diacetylspermine approximately = N1,N12-dipivaloylspermine. Also, the above analogues do not show any sparing effect on Mg2+ requirements for AcPhe-tRNA binding to ribosomes, in contrast to spermine. The presence of FWR fraction during the binding or acetylation of the secondary amines of spermine moderates or abolishes the stimulatory effect. In addition, all analogues tested enhance the stability of the ternary complex AcPhe-tRNA-poly(U)-ribosome and the extent of AcPhe-puromycin synthesis, particularly in the absence of the FWR fraction. At the kinetic phase of AcPhe-puromycin synthesis, the analogues display both stimulatory and inhibitory effects, depending on the absence (partial noncompetitive inhibition) or the presence of the FWR fraction (nonessential activation in concert with partial noncompetitive inhibition). Detailed kinetic analysis shows that the analogues tested can mimic the behaviour of spermine, however, the potency to affect the peptidyltransferase activity depends on their degree of acylation, acyl-substituent size, charge distribution and on their chain flexibility.


The hazards of suturing certain wounds of the liver.
Suturing of deep ruptures of the liver frequently produces complications of hemobilia, secondary hemorrhage and intrahepatic cavitation with sepsis and liver failure. Such complications require second and third risky operations in already critically ill patients. Such wounds should not be sutured, adequate drainage should be provided, low pressure venous bleeding should be controlled with temporary gauze tampons and arterial bleeding should be stopped by hepatic artery ligation. Such treatment obviates dangerous hepatic resections and morbid thoracoabdominal incisions and prevents hematobilia, secondary hemorrhage, intrahepatic cavitation and sepsis with hepatic failure.


The role of GABARAPL1/GEC1 in autophagic flux and mitochondrial quality control in MDA-MB-436 breast cancer cells.
GABARAPL1/GEC1 is an early estrogen-induced gene which encodes a protein highly conserved from C. elegans to humans. Overexpressed GABARAPL1 interacts with GABAA or kappa opioid receptors, associates with autophagic vesicles, and inhibits breast cancer cell proliferation. However, the function of endogenous GABARAPL1 has not been extensively studied. We hypothesized that GABARAPL1 is required for maintaining normal autophagic flux, and plays an important role in regulating cellular bioenergetics and metabolism. To test this hypothesis, we knocked down GABARAPL1 expression in the breast cancer MDA-MB-436 cell line by shRNA. Decreased expression of GABARAPL1 activated procancer responses of the MDA-MB-436 cells including increased proliferation, colony formation, and invasion. In addition, cells with decreased expression of GABARAPL1 exhibited attenuated autophagic flux and a decreased number of lysosomes. Moreover, decreased GABARAPL1 expression led to cellular bioenergetic changes including increased basal oxygen consumption rate, increased intracellular ATP, increased total glutathione, and an accumulation of damaged mitochondria. Taken together, our results demonstrate that GABARAPL1 plays an important role in cell proliferation, invasion, and autophagic flux, as well as in mitochondrial homeostasis and cellular metabolic programs.


A profile of HIV risk factors in the context of sex work environments among migrant female sex workers in Beijing, China.
Migrant female sex workers (FSWs) are one of the most at-risk populations for HIV in China. This study demonstrates how multiple risk factors are situated and vary by types of sex work environments in a sample of 348 migrant FSWs in Beijing. Participants reported high rates of clients' refusal to use condoms (76%), unsafe sex with both clients (32%), non-paid regular partners (e.g. boyfriend or husband) (76%), and a sexually transmitted infection symptom (79%) last year. Only 22% of FSWs had been tested for HIV. Risk factors were compared by three types of sex work environments: (1) entertainment establishments, (2) personal services sectors, and (3) street-based venues, including roadside brothels. Street-based FSWs, compared to the other FSWs, were more likely to be older, married with children, migrate from rural areas, and be arrested by police, and less likely to be educated, have contact with prevention services, be knowledgeable about HIV, and be tested for HIV. The FSWs in entertainment establishments were more likely than street-based FSWs to have reported being physically, verbally, and/or sexually abused by clients. Multiple discriminant analysis distinguished a profile of two different groups of risk factors: (1) police arrest, lack of protection from violence, access to prevention and health care, and HIV knowledge, and (2) verbal and physical abuse and clients' refusal of condom use. In the massive internal migration in China, disadvantages in economic sectors drive women to become involved in sex work. HIV prevention strategies must target socio-structural factors embedded in sex work environments.


Direct comparison between regional cerebral metabolism in progressive supranuclear palsy and Parkinson's disease.
The differentiation between progressive supranuclear palsy (PSP) and Parkinson's disease (PD) may be difficult, especially in the early stages of disease. Positron emission tomography potentially provides a tool for making such a distinction. To identify key features in the spatial distributions of cerebral glucose metabolism, 18F-fluorodeoxyglucose (FDG) measurements of 10 patients with probable or possible PSP were directly compared with those of 9 PD patients. This analysis was done with statistic parametric mapping. After normalization of global brain uptake, in PSP, relative uptake of FDG was reduced in the caudal (motor) part of the anterior cingulate gyrus (Brodmann's area BA 24; P < 0.05, corrected for multiple comparisons). At a lower threshold, an additional decrease was present in the dorsal mesencephalon. In PD, relative hypometabolism was seen in extrastriate visual, ventrolateral temporal, posterior parietal, and orbitofrontal regions. Only reduction in the right fusiform gyrus and the lateral extrastriate visual cortex reached statistical significance. We concluded that particularly the reduction of medial frontal metabolism may be a valuable diagnostic imaging parameter in distinguishing PSP from PD. For PD, a possible association between occipitotemporal FDG decrease and vulnerability to hallucinations is suggested.


