How close do we live to water? A global analysis of population distance to freshwater bodies.
Traditionally, people have inhabited places with ready access to fresh water. Today, over 50% of the global population lives in urban areas, and water can be directed via tens of kilometres of pipelines. Still, however, a large part of the world's population is directly dependent on access to natural freshwater sources. So how are inhabited places related to the location of freshwater bodies today? We present a high-resolution global analysis of how close present-day populations live to surface freshwater. We aim to increase the understanding of the relationship between inhabited places, distance to surface freshwater bodies, and climatic characteristics in different climate zones and administrative regions. Our results show that over 50% of the world's population lives closer than 3 km to a surface freshwater body, and only 10% of the population lives further than 10 km away. There are, however, remarkable differences between administrative regions and climatic zones. Populations in Australia, Asia, and Europe live closest to water. Although populations in arid zones live furthest away from freshwater bodies in absolute terms, relatively speaking they live closest to water considering the limited number of freshwater bodies in those areas. Population distributions in arid zones show statistically significant relationships with a combination of climatic factors and distance to water, whilst in other zones there is no statistically significant relationship with distance to water. Global studies on development and climate adaptation can benefit from an improved understanding of these relationships between human populations and the distance to fresh water.


Alcohol: no ordinary commodity--a summary of the second edition.
This article summarizes the contents of Alcohol: No Ordinary Commodity (2nd edn). The first part of the book describes why alcohol is not an ordinary commodity, and reviews epidemiological data that establish alcohol as a major contributor to the global burden of disease, disability and death in high-, middle- and low-income countries. This section also documents how international beer and spirits production has been consolidated recently by a small number of global corporations that are expanding their operations in Eastern Europe, Asia, Africa and Latin America. In the second part of the book, the scientific evidence for strategies and interventions that can prevent or minimize alcohol-related harm is reviewed critically in seven key areas: pricing and taxation, regulating the physical availability of alcohol, modifying the drinking context, drink-driving countermeasures, restrictions on marketing, education and persuasion strategies, and treatment and early intervention services. Finally, the book addresses the policy-making process at the local, national and international levels and provides ratings of the effectiveness of strategies and interventions from a public health perspective. Overall, the strongest, most cost-effective strategies include taxation that increases prices, restrictions on the physical availability of alcohol, drink-driving countermeasures, brief interventions with at risk drinkers and treatment of drinkers with alcohol dependence.


Identifiable images of bystanders extracted from corneal reflections.
Criminal investigations often use photographic evidence to identify suspects. Here we combined robust face perception and high-resolution photography to mine face photographs for hidden information. By zooming in on high-resolution face photographs, we were able to recover images of unseen bystanders from reflections in the subjects' eyes. To establish whether these bystanders could be identified from the reflection images, we presented them as stimuli in a face matching task (Experiment 1). Accuracy in the face matching task was well above chance (50%), despite the unpromising source of the stimuli. Participants who were unfamiliar with the bystanders' faces (n = 16) performed at 71% accuracy [t(15) = 7.64, p<.0001, d = 1.91], and participants who were familiar with the faces (n = 16) performed at 84% accuracy [t(15) = 11.15, p<.0001, d = 2.79]. In a test of spontaneous recognition (Experiment 2), observers could reliably name a familiar face from an eye reflection image. For crimes in which the victims are photographed (e.g., hostage taking, child sex abuse), reflections in the eyes of the photographic subject could help to identify perpetrators.


Defining objective clusters for rabies virus sequences using affinity propagation clustering.
Rabies is caused by lyssaviruses, and is one of the oldest known zoonoses. In recent years, more than 21,000 nucleotide sequences of rabies viruses (RABV), from the prototype species rabies lyssavirus, have been deposited in public databases. Subsequent phylogenetic analyses in combination with metadata suggest geographic distributions of RABV. However, these analyses somewhat experience technical difficulties in defining verifiable criteria for cluster allocations in phylogenetic trees inviting for a more rational approach. Therefore, we applied a relatively new mathematical clustering algorythm named 'affinity propagation clustering' (AP) to propose a standardized sub-species classification utilizing full-genome RABV sequences. Because AP has the advantage that it is computationally fast and works for any meaningful measure of similarity between data samples, it has previously been applied successfully in bioinformatics, for analysis of microarray and gene expression data, however, cluster analysis of sequences is still in its infancy. Existing (516) and original (46) full genome RABV sequences were used to demonstrate the application of AP for RABV clustering. On a global scale, AP proposed four clusters, i.e. New World cluster, Arctic/Arctic-like, Cosmopolitan, and Asian as previously assigned by phylogenetic studies. By combining AP with established phylogenetic analyses, it is possible to resolve phylogenetic relationships between verifiably determined clusters and sequences. This workflow will be useful in confirming cluster distributions in a uniform transparent manner, not only for RABV, but also for other comparative sequence analyses.


Serum vitamin B12, C and folate concentrations in the New Mexico elder health survey: correlations with cognitive and affective functions.
1) To compare serum vitamin B12, C and folate concentrations in a randomly selected sample of elderly (age 65 years or older) male and female Hispanics and nonHispanic whites (NHW) and 2) to examine associations between serum B12, C and folate concentrations compared to measures of cognitive and affective (depression) functions. Equal numbers of male and female Hispanics and NHW were randomly sampled from the Health Care Financing Administration (Medicare) registrant list for Bernalillo County, New Mexico, and asked to volunteer for a paid home interview followed by a paid comprehensive interview/examination covering health and health-related issues. In addition to serum determinations of B12, C and folate, associations were examined between these vitamins and measures of cognitive and affective functions. Males and Hispanics had lower serum vitamin B12, C and folate concentrations than females and NHW respectively. Participants taking a multivitamin supplement (MVI) had higher serum vitamin concentrations than those not taking MVI. There were significant associations between serum folate concentrations and measures of cognitive function, not seen with B12 or C, nor between any of the vitamins and affective function. Hispanics, even after adjustments for gender, age, vitamin supplementation, vitamin content of dietary foods, education and household income, had lower serum concentrations of B12, C and folate than NHW. The most significant associations observed were those between serum folate and various measures of cognitive function, even after adjusting for presence of depression.


Tracking virus outbreaks in the twenty-first century.
Emerging viruses have the potential to impose substantial mortality, morbidity and economic burdens on human populations. Tracking the spread of infectious diseases to assist in their control has traditionally relied on the analysis of case data gathered as the outbreak proceeds. Here, we describe how many of the key questions in infectious disease epidemiology, from the initial detection and characterization of outbreak viruses, to transmission chain tracking and outbreak mapping, can now be much more accurately addressed using recent advances in virus sequencing and phylogenetics. We highlight the utility of this approach with the hypothetical outbreak of an unknown pathogen, 'Disease X', suggested by the World Health Organization to be a potential cause of a future major epidemic. We also outline the requirements and challenges, including the need for flexible platforms that generate sequence data in real-time, and for these data to be shared as widely and openly as possible.


Non-Hodgkin Lymphoma, Body Mass Index, and Cytokine Polymorphisms: A Pooled Analysis from the InterLymph Consortium.
Excess adiposity has been associated with lymphomagenesis, possibly mediated by increased cytokine production causing a chronic inflammatory state. The relationship between obesity, cytokine polymorphisms, and selected mature B-cell neoplasms is reported. Data on 4,979 cases and 4,752 controls from nine American/European studies from the InterLymph consortium (1988-2008) were pooled. For diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), joint associations of body mass index (from self-reported height and weight) and 12 polymorphisms in cytokines IL1A (rs1800587), IL1B (rs16944, rs1143627), IL1RN (rs454078), IL2 (rs2069762), IL6 (rs1800795, rs1800797), IL10 (rs1800890, rs1800896), TNF (rs1800629), LTA (rs909253), and CARD15 (rs2066847) were investigated using unconditional logistic regression. BMI-polymorphism interaction effects were estimated using the relative excess risk due to interaction (RERI). Obesity (BMI ≥ 30 kg/m(2)) was associated with DLBCL risk [OR = 1.33; 95% confidence interval (CI), 1.02-1.73], as was TNF-308GA+AA (OR = 1.24; 95% CI, 1.07-1.44). Together, being obese and TNF-308GA+AA increased DLBCL risk almost 2-fold relative to those of normal weight and TNF-308GG (OR = 1.93; 95% CI, 1.27-2.94), with a RERI of 0.41 (95% CI, -0.05-0.84; Pinteraction = 0.13). For FL and CLL/SLL, no associations with obesity or TNF-308GA+AA, either singly or jointly, were observed. No evidence of interactions between obesity and the other polymorphisms were detected. Our results suggest that cytokine polymorphisms do not generally interact with BMI to increase lymphoma risk but obesity and TNF-308GA+AA may interact to increase DLBCL risk. Studies using better measures of adiposity are needed to further investigate the interactions between obesity and TNF-308G>A in the pathogenesis of lymphoma.


Molybdenum as a Factor Limiting Primary Productivity in Castle Lake, California.
A trace-element deficiency is evident from carbon-14 bioassays of Castle Lake's natural phytoplankton populations. Increase in photosynthetic rates with the addition of molybdic acid or sodium molybdate has been demonstrated throughout the year. It is likely that other trace elements may also be found to be limiting factors in lakes having a limited watershed.


The Forgotten Middle: Many Middle-Income Seniors Will Have Insufficient Resources For Housing And Health Care.
As people age and require more assistance with daily living and health needs, a range of housing and care options is available. Over the past four decades the market for seniors housing and care-including assisted living and independent living communities-has greatly expanded to accommodate people with more complex needs. These settings provide housing in a community environment that often includes personal care assistance services. Unfortunately, these settings are often out of the financial reach of many of this country's eight million middle-income seniors (those ages seventy-five and older). The private seniors housing industry has generally focused on higher-income people instead. We project that by 2029 there will be 14.4 million middle-income seniors, 60 percent of whom will have mobility limitations and 20 percent of whom will have high health care and functional needs. While many of these seniors will likely need the level of care provided in seniors housing, we project that 54 percent of seniors will not have sufficient financial resources to pay for it. This gap suggests a role for public policy and the private sector in meeting future long-term care and housing needs for middle-income seniors.


The human prefrontal cortex mediates integration of potential causes behind observed outcomes.
Prefrontal cortex has long been implicated in tasks involving higher order inference in which decisions must be rendered, not only about which stimulus is currently rewarded, but also which stimulus dimensions are currently relevant. However, the precise computational mechanisms used to solve such tasks have remained unclear. We scanned human participants with functional MRI, while they performed a hierarchical intradimensional/extradimensional shift task to investigate what strategy subjects use while solving higher order decision problems. By using a computational model-based analysis, we found behavioral and neural evidence that humans solve such problems not by occasionally shifting focus from one to the other dimension, but by considering multiple explanations simultaneously. Activity in human prefrontal cortex was better accounted for by a model that integrates over all available evidences than by a model in which attention is selectively gated. Importantly, our model provides an explanation for how the brain determines integration weights, according to which it could distribute its attention. Our results demonstrate that, at the point of choice, the human brain and the prefrontal cortex in particular are capable of a weighted integration of information across multiple evidences.


Cost-effectiveness analysis of sofosbuvir-based regimens for chronic hepatitis C.
A new scenario of therapy for chronic hepatitis C (CHC) is being established with the approval of sofosbuvir (SOF). To estimate the cost-effectiveness of SOF-based regimens approved in the Summary of Product Characteristics (SmPC) versus the standard of care for different genotypes and patient populations (naive or pretreated). A Markov model simulating CHC progression was used to estimate disease treatment costs and effects over patients' lifetimes, from the Spanish National Public Healthcare System perspective. Different therapeutic options were analysed for genotypes 1, 2 and 3 in naive population and for genotype 2 and 3 pretreated patients, according to data obtained from clinical trials. A one-way sensitivity analysis was performed to evaluate the uncertainty of certain parameters: treatment starting age, transition probabilities, drug costs and discount rate. A probabilistic sensitivity analysis was also carried out. For the naive population, the option SOF+pegylated-interferon-α (pIFN)+ribavirin (RBV) for 12 weeks recorded in SmPC for genotype 1 and 3 versus pIFN+RBV for 24 weeks estimated an incremental cost-effectiveness ratio (ICER) below the €40,000/quality-adjusted life-year (QALY) benchmark. For the pretreated population, SOF triple therapy reached an ICER on the threshold limit for genotype 3. Other options included in SmPC for different genotypes exceeded the accepted efficiency limit in our setting. The options that included SOF+RBV+pIFN in a 12-week course regimen fell below the efficiency threshold considered in our setting. IFN-free regimens administered for 24 weeks reached figures over the benchmark of €40,000/QALY.


The Effect of Pain on Major Cognitive Impairment in Older Adults.
Older adults frequently report pain; cross-sectional studies have shown that pain is associated with worse cognitive function. However, longitudinal studies are lacking. We prospectively studied 441 participants without dementia, including 285 with pain, aged 65 years and older, enrolled in the Central Control of Mobility in Aging study, a prospective cohort study. We analyzed the longitudinal association between pain (measured with the Medical Outcomes Study pain severity scale) and major cognitive impairment (measured with the Repeatable Battery for the Assessment of Neuropsychological Status and the Trail Making Test Delta) using Cox regression analysis adjusted for age, gender, ethnicity, and education. Over a mean follow-up of 2.75 years (standard deviation = 1.94), there was no difference in the risk of developing cognitive impairment between participants with pain and participants without pain. However, among those with pain, risk for developing major memory impairment was higher among those with high levels of pain than those with low levels of pain (adjusted hazard ratio = 3.47, 95% confidence interval = 1.42-8.46). The association with pain and incident impairments in attention or executive function was not significant. We did not find that pain is associated with incident cognitive impairment in general, but among older adults with pain, a high level of pain is associated with increased risk of developing incident memory impairment. PERSPECTIVE: Our study results suggest that high levels of pain may contribute to incident memory impairment. Further research is needed to determine whether a high level of chronic pain is a modifiable risk factor for cognitive impairment in older adults.


Subclinical psychosis syndromes in the general population: results from a large-scale epidemiological survey among residents of the canton of Zurich, Switzerland.
Aims. Prevalence and covariates of subclinical psychosis have gained increased interest in the context of early identification and treatment of persons at risk for psychosis. Methods. We analysed 9829 adults representative of the general population within the canton of Zurich, Switzerland. Two psychosis syndromes, derived from the SCL-90-R, were applied: 'schizotypal signs' and 'schizophrenia nuclear symptoms'. Results. Only a few subjects (13.2%) reported no schizotypal signs. While 33.2% of subjects indicated mild signs, only a small proportion (3.7%) reported severe signs. A very common outcome was no 'schizophrenia nuclear symptoms' (70.6%). Although 13.5% of the participants reported mild symptoms, severe nuclear symptoms were very rare (0.5%). Because these two syndromes were only moderately correlated (r = 0.43), we were able to establish sufficiently distinct symptom clusters. Schizotypal signs were more closely connected to distress than was schizophrenia nuclear symptoms, even though their distribution types were similar. Both syndromes were associated with several covariates, such as alcohol and tobacco use, being unmarried, low education level, psychopathological distress and low subjective well-being. Conclusions. Subclinical psychosis symptoms are quite frequent in the general population but, for the most part, are not very pronounced. In particular, our data support the notion of a continuous Wald distribution of psychotic symptoms in the general population. Our findings have enabled us to confirm the usefulness of these syndromes as previously assessed in other independent community samples. Both can appropriately be associated with well-known risk factors of schizophrenia.


Genome analysis of a major urban malaria vector mosquito, Anopheles stephensi.
Anopheles stephensi is the key vector of malaria throughout the Indian subcontinent and Middle East and an emerging model for molecular and genetic studies of mosquito-parasite interactions. The type form of the species is responsible for the majority of urban malaria transmission across its range. Here, we report the genome sequence and annotation of the Indian strain of the type form of An. stephensi. The 221 Mb genome assembly represents more than 92% of the entire genome and was produced using a combination of 454, Illumina, and PacBio sequencing. Physical mapping assigned 62% of the genome onto chromosomes, enabling chromosome-based analysis. Comparisons between An. stephensi and An. gambiae reveal that the rate of gene order reshuffling on the X chromosome was three times higher than that on the autosomes. An. stephensi has more heterochromatin in pericentric regions but less repetitive DNA in chromosome arms than An. gambiae. We also identify a number of Y-chromosome contigs and BACs. Interspersed repeats constitute 7.1% of the assembled genome while LTR retrotransposons alone comprise more than 49% of the Y contigs. RNA-seq analyses provide new insights into mosquito innate immunity, development, and sexual dimorphism. The genome analysis described in this manuscript provides a resource and platform for fundamental and translational research into a major urban malaria vector. Chromosome-based investigations provide unique perspectives on Anopheles chromosome evolution. RNA-seq analysis and studies of immunity genes offer new insights into mosquito biology and mosquito-parasite interactions.