[Effect of cocoa on excretion of oxalate, citrate, magnesium and calcium in the urine of children].
Cocoa is a strong carrier of oxalic acid (average: 400 mg per 100 g). In three calcium oxalate stone formers clinical observation had been suggestive of excessive intake of cocoa products contributing to calculus formation. We studied the effect on renal oxalate excretion of an oral cocoa load (30 g per m2 body surface given on 2 consecutive days) in 12 former stone formers (group 1), 14 children with isolated microscopic haematuria (group 2), 13 healthy boys (group 3), and 12 healthy girls (group 4). A new enzymatic method was used to measure oxalic acid in cocoa products as well as in urine samples by a two step reaction: 1. Oxalate decarboxylase, 2. formiate dehydrogenase with photometry of NADH. In addition, the daily excretion of the following substances was measured: Citrate, magnesium, and calcium. There was a significant increase of urinary oxalate excretion from an average of 14.5 mg/24 hours before to an average of 22.2 mg/24 hours after the load in healthy children, and a similar increase in stone formers, but not in children with microscopic haematuria. The excretion of citrate and magnesium did not change following cocoa intake. The calcium excretion was higher in stone formers than in the other groups, but the difference was significant only compared to group 2. It is concluded that the risk of calculus formation may increase following continuous and excessive intake of cocoa products in children with a tendency toward hypercalciuria. Counselling of the stone formers resulted in a marked drop of the daily oxalate excretion, and there was no recurrence of calculus formation over a period of 6 years.(ABSTRACT TRUNCATED AT 250 WORDS)


Reconstruction of bilateral cleft lip and nose deformity.
Bilateral cleft lip and nose deformity can be divided into several types according to the extent of the cleft, protruding premaxilla, size of prolabium and nose deformity. Many repair techniques introduced in the literatures were not perfect because of the change of facial profile under the influence of facial growth.The author uses 1-stage cheiloplasty with nose correction for bilateral cleft lip and nose deformity. Early lip adhesion is used before definitive corrections in wide-cleft patients. The lateral mucosal flaps are used for the lining of alveolar cleft. The lateral orbicularis oris peripheralis flaps with the mucosa approximate in front of premaxilla with creation of a buccal alveolar sulcus and continuity of an orbicularis oris muscle. The lateral orbicularis marginalis muscle flaps with white skin roll and vermillion are used for reconstruction of the Cupid's bow. To enhance the median tubercle, prolabial vermilliomucosal flap is inserted into the gap between an approximated orbicularis peripheralis flap and an approximated orbicularis marginalis flap. Z-plasty of the vestibular ridge and the fixation of lower lateral cartilages to dissect through alar rim excision achieve columella lengthening and tip projection. Lip scar revision is rare, but secondary nose correction using triple V-Y flap is frequent.


The psychosocial impact of life-threatening childhood food allergies.
The purpose of this integrated literature review was to bring understanding to medical professionals of the psychosocial impact of parenting a child with life-threatening food allergies. Prevalence of life-threatening food allergy among children is increasing, and families continue to navigate the effects it can have on all members of a family. A comprehensive literature review was performed related to chronic childhood illnesses and life-threatening food allergies. Commonalities among the conditions exist related to stress, coping, and adaptive responses when parental perceptions and experiences are considered. This information may provide a conceptual context for the adaptation process involved with parenting a young child with life-threatening food allergies, revealing areas where nursing can serve to intervene and support this process.


Machine learning to predict mortality for aneurysmal subarachnoid hemorrhage (aSAH) using a large nationwide EHR database.
Aneurysmal subarachnoid hemorrhage (aSAH) develops quickly once it occurs and threatens the life of patients. We aimed to use machine learning to predict mortality for SAH patients at an early stage which can help doctors make clinical decisions. In our study, we applied different machine learning methods to an aSAH cohort extracted from a national EHR database, the Cerner Health Facts EHR database (2000-2018). The outcome of interest was in-hospital mortality, as either passing away while still in the hospital or being discharged to hospice care. Machine learning-based models were primarily evaluated by the area under the receiver operating characteristic curve (AUC). The population size of the SAH cohort was 6728. The machine learning methods achieved an average of AUCs of 0.805 for predicting mortality with only the initial 24 hours' EHR data. Without losing the prediction power, we used the logistic regression to identify 42 risk factors, -examples include age and serum glucose-that exhibit a significant correlation with the mortality of aSAH patients. Our study illustrates the potential of utilizing machine learning techniques as a practical prognostic tool for predicting aSAH mortality at the bedside.