Phosphoproteomic analysis reveals interconnected system-wide responses to perturbations of kinases and phosphatases in yeast.
The phosphorylation and dephosphorylation of proteins by kinases and phosphatases constitute an essential regulatory network in eukaryotic cells. This network supports the flow of information from sensors through signaling systems to effector molecules and ultimately drives the phenotype and function of cells, tissues, and organisms. Dysregulation of this process has severe consequences and is one of the main factors in the emergence and progression of diseases, including cancer. Thus, major efforts have been invested in developing specific inhibitors that modulate the activity of individual kinases or phosphatases; however, it has been difficult to assess how such pharmacological interventions would affect the cellular signaling network as a whole. Here, we used label-free, quantitative phosphoproteomics in a systematically perturbed model organism (Saccharomyces cerevisiae) to determine the relationships between 97 kinases, 27 phosphatases, and more than 1000 phosphoproteins. We identified 8814 regulated phosphorylation events, describing the first system-wide protein phosphorylation network in vivo. Our results show that, at steady state, inactivation of most kinases and phosphatases affected large parts of the phosphorylation-modulated signal transduction machinery-and not only the immediate downstream targets. The observed cellular growth phenotype was often well maintained despite the perturbations, arguing for considerable robustness in the system. Our results serve to constrain future models of cellular signaling and reinforce the idea that simple linear representations of signaling pathways might be insufficient for drug development and for describing organismal homeostasis.


Cognitive impairments accompanying rodent mild traumatic brain injury involve p53-dependent neuronal cell death and are ameliorated by the tetrahydrobenzothiazole PFT-α.
With parallels to concussive mild traumatic brain injury (mTBI) occurring in humans, anesthetized mice subjected to a single 30 g weight drop mTBI event to the right parietal cortex exhibited significant diffuse neuronal degeneration that was accompanied by delayed impairments in recognition and spatial memory. To elucidate the involvement of reversible p53-dependent apoptosis in this neuronal loss and associated cognitive deficits, mice were subjected to experimental mTBI followed by the systemic administration of the tetrahydrobenzothiazole p53 inactivator, PFT-α, or vehicle. Neuronal loss was quantified immunohistochemically at 72 hr. post-injury by the use of fluoro-Jade B and NeuN within the dentate gyrus on both sides of the brain, and recognition and spatial memory were assessed by novel object recognition and Y-maze paradigms at 7 and 30 days post injury. Systemic administration of a single dose of PFT-α 1 hr. post-injury significantly ameliorated both neuronal cell death and cognitive impairments, which were no different from sham control animals. Cellular studies on human SH-SY5Y cells and rat primary neurons challenged with glutamate excitotoxicity and H2O2 induced oxidative stress, confirmed the ability of PFT-α and a close analog to protect against these TBI associated mechanisms mediating neuronal loss. These studies suggest that p53-dependent apoptotic mechanisms underpin the neuronal and cognitive losses accompanying mTBI, and that these are potentially reversible by p53 inactivation.


Changing clinical practice: views about the management of adult asthma.
A case study of clinical practice in adult asthma is presented. The case is part of a larger project, funded by the North Thames NHS Executive Research and Development Programme, that sought to explore the part played by clinicians in the implementation of research and development into practice in two areas: adult asthma and glue ear in children. The first case of glue ear in children was reported in a previous issue of this journal (Quality in Health Care 1999;8:99-107). Background information from secondary sources on the condition, treatment, and organisation and location of care is followed by an account of the results of semistructured interviews with 159 clinicians. The findings are reported in two sections: clinical management and the organisation of care, and clinicians' accounts of what, why, and how they introduce changes into their practice. The way clinicians talk about their learning, their expressed views on acceptable practice, and their willingness to change were shown to be informed by construction of legitimate and sufficient evidence, respected colleagues, and accumulated individual experience. There was little open acknowledgment of the influence of organisational factors in influencing practice. To investigate whether relationships between task performance and organisational arrangements found in other sectors apply to UK health, more robust measures by which performance can be evaluated are needed.


Evidence of increasing antibiotic resistance gene abundances in archived soils since 1940.
Mass production and use of antibiotics and antimicrobials in medicine and agriculture have existed for over 60 years, and has substantially benefited public health and agricultural productivity throughout the world. However, there is growing evidence that resistance to antibiotics (AR) is increasing both in benign and pathogenic bacteria, posing an emerging threat to public and environmental health in the future. Although evidence has existed for years from clinical data of increasing AR, almost no quantitative environmental data exist that span increased industrial antibiotic production in the 1950s to the present; i.e., data that might delineate trends in AR potentially valuable for epidemiological studies. To address this critical knowledge gap, we speculated that AR levels might be apparent in historic soil archives as evidenced by antibiotic resistance gene (ARG) abundances over time. Accordingly, DNA was extracted from five long-term soil-series from different locations in The Netherlands that spanned 1940 to 2008, and 16S rRNA gene and 18 ARG abundances from different major antibiotic classes were quantified. Results show that ARG from all classes of antibiotics tested have significantly increased since 1940, but especially within the tetracyclines, with some individual ARG being >15 times more abundant now than in the 1970s. This is noteworthy because waste management procedures have broadly improved and stricter rules on nontherapeutic antibiotic use in agriculture are being promulgated. Although these data are local to The Netherlands, they suggest basal environmental levels of ARG still might be increasing, which has implications to similar locations around the world.


Activation of EIF4E by Aurora Kinase A Depicts a Novel Druggable Axis in Everolimus-Resistant Cancer Cells.
Purpose: Aurora kinase A (AURKA) is overexpressed in several cancer types, making it an attractive druggable target in clinical trials. In this study, we investigated the role of AURKA in regulating EIF4E, cap-dependent translation, and resistance to mTOR inhibitor, RAD001 (everolimus).Experimental Design: Tumor xenografts and in vitro cell models of upper gastrointestinal adenocarcinomas (UGC) were used to determine the role of AURKA in the activation of EIF4E and cap-dependent translation. Overexpression, knockdown, and pharmacologic inhibition of AURKA were used in vitro and in vivoResults: Using in vitro cell models, we found that high protein levels of AURKA mediate phosphorylation of EIF4E and upregulation of c-MYC. Notably, we detected overexpression of endogenous AURKA in everolimus-resistant UGC cell models. AURKA mediated phosphorylation of EIF4E, activation of cap-dependent translation, and an increase in c-MYC protein levels. Targeting AURKA using genetic knockdown or a small-molecule inhibitor, alisertib, reversed these molecular events, leading to a decrease in cancer cell survival in acquired and intrinsic resistant cell models. Mechanistic studies demonstrated that AURKA binds to and inactivates protein phosphatase 2A, a negative regulator of EIF4E, leading to phosphorylation and activation of EIF4E in an AKT-, ERK1/2-, and mTOR-independent manner. Data from tumor xenograft mouse models confirmed that everolimus-resistant cancer cells are sensitive to alisertib.Conclusions: Our results indicate that AURKA plays an important role in the activation of EIF4E and cap-dependent translation. Targeting the AURKA-EIF4E-c-MYC axis using alisertib is a novel therapeutic strategy that can be applicable for everolimus-resistant tumors and/or subgroups of cancers that show overexpression of AURKA and activation of EIF4E and c-MYC. Clin Cancer Res; 23(14); 3756-68. ©2017 AACR.


Ataxia telangiectasia: report of two cases.
Ataxia telangiectasia (A-T) is a rare autosomal recessive multisystem disease. The diagnosis of A-T is based on the typical clinical picture: ataxia and telangiectasia. However, an increase in (alpha-fetoprotein (AFP) level and the identification of the A-T mutated gene (ATM) assist in an early diagnosis. Here we report two cases of A-T diagnosed in our hospital (case 1: a 7-year-old boy; case 2: an 8-year-old girl). Both of these patients had typical clinical pictures of ataxia and telangiectasia, AFP was also increased (case 1:471.2 ng/dL; case 2: 196 ng/dL). T-cell dysfunction was noted in both patients. Case 1 had IgG2 deficiency and case 2 had IgA, IgG2 and IgG3 deficiency. Case 2 developed malignant lymphoma at 9 years of age and died of pneumonia with respiratory failure at 10 years of age. Because of rhe rarity of A-T in Taiwan, we report two cases to help pediatricians make an early diagnosis of A-T if they have a patient with progressive ataxia and oculocutaneous telangiectasia.


Comparison of surface sampling methods for virus recovery from fomites.
The role of fomites in infectious disease transmission relative to other exposure routes is difficult to discern due, in part, to the lack of information on the level and distribution of virus contamination on surfaces. Comparisons of studies intending to fill this gap are difficult because multiple different sampling methods are employed and authors rarely report their method's lower limit of detection. In the present study, we compare a subset of sampling methods identified from a literature review to demonstrate that sampling method significantly influences study outcomes. We then compare a subset of methods identified from the review to determine the most efficient methods for recovering virus from surfaces in a laboratory trial using MS2 bacteriophage as a model virus. Recoveries of infective MS2 and MS2 RNA are determined using both a plaque assay and quantitative reverse transcription-PCR, respectively. We conclude that the method that most effectively recovers virus from nonporous fomites uses polyester-tipped swabs prewetted in either one-quarter-strength Ringer's solution or saline solution. This method recovers a median fraction for infective MS2 of 0.40 and for MS2 RNA of 0.07. Use of the proposed method for virus recovery in future fomite sampling studies would provide opportunities to compare findings across multiple studies.