Biological oxidations and P450 reactions. Recombinant mouse CYP1B1 expressed in Escherichia coli exhibits selective binding by polycyclic hydrocarbons and metabolism which parallels C3H10T1/2 cell microsomes, but differs from human recombinant CYP1B1.
Orthologs of a previously identified CYP1B subfamily designated CYP1B1, which are constitutively expressed in mammary, uterine, and embryonic cells, have previously been functionally linked to 7,12-dimethylbenz-a-anthracene (DMBA) metabolism. A chimeric construct of mouse CYP1B1 in which the 20 NH2-terminal amino acids have been replaced by eight residues from human CYP17 has been expressed in Escherichia coli. This recombinant mouse CYP1B1 (recCYP1B1m) exhibited DMBA metabolism accurately reproducing the characteristic product distribution and specific activity of 3.4 nmol/nmol P450/min seen in C3H10T1/2 cells from which this cDNA has been cloned. The high proportion of 10,11- and 3,4-dihydrodiols and near absence of 5,6-dihyrodiol- and 7-hydroxy-DMBA metabolites are seen only in rodent microsomes where CYP1B1 is highly expressed. This distribution of products from recCYP1B1m was highly dependent on addition of epoxide hydrolase, particularly the ratio of 3,4-dihydrodiol to 4-phenol metabolites. These characteristics in addition to inhibition by antibodies raised to recCYP1B1m establish that the CYP1B1 cDNA indeed encodes the P450 responsible for polycyclic aromatic hydrocarbon (PAH) metabolism from C3H10T1/2 cells. DMBA metabolites from cDNA-expressed human CYP1B1 (recCYP1B1h) however, exhibited a different regioselectivity toward DMBA resembling human CYP1A1 catalyzed DMBA metabolism. Reconstitution of recCYP1B1m with different concentrations of NADPH-P450 reductase indicated a high affinity interaction with an apparent Km of 3 nM. Large PAH such as benz[a]pyrene, benz[e]pyrene, benz[a]anthracene, DMBA, 3-methylcholanthrene, and 1-ethynylpyrene bound to recCYP1B1m with high affinity (Kd 0.08 to 0.22 microM) concomitant with substantial spectral shifts (40% low to high spin state change). Smaller PAHs like pyrene, phenanthrene, and naphthalene neither produced spectral changes nor inhibited the spectral change caused by benz[a]pyrene. Among tested steroids, progesterone bound weakly to recCYP1B1m (Kd > 20 microM) with a comparable spectral shift and was a weak inhibitor of DMBA metabolism, but was not metabolized. While 17beta-estradiol is a substrate for human CYP1B1 we have found no evidence for binding to mouse CYP1B1. This data establishes CYP1B1 as an important contributor to activation of PAHs, particularly in extra hepatic tissues that are susceptible to cancer where CYP1B1 in contrast to CYP1A1 is constitutively expressed.


[Induction of plastic changes in the excitability of neuronal electrogenic membranes during habituation].
Habituation of the postsynaptic response of a turtle cortical neurone to an orthodromic stimulus, induces enhanced excitability of the electro-excitable membrane which does not generate action potentials during habituation. Single excitation of the electro-excitable membrane by intracellular stimulation during this period, facilitates transmitter sensitivity of the chemoreceptor membrane. Habituation of the action potential to the intracellular electrical stimulus induces enhanced sensitivity of the chemoreceptor membrane. Single excitation of the chemoreceptor membrane during this period results in enhanced excitability of the electro-excitable membrane. Plastic changes during habituation involve the whole neurone membrane, although the monotonous stimulus activates only its local area.


Experimental Evidence for a Structural-Dynamical Transition in Trajectory Space.
Among the key insights into the glass transition has been the identification of a nonequilibrium phase transition in trajectory space which reveals phase coexistence between the normal supercooled liquid (active phase) and a glassy state (inactive phase). Here, we present evidence that such a transition occurs in experiments. In colloidal hard spheres, we find a non-Gaussian distribution of trajectories leaning towards those rich in locally favored structures (LFSs), associated with the emergence of slow dynamics. This we interpret as evidence for a nonequilibrium transition to an inactive LFS-rich phase. Reweighting trajectories reveals a first-order phase transition in trajectory space between a normal liquid and a LFS-rich phase. We also find evidence for a purely dynamical transition in trajectory space.


Injury risks associated with tackling in rugby union.
To examine factors associated with tackles in rugby union and to assess their impact on the risk of injury. Two-season (2003/2004 and 2005/2006) prospective cohort design with video analysis. 13 English Premiership clubs. 645 players. RR (95% CI) calculated by comparing the frequency of occurrence of risk factors in a cohort of players injured during tackles with their frequency of occurrence in tackles in general play. Playing position; player's speed, impact force, head position, head/neck flexion and body region struck in the tackle; sequence, direction and type of tackle; and location and type of injury. High-speed going into the tackle, high impact force, collisions and contact with a player's head/neck were identified as significant (p<0.01) risk factors for ball carriers (BCs) and tacklers. Midfield backs were significantly (p<0.01) more prone to injury when tackling than other players. Relatively few tacklers were penalised by referees for collision tackles (general play: 2.0%; injured players: 3.3%) and tackles above the line of the shoulder (general play: 5.9%; injured players: 16.7%). Advice in national and international injury prevention programmes for reducing the risk of injury in tackles is strongly supported by the results obtained from this study. These programmes should be reviewed, however, to provide specific advice for each type of tackle. Stricter implementation of the Laws of Rugby relating to collisions and tackles above the line of the shoulder may reduce the number of head/neck injuries sustained by BCs.