Tryptophan synthetic pathway and its regulation in Chromobacterium violaceum.
Extracts of Chromobacterium violaceum catalyzed all of the reactions involved in synthesizing tryptophan from chorismic acid. Tryptophan auxotrophs which had lost any of these activities did not produce the characteristic purple pigment, violacein, when grown on a medium in which tryptophan was limiting. Gel filtration of extracts allowed us to estimate molecular weights for the tryptophan enzymes. All of the enzymes appeared to have molecular weights below 100,000. No enzymes were observed to occur in aggregates. The specific activities of the enzymes of the tryptophan pathway did not change when mutants were grown under conditions of limiting or excess tryptophan. The first enzyme in the pathway, anthranilate synthetase, was subject to feedback control by the end product, tryptophan. Tryptophan acted as a noncompetitive inhibitor with respect to glutamine, one of the substrates for anthranilate synthetase, and as a competitive inhibitor of the reaction when chorismate, the other substrate, was varied. The nonlinearity observed in the Lineweaver-Burk plot in the latter case suggests that there may be more than one chorismate-binding site on anthranilate synthetase.


Screening for carcinoma of the prostate by digital rectal examination in a randomly selected population.
To study the acceptability, costs, psychosocial consequences, and organisation of screening for carcinoma of the prostate. A randomly selected population was personally invited for digital rectal examination by a urologist and a general practitioner. Further examinations were performed if induration was felt. Each man completed a questionnaire on his response to the examination. General practices in the area of Norrköping. 1494 Men aged 50-69 randomly selected from a population of 9026. Prostates having a firm nodular consistency. Carcinoma of the prostate was suspected in 45 of 1163 patients examined; in 10 by the general practitioners, in 10 by the urologists, and in 25 by both. Forty four men had a fine needle aspiration biopsy, and carcinomas were found in 13 cases. Of these, one had been suspected by the general practitioner, four by urologists, and eight by both. The cost for each man was 11.60 pounds, and the cost for each case of carcinoma detected and treated by potentially curative methods was 2477 pounds. Of the 13 men with carcinoma, 10 underwent radical prostatectomy and one radiotherapy. One man had advanced disease and was given endocrine treatment, another was not treated. Only 193 men felt distress during the initial examination. Of the 44 men who had an aspiration biopsy, 25 experienced anxiety. Screening for carcinoma of the prostate by a urologist or a general practitioner using digital rectal examination is a cost effective method of early diagnosis. Whether such screening leads to prolonged survival, however, remains doubtful.


High-dose fenoldopam reduces postoperative neutrophil gelatinase-associated lipocaline and cystatin C levels in pediatric cardiac surgery.
The aim of the study was to evaluate the effects of high-dose fenoldopam, a selective dopamine-1 receptor, on renal function and organ perfusion during cardiopulmonary bypass (CPB) in infants with congenital heart disease (CHD). A prospective single-center randomized double-blind controlled trial was conducted in a pediatric cardiac surgery department. We randomized infants younger than 1 year with CHD and biventricular anatomy (with exclusion of isolated ventricular and atrial septal defect) to receive blindly a continuous infusion of fenoldopam at 1 μg/kg/min or placebo during CPB. Perioperative urinary and plasma levels of neutrophil gelatinase-associated lipocaline (NGAL), cystatin C (CysC), and creatinine were measured to assess renal injury after CPB. We enrolled 80 patients: 40 received fenoldopam (group F) during CPB, and 40 received placebo (group P). A significant increase of urinary NGAL and CysC levels from baseline to intensive care unit (ICU) admission followed by restoration of normal values after 12 hours was observed in both groups. However, urinary NGAL and CysC values were significantly reduced at the end of surgery and 12 hours after ICU admission (uNGAL only) in group F compared with group P (P = 0.025 and 0.039, respectively). Plasma NGAL and CysC tended to increase from baseline to ICU admission in both groups, but they were not significantly different between the two groups. No differences were observed on urinary and plasma creatinine levels and on urine output between the two groups. Acute kidney injury (AKI) incidence in the postoperative period, as indicated by pRIFLE classification (pediatric score indicating Risk, Injury, Failure, Loss of function, and End-stage kidney disease level of renal damage) was 50% in group F and 72% in group P (P = 0.08; odds ratio (OR), 0.38; 95% confidence interval (CI), 0.14 to 1.02). A significant reduction in diuretics (furosemide) and vasodilators (phentolamine) administration was observed in group F (P = 0.0085; OR, 0.22; 95% CI, 0.07 to 0.7). The treatment with high-dose fenoldopam during CPB in pediatric patients undergoing cardiac surgery for CHD with biventricular anatomy significantly decreased urinary levels of NGAL and CysC and reduced the use of diuretics and vasodilators during CPB. Clinical Trial.Gov NCT00982527.


TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice.
Vascular-disrupting agents (VDAs) such as combretastatin A4 phosphate (CA4P) selectively disrupt blood vessels in tumors and induce tumor necrosis. However, tumors rapidly repopulate after treatment with such compounds. Here, we show that CA4P-induced vessel narrowing, hypoxia, and hemorrhagic necrosis in murine mammary tumors were accompanied by elevated tumor levels of the chemokine CXCL12 and infiltration by proangiogenic TIE2-expressing macrophages (TEMs). Inhibiting TEM recruitment to CA4P-treated tumors either by interfering pharmacologically with the CXCL12/CXCR4 axis or by genetically depleting TEMs in tumor-bearing mice markedly increased the efficacy of CA4P treatment. These data suggest that TEMs limit VDA-induced tumor injury and represent a potential target for improving the clinical efficacy of VDA-based therapies.


The ability of human nuclear DNA to cause false positive low-abundance heteroplasmy calls varies across the mitochondrial genome.
Low-abundance mutations in mitochondrial populations (mutations with minor allele frequency ≤ 1%), are associated with cancer, aging, and neurodegenerative disorders. While recent progress in high-throughput sequencing technology has significantly improved the heteroplasmy identification process, the ability of this technology to detect low-abundance mutations can be affected by the presence of similar sequences originating from nuclear DNA (nDNA). To determine to what extent nDNA can cause false positive low-abundance heteroplasmy calls, we have identified mitochondrial locations of all subsequences that are common or similar (one mismatch allowed) between nDNA and mitochondrial DNA (mtDNA). Performed analysis revealed up to a 25-fold variation in the lengths of longest common and longest similar (one mismatch allowed) subsequences across the mitochondrial genome. The size of the longest subsequences shared between nDNA and mtDNA in several regions of the mitochondrial genome were found to be as low as 11 bases, which not only allows using these regions to design new, very specific PCR primers, but also supports the hypothesis of the non-random introduction of mtDNA into the human nuclear DNA. Analysis of the mitochondrial locations of the subsequences shared between nDNA and mtDNA suggested that even very short (36 bases) single-end sequencing reads can be used to identify low-abundance variation in 20.4% of the mitochondrial genome. For longer (76 and 150 bases) reads, the proportion of the mitochondrial genome where nDNA presence will not interfere found to be 44.5 and 67.9%, when low-abundance mutations at 100% of locations can be identified using 417 bases long single reads. This observation suggests that the analysis of low-abundance variations in mitochondria population can be extended to a variety of large data collections such as NCBI Sequence Read Archive, European Nucleotide Archive, The Cancer Genome Atlas, and International Cancer Genome Consortium.


Fourier ptychography: current applications and future promises.
Traditional imaging systems exhibit a well-known trade-off between the resolution and the field of view of their captured images. Typical cameras and microscopes can either "zoom in" and image at high-resolution, or they can "zoom out" to see a larger area at lower resolution, but can rarely achieve both effects simultaneously. In this review, we present details about a relatively new procedure termed Fourier ptychography (FP), which addresses the above trade-off to produce gigapixel-scale images without requiring any moving parts. To accomplish this, FP captures multiple low-resolution, large field-of-view images and computationally combines them in the Fourier domain into a high-resolution, large field-of-view result. Here, we present details about the various implementations of FP and highlight its demonstrated advantages to date, such as aberration recovery, phase imaging, and 3D tomographic reconstruction, to name a few. After providing some basics about FP, we list important details for successful experimental implementation, discuss its relationship with other computational imaging techniques, and point to the latest advances in the field while highlighting persisting challenges.