Cell Death Mechanisms in a Mouse Model of Retinal Degeneration in Spinocerebellar Ataxia 7.
Spino-cerebellar ataxia type 7 (SCA7) is a polyglutamine (polyQ) disorder characterized by neurodegeneration of the brain, cerebellum, and retina caused by a polyglutamine expansion in ataxin7. The presence of an expanded polyQ tract in a mutant protein is known to induce protein aggregation, cellular stress, toxicity, and finally cell death. However, the consequences of the presence of mutant ataxin7 in the retina and the mechanisms underlying photoreceptor degeneration remain poorly understood. In this study, we show that in a retinal SCA7 mouse model, polyQ ataxin7 induces stress within the retina and activates Muller cells. Moreover, unfolded protein response and autophagy are activated in SCA7 photoreceptors. We have also shown that the photoreceptor death does not involve a caspase-dependent apoptosis but instead involves apoptosis inducing factor (AIF) and Leukocyte Elastase Inhibitor (LEI/L-DNase II). When these two cell death effectors are downregulated by their siRNA, a significant reduction in photoreceptor death is observed. These results highlight the consequences of polyQ protein expression in the retina and the role of caspase-independent pathways involved in photoreceptor cell death.


Performance of a Deep-Learning Neural Network Model in Assessing Skeletal Maturity on Pediatric Hand Radiographs.
Purpose To compare the performance of a deep-learning bone age assessment model based on hand radiographs with that of expert radiologists and that of existing automated models. Materials and Methods The institutional review board approved the study. A total of 14 036 clinical hand radiographs and corresponding reports were obtained from two children's hospitals to train and validate the model. For the first test set, composed of 200 examinations, the mean of bone age estimates from the clinical report and three additional human reviewers was used as the reference standard. Overall model performance was assessed by comparing the root mean square (RMS) and mean absolute difference (MAD) between the model estimates and the reference standard bone ages. Ninety-five percent limits of agreement were calculated in a pairwise fashion for all reviewers and the model. The RMS of a second test set composed of 913 examinations from the publicly available Digital Hand Atlas was compared with published reports of an existing automated model. Results The mean difference between bone age estimates of the model and of the reviewers was 0 years, with a mean RMS and MAD of 0.63 and 0.50 years, respectively. The estimates of the model, the clinical report, and the three reviewers were within the 95% limits of agreement. RMS for the Digital Hand Atlas data set was 0.73 years, compared with 0.61 years of a previously reported model. Conclusion A deep-learning convolutional neural network model can estimate skeletal maturity with accuracy similar to that of an expert radiologist and to that of existing automated models. © RSNA, 2017 An earlier incorrect version of this article appeared online. This article was corrected on January 19, 2018.


NMR mapping of RANTES surfaces interacting with CCR5 using linked extracellular domains.
Chemokines constitute a large family of small proteins that regulate leukocyte trafficking to the site of inflammation by binding to specific cell-surface receptors belonging to the G-protein-coupled receptor (GPCR) superfamily. The interactions between N-terminal (Nt-) peptides of these GPCRs and chemokines have been studied extensively using NMR spectroscopy. However, because of the lower affinities of peptides representing the three extracellular loops (ECLs) of chemokine receptors to their respective chemokine ligands, information concerning these interactions is scarce. To overcome the low affinity of ECL peptides to chemokines, we linked two or three CC chemokine receptor 5 (CCR5) extracellular domains using either biosynthesis in Escherichia coli or chemical synthesis. Using such chimeras, CCR5 binding to RANTES was followed using (1)H-(15)N-HSQC spectra to monitor titration of the chemokine with peptides corresponding to the extracellular surface of the receptor. Nt-CCR5 and ECL2 were found to be the major contributors to CCR5 binding to RANTES, creating an almost closed ring around this protein by interacting with opposing faces of the chemokine. A RANTES positively charged surface involved in Nt-CCR5 binding resembles the positively charged surface in HIV-1 gp120 formed by the C4 and the base of the third variable loop of gp120 (V3). The opposing surface on RANTES, composed primarily of β2-β3 hairpin residues, binds ECL2 and was found to be analogous to a surface in the crown of the gp120 V3. The chemical and biosynthetic approaches for linking GPCR surface regions discussed herein should be widely applicable to the investigation of interactions of extracellular segments of chemokine receptors with their respective ligands.


Surface functional properties of native, acid-treated, and reduced soy glycinin. 1. Foaming properties.
Foaming properties of native and chemically modified glycinin were evaluated. Effects of ionic strength and glycinin composition and concentration on foam formation and stabilization were studied. Glycinin was modified by means of combined treatments: cold or hot acidic treatments, with or without later disulfide bridges reduction. Modified proteins obtained from glycinin present different degrees of dissociation, deamidation, and as consequence, varied surface hydrophobicity and molecular size. Parameters of forming and stabilizing of foam were correlated with both deamidation and dissociation degrees of modified and native glycinin samples. A positive relationship was observed between surface behavior and foaming properties of different protein species. Results show that dissociation, deamidation, and reduction have produced structural changes on glycinin (increased surface hydrophobicity, increased net charge, decreased molecular size) which enhance the adsorption and anchorage of proteins at the air-water interface and, consequently, improve the foam forming and stabilizing capacities.


Retinol-binding protein 4 and insulin resistance are related to body fat in primary and secondary schoolchildren: the Ouro Preto study.
Evidence suggests that plasma retinol-binding protein 4 (RBP4) and insulin resistance are related to body fat (BF). We aimed to assess the relationship between RBP4 and insulin resistance with obesity in a mixed (skin color) cohort of the Brazilian population. A nested case-control study was conducted in 227 schoolchildren aged 7-14 years. Schoolchildren with a high BF percentage (% BF, ≥ 30 for girls and ≥ 25 for boys) were identified as the obese group (n = 137), and those with lower values were identified as the non-obese group (n = 90). Percentage of body fat (% BF) was determined by tetrapolar bioimpedance (Quantum II, RJL System), RBP4 by enzyme-linked immunosorbent assay (Immunology Consultants Laboratory), plasma fasting insulin by chemiluminescent immunoassay (Access(®) Immunoassay System) and insulin resistance by the homeostasis model insulin resistance (IR(HOMA)) index. Serum lipid profile and arterial blood pressure were evaluated. The significant independent risk factors associated with obesity were as follows: male sex, increased serum LDL-C, RBP4 and IR(HOMA). Among children with higher RBP4, the association with obesity increased significantly (from 3.1 to 8.5) in the presence of insulin resistance, when compared to higher RBP4 and non-insulin resistance. IR(HOMA) and RBP4 showed significant associations with obesity and traditional CVD risk factors. They might therefore be used as a marker for CVD risk and have clinical implications in the development of comorbidities associated with obesity.


Disseminated Herpes Simplex Masquerading as Hemophagocytic Lymphohistiocytosis: A Case Report.
Marked elevation in serum ferritin levels may be seen in disseminated infection or severe organ failure states, but it is also present in hemophagocytic lymphohistiocytosis (HLH). Herpes simplex virus (HSV) hepatitis has a high mortality rate, even in immunocompetent individuals, in whom it is rarely reported. We present a case of hyperferritinemia with features initially suggestive of a diagnosis of HLH but that ultimately proved to be fulminant HSV hepatitis. A 56-year-old man with an indolent undiagnosed brain mass presented with progressive neurologic deficits and was found to have fevers, cytopenias, transaminitis, and hyperferritinemia. Initially, HLH was suspected; however, the ultimate diagnosis was HSV hepatitis with dissemination. Although the patient was treated with intravenous acyclovir, multiorgan failure developed, and he died. This case highlights the importance of considering alternative causes for a rise in ferritin levels when HLH is on the differential. Additionally, we discuss the diagnostic and therapeutic implications of HSV hepatitis, and we review the literature for cases presenting in immunocompetent hosts.


Pharmacological inhibition of Lin28 promotes ketogenesis and restores lipid homeostasis in models of non-alcoholic fatty liver disease.
Lin28 RNA-binding proteins are stem-cell factors that play key roles in development. Lin28 suppresses the biogenesis of let-7 microRNAs and regulates mRNA translation. Notably, let-7 inhibits Lin28, establishing a double-negative feedback loop. The Lin28/let-7 axis resides at the interface of metabolic reprogramming and oncogenesis and is therefore a potential target for several diseases. In this study, we use compound-C1632, a drug-like Lin28 inhibitor, and show that the Lin28/let-7 axis regulates the balance between ketogenesis and lipogenesis in liver cells. Hence, Lin28 inhibition activates synthesis and secretion of ketone bodies whilst suppressing lipogenesis. This occurs at least partly via let-7-mediated inhibition of nuclear receptor co-repressor 1, which releases ketogenesis gene expression mediated by peroxisome proliferator-activated receptor-alpha. In this way, small-molecule Lin28 inhibition protects against lipid accumulation in multiple cellular and male mouse models of hepatic steatosis. Overall, this study highlights Lin28 inhibitors as candidates for the treatment of hepatic disorders of abnormal lipid deposition.


[Collagenase activity of Streptomyces sp. 1349].
Streptomyces sp. 1349 is the active producer of collagenase. The dynamics of growth, influence of pH and temperature on collagenase activity and heterogeneity of population were studied. Maxima of the enzyme activity, proteins and biomass reach their highest point on the 3-4th day. The complex of enzymes obtained from culture liquid has pH-optimum of collagenase activity in neutral (pH 6-7) and alkaline (pH 9-10) regions, and thermooptimum at 37 and 60 degrees C. The preparation is stable. Four types of colonies with different level of collagenase activity were revealed during analysis of the heterogeneity of Streptomyces sp. 1349 population. The variant of basic type was selected for further work with activity that exceeds 2-3 times that of the control.


Venus lower atmospheric composition: preliminary results from pioneer venus.
Initial examination of data from the neutral mass spectrometer on the Pioneer Venus sounder probe indicates that the abundances of argon-36, argon-38, and neon-20 in the Venus atmosphere are much higher than those of the corresponding gases in Earth's atmosphere, although the abundance of radiogenic argon-40 is apparently similar for both planets. The lower atmosphere of Venus includes significant concentrations of various gaseous sulfur compounds. The inlet leak to the mass spectrometer was temporarily blocked by an apparently liquid component of the Venus clouds during passage through the dense cloud layer. Analysis of gases released during the evaporation of the droplets shows the presence of water vapor to some compound or compounds of sulfur.