Commensal Oral Rothia mucilaginosa Produces Enterobactin, a Metal-Chelating Siderophore.
Next-generation sequencing studies of saliva and dental plaque from subjects in both healthy and diseased states have identified bacteria belonging to the Rothia genus as ubiquitous members of the oral microbiota. To gain a deeper understanding of molecular mechanisms underlying the chemical ecology of this unexplored group, we applied a genome mining approach that targets functionally important biosynthetic gene clusters (BGCs). All 45 genomes that were mined, representing Rothia mucilaginosa, Rothia dentocariosa, and Rothia aeria, harbored a catechol-siderophore-like BGC. To explore siderophore production further, we grew the previously characterized R. mucilaginosa ATCC 25296 in liquid cultures, amended with glycerol, which led to the identification of the archetype siderophore enterobactin by using tandem liquid chromatography-mass spectrometry (LC-MS/MS), high-performance liquid chromatography (HPLC), and nuclear magnetic resonance (NMR) spectroscopy. Normally attributed to pathogenic gut bacteria, R. mucilaginosa is the first commensal oral bacterium found to produce enterobactin. Cocultivation studies including R. mucilaginosa or purified enterobactin revealed that enterobactin reduced growth of certain strains of cariogenic Streptococcus mutans and pathogenic strains of Staphylococcus aureus Commensal oral bacteria were either unaffected, reduced in growth, or induced to grow adjacent to enterobactin-producing R. mucilaginosa or the pure compound. Taken together with Rothia's known capacity to ferment a variety of carbohydrates and amino acids, our findings of enterobactin production add an additional level of explanation to R. mucilaginosa's prevalence in the oral cavity. Enterobactin is the strongest Fe(III) binding siderophore known, and its role in oral health requires further investigation.IMPORTANCE The communication language of the human oral microbiota is vastly underexplored. However, a few studies have shown that specialized small molecules encoded by BGCs have critical roles such as in colonization resistance against pathogens and quorum sensing. Here, by using a genome mining approach in combination with compound screening of growth cultures, we identified that the commensal oral community member R. mucilaginosa harbors a catecholate-siderophore BGC, which is responsible for the biosynthesis of enterobactin. The iron-scavenging role of enterobactin is known to have positive effects on the host's iron pool and negative effects on host immune function; however, its role in oral health remains unexplored. R. mucilaginosa was previously identified as an abundant community member in cystic fibrosis, where bacterial iron cycling plays a major role in virulence development. With respect to iron's broad biological importance, iron-chelating enterobactin may explain R. mucilaginosa's colonization success in both health and disease.


Cross-sectional and longitudinal relationship between physical fitness and academic achievement in Japanese adolescents.
Although cross-sectional studies regarding the relationship between physical fitness and academic achievement among Japanese children have been previously reported, no longitudinal study has yet been reported for Japanese children. The purpose of this study was to examine the cross-sectional and longitudinal relationships between physical fitness and academic achievement among Japanese adolescents. This cohort study included 1,189 seventh- and ninth-grade students from two schools. The follow-up period was 2 years. A physical fitness test involving eight test items (hand grip, sit-ups, sit and reach, side-to-side jump, 20-m shuttle run, 50-m dash, standing broad jump and handball throwing) was conducted to evaluate the fitness of the participants. Academic achievement in Japanese, mathematics and a foreign language (English) was assessed at baseline and follow-up using cumulative guidance records. Participants were classified into low-low, high-low, low-high, and high-high groups based on physical fitness test results at baseline and follow-up. Compared with the groups showing low fitness levels, those showing high fitness levels for all items of the physical fitness test expect handball throwing had increased odds of showing high academic achievement levels in all three subjects at baseline and/or follow-up compared with the low-fitness groups. Sit-ups and 20-m shuttle run in the high-high and low-high groups were related to higher academic achievement levels at follow-up compared with those in the low-low group for both boys and girls. Therefore, this study suggests that various physical fitness outcomes are positively associated with high academic achievement levels for Japanese children.


A first large cohort study of personality trait stability over the 40 years between elementary school and midlife.
This report provides some initial findings from an investigation of the relations between childhood Big Five personality traits assessed by elementary school teachers and similar traits assessed 40 years later by self-reports at midlife (N = 799). Short-term (1-3 years) test-retest reliabilities were lower (.22-.53) in childhood when personality was developing than they were in adulthood (.70-.79) when personality stability should be at its peak. Stability coefficients across the 40-year interval between the childhood assessment and the 2 measures of adulthood personality were higher for Extraversion (e.g., .29) and Conscientiousness (e.g., .25) than for Openness (e.g., .16), Agreeableness (e.g., .08), and Neuroticism (e.g., .00). Construct continuity between childhood and adulthood was evaluated by canonical analysis and by structural equation modeling and indicated continuity at both a broad, two-dimensional level and at the level of the Big Five. The findings are discussed in relation to A. Caspi, B. W. Roberts, and R. L. Shiner's (2005) principles of rank-order personality stability.


Formation of macroscopic surface layers on Fe(0) electrocoagulation electrodes during an extended field trial of arsenic treatment.
Extended field trials to remove arsenic (As) via Fe(0) electrocoagulation (EC) have demonstrated consistent As removal from groundwater to concentrations below 10 μg L(-1). However, the coulombic performance of long-term EC field operation is lower than that of laboratory-based systems. Although EC electrodes used over prolonged periods show distinct passivation layers, which have been linked to decreased treatment efficiency, the spatial distribution and mineralogy of such surface layers have not been investigated. In this work, we combine wet chemical measurements with sub-micron-scale chemical maps and selected area electron diffraction (SAED) to determine the chemical composition and mineral phase of surface layers formed during long-term Fe(0) EC treatment. We analyzed Fe(0) EC electrodes used for 3.5 months of daily treatment of As-contaminated groundwater in rural West Bengal, India. We found that the several mm thick layer that formed on cathodes and anodes consisted of primarily magnetite, with minor fractions of goethite. Spatially-resolved SAED patterns also revealed small quantities of CaCO3, Mn oxides, and SiO2, the source of which was the groundwater electrolyte. We propose that the formation of the surface layer contributes to decreased treatment performance by preventing the migration of EC-generated Fe(II) to the bulk electrolyte, where As removal occurs. The trapped Fe(II) subsequently increases the surface layer size at the expense of treatment efficiency. Based on these findings, we discuss several simple and affordable methods to prevent the efficiency loss due to the surface layer, including alternating polarity cycles and cleaning the Fe(0) surface mechanically or via electrolyte scouring.


Salinomycin and its derivatives as potent RET transcriptional inhibitors for the treatment of medullary thyroid carcinoma.
Rearranged during transfection kinase (RET) is a validated molecular target in medullary thyroid cancer (MTC), as activating mutations in RET are often associated with the development of MTC. The present study reports the first preclinical characterization of salinomycin and selected analogs as potent RET transcriptional inhibitors. Reverse transcription‑PCR and immunoblotting revealed that salinomycin profoundly decreased RET expression in the TT human MTC cell line by inhibiting RET transcription. Moreover, salinomycin resulted in remarkable anti‑proliferative activity against MTC that is driven by RET (gain of function mutation) by selectively inhibiting the intracellular PI3K/Akt/mTOR signaling pathway. Also, flow cytometry and fluorescence‑activated cell sorting showed that salinomycin induces G1 phase arrest and apoptosis by reducing the expression of retinoblastoma protein, E2F1, cyclin D and CDK4. The structure‑activity relationship of salinomycin was investigated in this study. Some of the salinomycin derivatives showed the ability to reduce RET expression where others fail to alter RET expression. These results suggest that the RET‑suppressing effect of salinomycin may be largely attributed to disruption of the Wnt pathway, presumably through interference with the ternary LRP6‑Frizzled‑Wnt complex. Furthermore, these findings support the further preclinical evaluation of salinomycin and its analogs as a promising new class of therapeutic agents for the improved treatment of MTC.


The relationship between boundary layer stability and cloud cover in the post-cold frontal region.
Using NASA-Aqua MODIS and AIRS data, the relationship between low-level cloud cover (cloud top below the 700 hPa level) and boundary layer stability is explored in post-cold frontal conditions. A linear relationship is found between seasonal cloud cover and two separate measures of inversion strength, the lower tropospheric stability (LTS) and the estimated inversion strength (EIS), for two specific regions in the north Atlantic and Pacific in quiescent and weakly subsiding conditions. The relationship barely changes when considering dynamically active and subsiding post-cold frontal conditions for the same regions. To explore the generality of this result and increase sample size, cold front centered composites of cloud cover and stability are constructed. The northern and southern hemisphere seasonal cloud cover and stability distributions in the post-cold frontal regions are then compared. A fairly good correlation between cloud cover and EIS is found in both hemispheres across all seasons, suggesting that a linear relationship between cloud cover and inversion strength proposed for quiescent conditions exists also in more dynamically active subsiding post-cold frontal conditions. However, for a given season and hemisphere, the correlation between cloud cover and EIS degrades in post-cold frontal regions, especially in the northern hemisphere. At these scales, other large scale factors tend to correlate better with cloud cover.