Clinical Characteristics and Outcomes of Older Patients with Coronavirus Disease 2019 (COVID-19) in Wuhan, China: A Single-Centered, Retrospective Study.
In December 2019, the coronavirus disease 2019 (COVID-19) emerged in Wuhan city and spread rapidly throughout China and the world. In this study, we aimed to describe the clinical course and outcomes of older patients with COVID-19. This is a retrospective investigation of hospitalized older patients with confirmed COVID-19 at Zhongnan Hospital of Wuhan University from January 1, 2020, to February 10, 2020. In total, 203 patients were diagnosed with COVID-19, with a median age of 54 years (interquartile range, 41-68; range, 20-91 years). Men accounted for 108 (53.2%) of the cases, and 55 patients (27.1%) were more than 65 years of age. Among patients who were 65 years and older, the mortality rate was 34.5% (19/55), which was significantly higher than that of the younger patients at 4.7% (7/148). Common symptoms of older patients with COVID-19 included fever (94.5%; n = 52), dry cough (69.1%; n = 38), and chest distress (63.6%; n = 35). Compared with young patients, older patients had more laboratory abnormalities and comorbidities. Through a multivariate analysis of the causes of death in older patients, we found that males, comorbidities, time from disease onset to hospitalization, abnormal kidney function, and elevated procalcitonin levels were all significantly associated with death. In the recent outbreak of COVID-19, our local hospital in Wuhan found that patients aged 65 and older had greater initial comorbidities, more severe symptoms, and were more likely to experience multiorgan involvement and death, as compared to younger patients.


Histological and steroidogenic changes in dominant ovarian follicles during oestradiol-induced atresia in heifers.
Histological and steroidogenic changes within dominant ovarian follicles (DFs) undergoing atresia following systemic administration of oestradiol benzoate (ODB) were characterized in beef heifers. At 5.6+/-0.1 days after the onset of oestrus, heifers received 1 mg ODB i.m./500 kg body weight (ODB; n=15) or served as controls (n=15). Timing of treatment initiation was designated as hour (h) 0 on day (d) 0, and coincided with the presence of the DF of the first follicular wave (DF1). Within treatments, the DF1 was collected following ovariectomy in four animals at h 12, h 36 or after ultrasonic detection of a new wave (NW) of ovarian follicular development. In heifers of the NW groups (n=7 per treatment), blood samples were collected at intervals of 20 min for 12 h beginning at h-12, 0, 24 and 48 to characterize circulating LH patterns. Administration of ODB suppressed (P<0.01) mean concentrations of LH at h 24 and h 48 by preventing (P<0.05) the increase in LH pulse amplitude observed in controls, but had no effect on FSH. Follicular fluid (FF) concentrations of androgens and oestradiol were reduced at h 36 in the ODB-treated group. The diameter of the DF1 and the number of granulosa cell layers were also reduced in ODB-treated as compared with control heifers. Treatment differences were not observed in the proportion of apoptotic granulosa cells as assessed using the TUNEL assay method, and timing of a new wave of follicular development (d 4.6+/-0.2) was similar (P>0.1) among treatments. A prominent characteristic of oestradiol-induced atresia of the DF1 of the oestrous cycle in heifers was a loss in oestrogenic function associated with reduced LH support. However, the timing of new follicular development may be influenced by a factor(s) other than the status of the DF undergoing oestradiol-induced atresia.


[Clinical and instrumental characteristics of primary high altitude arterial pulmonary hypertension].
The clinical pattern of primary high altitude pulmonary arterial hypertension observed in permanent residents of mountain regions is described. The diagnostic value of some non-invasive instrumental methods in primary high altitude pulmonary artery hypertension is analysed: electro- and vectorcardiography, rheopulmonography, and indirect pulmonary artery pressure determination. It is suggested to distinguish the labile, stable and decompensated forms of the disease on the basis of its clinical and functional peculiarities. The criterion for the initial two forms consists in the persistence of the pulmonary artery pressure elevation, while the latter form is established when the high altitude cor pulmonale gets decompensated. Functional vasoconstriction of the pulmonary resistive vessels was shown to play an important role in the genesis of the disease: the administration of 0.5 mg of nitroglycerine and a 5-minute oxygen inhalation caused a positive dynamics in the indices of the pulmonary rheogramme and a reduction of the pulmonary artery pressure, which did not reach the level of the plane inhabitants, though.


A dendritic catiomer with an MOF motif for the construction of safe and efficient gene delivery systems.
Ethanolamine (EA)-functionalized poly (glycidyl methacrylate) (PGMA-EA) has been validated by our pioneering studies as a promising material for the manufacture of gene delivery systems. Herein, PGMA-EA was schemed to attach at the terminus of MOF ligands for the construction of a nanoscaled dendritic catiomer. The resulting molecular structure was arranged to possess well-defined flanking secondary amine and hydroxyl groups, which consequently exerted drastic potency in DNA condensation (approximately 100 nm) and provided appreciable colloidal stabilities in the biological milieu. Note that as compared to the commercial gold standard of branched PEI (25 kDa), the proposed catiomer exhibited markedly higher transfection efficiency because of the appreciable cationic dendritic structure and lower cytotoxicity because of rational arrangement of hydroxyl groups. Therefore, the present study encouraged the utility of an MOF-motif in engineering spatial functional and biological functional nanoscaled structures for biomedical applications.


Distinct neural mechanisms for body form and body motion discriminations.
Actions can be understood based on form cues (e.g., static body posture) as well as motion cues (e.g., gait patterns). A fundamental debate centers on the question of whether the functional and neural mechanisms processing these two types of cues are dissociable. Here, using fMRI, psychophysics, and transcranial magnetic stimulation (TMS), all within the same human participants, we show that mechanisms underlying body form and body motion processing are functionally and neurally distinct. Multivoxel fMRI activity patterns in the extrastriate body area (EBA), but not in the posterior superior temporal sulcus (pSTS), carried cue invariant information about the body form of an acting human. Conversely, multivoxel patterns in pSTS, but not in EBA, carried information about the body motion of the same actor. In a psychophysical experiment, we selectively impaired body form and body motion discriminations by manipulating different visual cues: misaligning the ellipses that made up a dynamic walker stimulus selectively disrupted body form discriminations, while varying the presentation duration of the walker selectively affected body motion discriminations. Finally, a TMS experiment revealed causal evidence for a double-dissociation between neural mechanisms underlying body form and body motion discriminations: TMS over EBA selectively disrupted body form discrimination, whereas TMS over pSTS selectively disrupted body motion discrimination. Together, these findings reveal complementing but dissociable functions of EBA and pSTS during action perception. They provide constraints for theoretical and computational models of action perception by showing that action perception involves at least two parallel pathways that separately contribute to the understanding of others' behavior.


[Screening the risk for functional loss: a basic strategy for organizing the elderly health care network].
From a critical analysis of experiments in the use of screening tools for functional loss in the elderly, it was observed that the main motivation to develop and implement a screening instrument is to improve health care for the frail elderly or those at risk of functional loss and repeated hospital admissions. The instruments are preferably short questionnaires with no more than 16 self-reported questions. The main intervention performed after screening was monitoring the elderly by a specialized nursing service that, when necessary, referring them to the medical service. The results of this approach included the reduction of functional loss, hospital admissions, deaths, lower health expenses and greater consumer satisfaction.


Monitoring multiwalled carbon nanotube exposure in carbon nanotube research facility.
With the increased production and widespread use of multiwalled carbon nanotubes (MWCNTs), human and environmental exposure to MWCNTs is inevitably increasing. Therefore, this study monitored the possible exposure to MWCNT release in a carbon nanotube research laboratory. To estimate the potential exposure of researchers and evaluate the improvement of the workplace environment after the implementation of protective control measures, personal and area monitoring were conducted in an MWCNT research facility where the researchers handled unrefined materials. The number, composition, and aspect ratio of MWCNTs were measured using scanning transmission electron microscopy with an energy-dispersive x-ray analyzer. The gravimetric concentrations of total dust before any control measures ranged from 0.21 to 0.43 mg/m(3), then decreased to a nondetectable level after implementing the control measures. The number of MWCNTs in the samples obtained from the MWCNT blending laboratory ranged from 172.9 to 193.6 MWCNTs/cc before the control measures, and decreased to 0.018-0.05 MWCNTs/cc after the protective improvements. The real-time monitoring of aerosol particles provided a signature of the MWCNTs released from the blending equipment in laboratory C. In particular, the number size response of an aerodynamic particle sizer with a relatively high concentration in the range of 2 to 3 microm in aerodynamic diameter revealed the evidence of MWCNT exposure. The black carbon mass concentration also increased significantly during the MWCNT release process. Therefore, the present study suggests that the conventional industrial hygiene measures can significantly reduce exposure to airborne MWCNTs and other particulate materials in a nano research facility.


Auditory frequency and intensity discrimination explained using a cortical population rate code.
The nature of the neural codes for pitch and loudness, two basic auditory attributes, has been a key question in neuroscience for over century. A currently widespread view is that sound intensity (subjectively, loudness) is encoded in spike rates, whereas sound frequency (subjectively, pitch) is encoded in precise spike timing. Here, using information-theoretic analyses, we show that the spike rates of a population of virtual neural units with frequency-tuning and spike-count correlation characteristics similar to those measured in the primary auditory cortex of primates, contain sufficient statistical information to account for the smallest frequency-discrimination thresholds measured in human listeners. The same population, and the same spike-rate code, can also account for the intensity-discrimination thresholds of humans. These results demonstrate the viability of a unified rate-based cortical population code for both sound frequency (pitch) and sound intensity (loudness), and thus suggest a resolution to a long-standing puzzle in auditory neuroscience.