Effects of Intrinsic Local Fields on Molecular Fluorescence and Energy Transfer: Dipole Mechanisms and Surface Potentials.
A general theory is developed to identify the influence of local dipole fields on fluorescence and intermolecular electronic excitation transfer. The analysis, based on electrodynamical principles, identifies the fundamental quantum mechanisms and delivers full analytical results. The aim is to afford new physical insights, assisting the interpretation of measurements on the specific effects of local molecular dipoles on direct fluorescence and on fluorescence resonance energy transfer. Dipole field effects, which include those originating from intrinsically polar chromophores and surface field gradients, also prove to be manifest in electronic transitions of quadrupole symmetry character. The results have particular significance for fluorescence studies of cell membrane biophysics.


Associations of C-Reactive Protein, Granulocytes and Granulocyte-to-Lymphocyte Ratio with Mortality from Breast Cancer in Non-Institutionalized American Women.
Inflammation may play a role in breast cancer, but evidence in the general population is lacking. We investigated the association between serum inflammatory markers (C-reactive protein (CRP), absolute granulocyte count (AGC) and granulocyte-to-lymphocyte (G/L) ratio) and breast cancer (BCa) mortality in American women while accounting for adiposity. From the Third National Health and Nutrition Examination Survey (NHANES III) we selected all women aged 20+ without any known history of cancer (n = 7,780). Multivariable Cox regression models were used to assess CRP, AGC and G/L ratio in relation to mortality from BCa, all cancer, cardiovascular disease and all causes. Stratification analyses by body mass index (BMI) and waist circumference were performed to investigate the effect of adiposity on this association. During a mean follow-up of 167 months, 44 women died from BCa. After adjustments for BMI and waist circumference, only G/L ratio was associated to risk of BCa death (e.g. HR: 2.35, 95% CI: 1.36-4.06 for the 3rd compared to the 1st tertile, Ptrend = 0.01). Except for a borderline interaction between CRP categories and obesity by BMI, no statistically significant interaction between markers and categories of BMI or waist circumference was observed. All three markers were associated with mortality from cardiovascular disease and all causes. Our findings support a role of inflammation in BCa mortality which may involve mechanisms apart from obesity, and potential usefulness of GLR as a marker in assessing inflammation and cancer.


Evaluation of Nutritional Biochemical Parameters in Haemodialysis Patients over a Ten-year Period.
Protein-energy malnutrition as well as systemic inflammation and metabolic disorders are common in patients with chronic kidney failure, who require renal replacement therapy (haemodialysis). Such malnutrition is a factor that significantly contributes to their morbidity and mortality. This study evaluated the nutritional status of haemodialysis patients by assessing biochemical and anthropometric parameters in order to determine whether these patients suffered disorders reflecting nutritional deterioration directly related to time on haemodialysis. This research comprised 90 patients of both genders with chronic kidney failure, who regularly received haemodialysis at our unit over a period of ten years. The patients' blood was tested quarterly for plasma albumin, total cholesterol and total proteins, and tested monthly for transferrin. The patients' weight, height and body mass index (BMI) were monitored. Body mass index was calculated using the formula: weight (kg)/height (m2 ) and classified in one of the following categories defined in the World Health Organization (WHO) Global Database on Body Mass Index: (i) underweight [BMI < 18.50], (ii) normal [BMI 18.50 - 24.99], (iii) overweight [BMI 25 - 29.99], (iv) obese [BMI > 30]. In the ten-year period of the study, the patients experienced a substantial decline in their biochemical parameters. Nevertheless, their BMI did not show any significant changes despite the patients' state of malnutrition. The prevalence of malnutrition in haemodialysis patients was evident. Nevertheless, the BMI of the subjects did not correspond to the biochemical parameters measured. Consequently, the results showed that the nutritional deterioration of these patients was mainly reflected in their biochemical parameters rather than in their anthropometric measurements.


Dose painting based on tumor uptake of Cu-ATSM and FDG: a comparative study.
Hypoxia and increased glycolytic activity of tumors are associated with poor prognosis. The purpose of this study was to investigate differences in radiotherapy (RT) dose painting based on the uptake of 2-deoxy-2-[(18) F]-fluorodeoxyglucose (FDG) and the proposed hypoxia tracer, copper(II)diacetyl-bis(N(4))-methylsemithiocarbazone (Cu-ATSM) using spontaneous clinical canine tumor models. Positron emission tomography/computed tomography scans of five spontaneous canine sarcomas and carcinomas were obtained; FDG on day 1 and (64)Cu-ATSM on day 2 and 3 (approx. 3 and 24 hours pi.). Sub-volumes for dose escalation were defined by a threshold-based method for both tracers and five dose escalation levels were formed in each sub-volume. Volumetric modulated arc therapy plans were optimized based on the dose escalation regions for each scan for a total of three dose plans for each dog. The prescription dose for the GTV was 45 Gy (100%) and it was linearly escalated to a maximum of 150%. The correlations between dose painting plans were analyzed with construction of dose distribution density maps and quality volume histograms (QVH). Correlation between high-dose regions was investigated with Dice correlation coefficients. Comparison of dose plans revealed varying degree of correlation between cases. Some cases displayed a separation of high-dose regions in the comparison of FDG vs. (64)Cu-ATSM dose plans at both time points. Among the Dice correlation coefficients, the high dose regions showed the lowest degree of agreement, indicating potential benefit of using multiple tracers for dose painting. QVH analysis revealed that FDG-based dose painting plans adequately covered approximately 50% of the hypoxic regions. Radiotherapy plans optimized with the current approach for cut-off values and dose region definitions based on FDG, (64)Cu-ATSM 3 h and 24 h uptake in canine tumors had different localization of the regional dose escalation levels. This indicates that (64)Cu-ATSM at two different time-points and FDG provide different biological information that has to be taken into account when using the dose painting strategy in radiotherapy treatment planning.


Dynamical reweighting methods for Markov models.
Conformational dynamics is essential to biomolecular processes. Markov State Models (MSMs) are widely used to elucidate dynamic properties of molecular systems from unbiased Molecular Dynamics (MD). However, the implementation of reweighting schemes for MSMs to analyze biased simulations is still at an early stage of development. Several dynamical reweighing approaches have been proposed, which can be classified as approaches based on (i) Kramers rate theory, (ii) rescaling of the probability density flux, (iii) reweighting by formulating a likelihood function, (iv) path reweighting. We present the state-of-the-art and discuss the methodological differences of these methods, their limitations and recent applications.


Use, adoption, and effectiveness of tippy-tap handwashing station in promoting hand hygiene practices in resource-limited settings: a systematic review.
Tippy-taps are locally made devices for washing hands with running water. They are simple and low-cost, enabling technology that provides adequate water sources, handwashing stations and motivation for people to prioritise handwashing. This systematic review aimed to establish the use, benefits, adoption and effectiveness of enabling technology; tippy-tap handwashing station, in resource-limited settings. We systematically searched for articles in the PubMed, EMBASE, PsycINFO, AMED, CINAHL, DOAJ and Google Scholar databases guided by the acceptable best practice developed by the PROSPERO and COCHRANE for systematic search and selection of articles. Search terms such as tippy-taps, enabling technology, hand-washing station, hand-washing behaviour, diarrhoea, respiratory infection, increase handwashing behaviour were used. In addition, a PRISMA flow diagram was used to elaborate on the number of articles retrieved, retained, excluded and reasons for every action. Studies that used tippy-tap hand washing station as a handwashing facility regardless of the design were included in this review. A mixed method appraisal tool was used to appraise studies. Twenty articles met the eligibility criteria. The use of tippy-taps for handwashing by household members or school children was reported by authors of 16 studies, and it ranged from 2.7 to 80%. The availability of tippy-taps increased handwashing and use of soap among participants. Furthermore, the majority of people who were oriented to tippy-taps or recruited to tippy-tap studies built their tippy-tap stations even after the promotional activities or programs had ended. In one study, tippy-taps were reported by participant to be effective in preventing episodes of stomach pain among participants. Tippy-tap handwashing station could help in promoting handwashing practice in resource constraint settings. Future studies are needed to evaluate the effectiveness of tippy-tap hand washing station on preventing water and hygiene-related infections.


The history and evolution of outpatient parenteral antibiotic therapy (OPAT).
Outpatient parenteral antibiotic therapy (OPAT) is now a widely accepted and safe therapeutic option for carefully selected patients. Benefits include cost savings and improved patient satisfaction; risks include failure to adhere to care, unexpected changes in the underlying infection, and adverse drug and intravenous access events. We report on our 40-year experience with OPAT in a single healthcare system in the USA and highlight OPAT developments in several countries. We compared data on patients treated in our programme over two time periods: Period 1 from 1978 to 1990; and Period 2, calendar year 2014. In Period 2 paediatric patients were excluded. Between Periods 1 and 2, changes included an almost three-fold increase in the number of patients treated per year (80 vs. 229), treatment of more patients with severe orthopaedic-related infections (20% vs. 38%), a marked increase in the use of peripherally inserted central catheters to administer antibiotics (20% vs. 98%), a shorter duration of inpatient stay and a longer duration of OPAT (13 days vs. 24 days). Other changes in Period 2 included treatment of 20% of patients without antecedent hospitalisation, and use of carbapenems rather than cephalosporins as the most frequently administered agents. OPAT was safe, with rehospitalisation rates of 6% and 1% in Periods 1 and 2, respectively. We recommend increased access to structured OPAT teams and the development of standard definitions and criteria for important outcome measures (e.g. clinical 'cure' and unplanned hospital re-admissions). These steps are critical for patient safety and financial stewardship of resources.


A multi-locus molecular phylogeny for Australia's iconic Jacky Dragon (Agamidae: Amphibolurus muricatus): phylogeographic structure along the Great Dividing Range of south-eastern Australia.
Jacky dragons (Amphibolurus muricatus) are ubiquitous in south-eastern Australia and were one of the first Australian reptiles to be formally described. Because they are so common, Jacky dragons are widely used as a model system for research in evolutionary biology and ecology. In addition, their distribution along the Great Dividing Range of eastern Australia provides an opportunity to examine the influence of past biogeographical processes, particularly the expansion and contraction of forest habitats, on the diversification of this iconic agamid lizard. We generated sequence data for two mitochondrial and three nuclear DNA loci (4251base pairs) for 62 Jacky dragons sampled from throughout their distribution. Phylogenetic analyses based on maximum likelihood and Bayesian species-tree methods revealed five geographically structured clades separated by up to 6% mitochondrial and 0.7% nuclear sequence divergence. We also quantified body proportion variation within and between these genetic clades for more than 500 specimens and found no evidence of any significant differentiation in body proportions across their range. Based on body proportion homogeneity and lack of resolution in the nuclear loci, we do not support taxonomic recognition of any of the mitochondrial clades. Instead, A. muricatus is best thought of as a single species with phylogeographic structure. The genetic patterns observed in the Jacky dragon are consistent with fragmented populations reduced to multiple refugia during cold, arid phases when forested habitats were greatly restricted. Consequently, the inferred biogeographic barriers for this taxon appear to be in line with lowland breaks in the mountain ranges. Our results are congruent with studies of other reptiles, frogs, mammals, birds and invertebrates, and together highlight the overarching effects of widespread climatic and habitat fluctuations along the Great Dividing Range since the Pliocene.


The detection of intentional contingencies in simple animations in patients with delusions of persecution.
It has been proposed that delusions of persecution are caused by the tendency to over-attribute malevolent intentions to other people's actions. One aspect of intention attribution is detecting contingencies between an agent's actions and intentions. Here, we used simplified stimuli to test the hypothesis that patients with persecutory delusions over-attribute contingency to agents' movements. Short animations were presented to three groups of subjects: (1) schizophrenic patients; (2) patients with affective disorders; and (3) normal control subjects. Patients were divided on the basis of the presence or absence of delusions of persecution. Participants watched four types of film featuring two shapes. In half the films one shape's movement was contingent on the other shape. Contingency was either 'intentional': one shape moved when it 'saw' another shape; or 'mechanical': one shape was launched by the other shape. Subjects were asked to rate the strength of the relationship between the movement of the shapes. Normal control subjects and patients without delusions of persecution rated the relationship between the movement of the shapes as stronger in both mechanical and intentional contingent conditions than in non-contingent conditions. In contrast, there was no significant difference between the ratings of patients with delusions of persecution for the conditions in which movement was animate. Patients with delusions of persecution perceived contingency when there was none in the animate non-contingent condition. The results suggest that delusions of persecution may be associated with the over-attribution of contingency to the actions of agents.


A manipulative technique of Andrew Taylor Still as reported by Charles Hazzard, DO, in 1905.
This article presents rediscovered osteopathic manipulative techniques described by Charles Hazzard in 1905 and ascribed by him to Andrew Taylor Still, the founder of osteopathic medicine. Still refrained from writing about his manipulative techniques in any significant detail, apparently intentionally. The techniques published by Hazzard have both internal consistency and similarity to those less well described by Still, suggesting that the attribution is accurate. The techniques are analyzed and presented as a variant of a direct articulatory technique with axial compression. In honour of their originator, they are being termed the Still techniques.


Prevalence of Syphilis among Blood and Stem Cell Donors in Saudi Arabia: An Institutional Experience.
Syphilis is one of the known transfusion-transmissible infections and causes 100,000 deaths yearly, with around 90% of these deaths occurring in the developing world. Little data is available regarding the prevalence of syphilis among Saudi blood and stem cell donors. We conducted a survey on the incidence of syphilis among all blood and stem cell donors. This study was conducted at the Prince Sultan Military Medical City in Riyadh, Saudi Arabia in the 10 years period data during 2006-2015. Data were analyzed about full history, physical examination, age, sex, weight, profession, marital status, number of the donations, data of last donation, having a relation who received blood transfusion, as well as the screening test results of the donated blood. We determined the seroprevalence of infection and compared by sex and other variable through frequency analysis, Chi square, Fisher, and prevalence ratios. Approximately 240,000 blood donors were screened and studied in the period of study. Most of the blood donors were male (98.3%) and 89% of them were citizens of Saudi Arabia. According to our findings, we estimated that, in the last 10 years, approximately 0.044% of all the blood donors were syphilis positive cases. No cases were detected as positive for syphilis among stem cell donors. Only 60 blood donors tested positive for syphilis. In addition, we studied 202 stem cell transplant donors during the same period, of which 59% were male and none texted positive for syphilis. A concerted effort between the government, health care providers, regulatory bodies and accreditation agencies have all contributed in eliminating the risk of spreading syphilis among blood donors.


Prelabor Rupture of Membranes: ACOG Practice Bulletin, Number 217.
Preterm birth occurs in approximately 10% of all births in the United States and is a major contributor to perinatal morbidity and mortality (). Prelabor rupture of membranes (PROM) that occurs preterm complicates approximately 2-3% of all pregnancies in the United States, representing a significant proportion of preterm births, whereas term PROM occurs in approximately 8% of pregnancies (). The optimal approach to assessment and treatment of women with term and preterm PROM remains challenging. Management decisions depend on gestational age and evaluation of the relative risks of delivery versus the risks (eg, infection, abruptio placentae, and umbilical cord accident) of expectant management when pregnancy is allowed to progress to a later gestational age. The purpose of this document is to review the current understanding of this condition and to provide management guidelines that have been validated by appropriately conducted outcome-based research when available. Additional guidelines on the basis of consensus and expert opinion also are presented. This Practice Bulletin is updated to include information about diagnosis of PROM, expectant management of PROM at term, and timing of delivery for patients with preterm PROM between 34 0/7 weeks of gestation and 36 6/7 weeks of gestation.


The Effect of Route of Anvil Insertion on Stricture Rates with Circular Stapled Gastrojejunostomy During Laparoscopic Gastric Bypass.
A higher incidence of gastrojejunal (GJ) anastomotic strictures has been reported following laparoscopic gastric bypass (LRYGB) with the 21 mm compared to 25 mm circular stapler. We hypothesized that the rate of stricture formation is affected by route of anvil insertion and its position relative to the gastric pouch staple line [trans-gastric above staple line (trans-gastric) vs. trans-oral through staple line (trans-oral)] following LRYGB. Retrospective review of consecutive patients who underwent LRYGB with circular stapled GJ studied in four groups: trans-gastric-21 mm, trans-gastric-25 mm, trans-oral-21 mm, and trans-oral-25 mm. Primary outcome studied was GJ stricture; secondary outcomes were results with endoscopic therapy and weight loss at 12 months. Predictors studied were age, gender, body mass index (BMI), comorbidities, and operative technical factors including anvil size and insertion route. Regression analyses were performed to identify predictors of GJ stricture. Eight hundred seventy-six patients underwent LRYGB. Seventy-six (8.7 %) developed a GJ stricture. The highest stricture rate occurred in the trans-gastric-21 mm group (17 %, p < .01 for all comparisons). Stricture rates were similar for trans-gastric-25 mm (8.4 %), trans-oral-21 mm (5.2 %), and trans-oral-25 mm (1.6 %) groups. Independent predictors of stricture were: trans-gastric-21 mm (OR 10.9, 95%CI 1.4-85.1; p = .022) and age (OR 0.97, 95%CI 0.95-0.99; p = .002). Endoscopic dilation relieved symptoms in all patients. There was no difference in %EWL at 12 months in patients with and without a stricture. We conclude that the trans-oral-21 mm anvil is associated with a low stricture rate. With the advantage of smaller abdominal wall wound, trans-oral-21 mm may be the preferred size and route of anvil insertion.