Effects of an Educational Program for Professional Caregivers on Behavioral Alterations in Nursing Home Residents: Pilot Study.
This pilot study aims to analyze the effectiveness of a type of non-pharmacological intervention such as the educating and training of professional caregivers on behavioral alterations and prescription of psychotropic drugs of older adults in nursing homes. One hundred and forty-five people from two nursing homes were randomized to either treatment (educational training program for healthcare professionals) or a no-treatment group. Twenty-two professional caregivers in the experimental group received 20 h of a training program. Five data collection points were collected (pre and post, and three follow-ups, all six months apart). Intervention consisted of the behavioral alterations and psychopharmacological treatment. The analysis of variance for repeated measures showed significant differences in the time-group interaction for the educational program's effectiveness in reducing behavior alterations and psycho-pharmaceuticals' record. The results show that an improvement in the educating and training of professional caregivers can reduce behavioral alterations (F3,407 = 9.29, p < 0.001, η2= 0.063) and prescription of psychotropic drugs (F2,10 = 18.90, p < 0.001, η2 = 0.117). In addition, these effects are maintained over time. Educating health professionals on ways to care for residents who present behavioral alterations may be one alternative for improving the quality of care that residents receive. Non-pharmacological interventions, besides being individualized and adapted to the needs and experiences of individuals, achieve effects that last longer at low cost. An educational program shows new alternatives to pharmacological intervention, achieving a reduction in behavioral alterations without the costs and effects that psychopharmaceuticals entail.


Strategic planning processes and hospital financial performance.
Many common management practices in healthcare organizations, including the practice of strategic planning, have not been subject to widespread assessment through empirical research. If management practice is to be evidence-based, evaluations of such common practices need to be undertaken. The purpose of this research is to provide evidence on the extent of strategic planning practices and the association between hospital strategic planning processes and financial performance. In 2006, we surveyed a sample of 138 chief executive officers (CEOs) of hospitals in the state of Texas about strategic planning in their organizations and collected financial information on the hospitals for 2003. Among the sample hospitals, 87 percent reported having a strategic plan, and most reported that they followed a variety of common practices recommended for strategic planning-having a comprehensive plan, involving physicians, involving the board, and implementing the plan. About one-half of the hospitals assigned responsibility for the plan to the CEO. We tested the association between these planning characteristics in 2006 and two measures of financial performance for 2003. Three dimensions of the strategic planning process--having a strategic plan, assigning the CEO responsibility for the plan, and involving the board--are positively associated with earlier financial performance. Further longitudinal studies are needed to evaluate the cause-and-effect relationship between planning and performance.


[Physical activity during commuting by adults and elderly in Brazil: prevalence and associated factors].
Evidence in the literature shows that physical activity associated with commuting (routine coming and going) can have a positive impact on health. The current study describes physical activity during commuting and some associated factors. A cross-sectional population-based study was conducted with 12,402 adults and 6,624 elderly in 100 municipalities (counties) from 23 States of Brazil. The outcome was based on the commuting section from the long version of the International Physical Activity Questionnaire (IPAQ). Prevalence of insufficient physical activity during commuting (< 150 minutes per week) was 66.6% in adults and 73.9% in the elderly. Among the elderly, the very old showed 25 times higher odds of being insufficiently active as compared to younger elders. Individuals with self-reported "white" skin color were less active in commuting. The findings show that prevalence of physical activity in commuting in Brazil is low, and that encouraging physically active commuting can be an effective strategy for increasing levels of physical activity and improving health.


Novel methods and technologies for 21st-century clinical trials: a review.
New technologies are rapidly reshaping health care. However, their effect on drug development to date generally has been limited. To evaluate disease modeling and simulation, alternative study design, novel objective measures, virtual research visits, and enhanced participant engagement and to examine their potential effects as methods and tools on clinical trials. We conducted a systematic search of relevant terms on PubMed (disease modeling and clinical trials; adaptive design, clinical trials, and neurology; Internet, clinical trials, and neurology; and telemedicine, clinical trials, and neurology), references of previous publications, and our files. The search encompassed articles published from January 1, 2000, through November 30, 2014, and produced 7976 articles, of which 22 were determined to be relevant and are included in this review. Few of these new methods and technologies have been applied to neurology clinical trials. Clinical outcomes, including cognitive and stroke outcomes, increasingly are captured remotely. Other therapeutic areas have successfully implemented many of these tools and technologies, including web-enabled clinical trials. Increased use of new tools and approaches in future clinical trials can enhance the design, improve the assessment, and engage participants in the evaluation of novel therapies for neurologic disorders.


Creation of the Forearm 3D-Model with Veins from Transversal Ultrasonography Image Sequence.
This study developed an automatic detection algorithm of vessel and skin regions in a transversal ultrasonography image on the arm. We also developed an algorithm to generate a 3D model from detected areas to assist vein puncture. In the algorithm, the vessel's candidate regions in the ultrasonography image were detected using U-Net or Mask R-CNN, which are a kind of deep learning method for segmentation. Then vessel regions were selected among the candidates based on continuous properties in an image sequence. The skin regions were also detected. The 3D polygon data was created from paired pixels in sequential images. The experiments demonstrated that Mask R-CNN could correctly estimate the branch of vessel which were difficult to identify accurate region separately using U-Net, and achieved an overall IoU of 80%. The confirmation experiment of 3D model demonstrated that generated model have enough feasibility for assessment of appropriate veins and locations for puncture.Clinical relevance-The developed 3D model generation from ultrasonography images will be useful for support to identify the appropriate veins for puncture.