Electrophysiological evidence for convergence of inputs from the medial prefrontal cortex and lateral habenula on single neurons in the dorsal raphe nucleus.
Neuronal projections to the dorsal raphe nucleus (DRN) from the medial prefrontal cortex (mPFC) and lateral habenula nucleus (LHb) provide the two key routes by which information processed by mood regulatory, cortico-limbic-striatal circuits input into the 5-HT system. These two projections may converge as it appears that both activate local GABAergic neurons to inhibit 5-HT neurons in the DRN. Here we have tested this hypothesis by measuring the effect of stimulation of the mPFC and LHb on the activity of 5-HT and non-5-HT, putative gamma-amino butyric acid (GABA) neurons in the DRN using extracellular recordings in anaesthetized rats. A total of 119 5-HT neurons (regular, slow firing, broad spike width) and 21 non-5-HT, putative GABA neurons (fast-firing, narrow spike width) were tested. Electrical stimulation of the mPFC or LHb caused a poststimulus inhibition (30 ms latency) of 101/119 5-HT neurons, of which 61 (60%) were inhibited by both the mPFC and LHb. Electrical stimulation of the mPFC or LHb also caused a short latency (12-20 ms) poststimulus facilitation of 10/21 non-5-HT neurons, of which 5 (50%) were activated by both the mPFC and LHb. These data indicate that a significant number of 5-HT neurons and non-5-HT neurons in the DRN are influenced by both the mPFC and LHb. Moreover, the data are compatible with the hypothesis and that there is a convergence of mPFC and LHb inputs on local circuit GABAergic neurons in the DRN which in turn inhibit the activity of 5-HT neurons.


Separation of Phosvitin from Egg Yolk without Using Organic Solvents.
The objective of this study was to develop a new method to separate phosvitin from egg yolk without using organic solvents. Phosvitin was extracted from yolk granules using 10% NaCl or 10% (NH4)2SO4 (final concentration) and then treated with heat to precipitate the lipoproteins from the extracted solution. The optimal pH for the phosvitin extraction from yolk granules was determined, and the iron-binding ability of the extracted phosvitin (final product) was tested. Adding 10% (NH4)2SO4 disrupted the granules, and the subsequent thermal treatment at 90°C for 1 h precipitated low density and high density lipoproteins, which enabled separation of phosvitin by centrifugation. The phosvitin concentration in the extract was significantly higher when the pH of the solution was adjusted to pH ≥9. The purity and recovery rate of phosvitin at the end of the separation process were approximately 78% and 56%, respectively. The separated phosvitin was confirmed to have ferrous and ferric iron binding ability. The advantages of this new method compared with the traditional methods include no organic solvents and high-priced equipment are needed for the separation. Also, this method is more environment and consumer friendly than that of the traditional methods.


Formaldehyde damage to DNA and inhibition of DNA repair in human bronchial cells.
Cultured bronchial epithelial and fibroblastic cells from humans were used to study DNA damage and toxicity caused by formaldehyde. Formaldehyde caused the formation of cross-links between DNA and proteins, caused single-strand breaks in DNA, and inhibited the resealing of single-strand breaks produced by ionizing radiation. Formaldehyde also inhibited the unscheduled DNA synthesis that occurs after exposure of cells to ultraviolet irradiation or to benzo[a]pyrene diolexpoxide but at doses substantially higher than those required to inhibit the resealing of x-ray-induced single-strand breaks. Therefore, formaldehyde could exert its mutagenic and carcinogenic effects by both damaging DNA and inhibiting DNA repair.


Factors associated with high-severity disciplinary action by a state medical board: a Texas study of medical license revocation.
There has been an increase in research evaluating factors associated with disciplinary action of physicians by state medical boards. However, factors related to the severity of disciplinary action are lacking. By investigating these factors while controlling for the type of violation, the authors sought to determine whether physician characteristics influenced the process of disciplinary action by state medical boards. Physicians disciplined by the Texas Medical Board between January 1, 1989, and December 31, 1998, were included in this case-controlled study (N=1129). Multivariate logistic regression analysis was used to compute odds ratios (ORs) and 95% confidence intervals (CIs) for factors associated with license revocation, the most severe disciplinary action, compared with all other forms of disciplinary action combined. Anesthesiologists (OR, 2.45; 95% CI, 1.05-5.74), general practitioners (OR, 1.80; 95% CI, 1.01-3.19), and psychiatrists (OR, 2.68; 95% CI, 1.41-5.13), as well as those with multiple disciplinary actions (OR, 1.91; 95% CI, 1.29-2.83) were most susceptible to license revocation. The more years a disciplined physician was in practice, the greater risk he or she had of license revocation (OR, 1.05; 95% CI, 1.04-1.07). Factors associated with a greater likelihood of license revocation for physicians are: primary medical specialty, number of years in practice, and a history of multiple disciplinary actions.


Importance of livestock diseases identified using participatory epidemiology in the highlands of Ethiopia.
Livestock are a major cornerstone for livelihoods of smallholders in the highlands of Ethiopia. However, infectious diseases are a key constraint in livestock production affecting productivity and food security. This study aimed to understand livestock producers' perception on importance and epidemiology of livestock diseases. Participatory tools using focus group discussions were used to identify and rank livestock species, major livestock diseases, and their epidemiological patterns in smallholder systems. The study covered 17 districts in four regions, with two or three kebeles (smallest administrative unit) included in each district. To capture views of women and men, separate focus group discussions (FGD) were conducted. Data collected through proportional piling were used in generalized linear model analysis. Taking sheep as a reference, cattle were significantly the most preferred species with the odds of cattle scoring higher than sheep being 2.08 times (P = 0.000). Sheep and poultry were equally the second most important livestock, followed by goat and equine. There were no statistically significant differences between men and women FGD groups and between the four regions in their preference for livestock species. Twelve out of 28 identified livestock diseases were mentioned by at least 10% of FGDs in their list of five most important diseases. Blackleg, foot, and mouth disease, lumpy skin disease, anthrax, and bovine pasteurellosis were ranked as the top five diseases by both men and women focus groups. Reasons for high scores included suddenness of death, zoonosis risks, animal age groups and species affected, frequency of occurrence, rate of transmission in herds, curability, and inefficient vaccination. Seasonality and agro-ecology were also factors associated with disease occurrence. The study also documents that adult men and women are more involved in activities related to disease transmission compared with other family members. When asked about impacts of diseases, loss of livelihood, displacement, and infection with zoonoses were mentioned, with women considered equally affected as men. In conclusion, participatory tools allowed understanding disease priorities of and their perceived epidemiology in smallholder systems. The perceptions and priorities of men and women are very similar, and both need to be involved in designing health management interventions. Based on the findings of this study, the intervention strategies listed in the 2013 animal health strategy of Ethiopia (MoA and ILRI 2013) seem pertinent and need to be implemented to overcome the challenges of diseases.


Contribution of the lymphotoxin beta receptor to liver regeneration.
The liver has an enormous capacity to regenerate in response to insults, but the cellular events and molecules involved in liver regeneration are not well defined. In this study, we report that ligands expressed on the surface of lymphocytes have a substantial effect on liver homeostasis. We demonstrate that a T cell-restricted ligand, homologous to lymphotoxin, exhibits inducible expression, competes with herpesvirus glycoprotein D for herpesvirus entry mediator on T cells (LIGHT), signaling through the lymphotoxin receptor (LTbetaR) expressed on mature hepatocytes induces massive hepatomegaly. Using genetic targeting and a receptor fusion protein, we further show that mice deficient in LTbetaR signaling have a severe defect in their ability to survive partial hepatectomy with marked liver damage and failure to initiate DNA synthesis after partial hepatectomy. We further show that mice deficient in a LTbetaR ligand, LTalpha, also show decreased ability to survive partial hepatectomy with similar levels of liver damage and decreased DNA synthesis. Therefore, our study has revealed an unexpected role of lymphocyte-restricted ligands and defined a new pathway in supporting liver regeneration.


Toward the use of genomics to study microevolutionary change in bacteria.
Bacteria evolve rapidly in response to the environment they encounter. Some environmental changes are experienced numerous times by bacteria from the same population, providing an opportunity to dissect the genetic basis of adaptive evolution. Here I discuss two examples in which the patterns of rapid change provide insight into medically important bacterial phenotypes, namely immune escape by Neisseria meningitidis and host specificity of Campylobacter jejuni. Genomic analysis of populations of bacteria from these species holds great promise but requires appropriate concepts and statistical tools.


Creation, characterization, and assignment of opsonic values for a new pneumococcal OPA calibration serum panel (Ewha QC sera panel A) for 13 serotypes.
Pneumococcal conjugate vaccines (PCVs) have been very effective in reducing the disease burden caused by Streptococcus pneumoniae serotypes covered by the current vaccine formulations. However, the incidence of disease caused by serotypes not covered by the vaccine is increasing. Consequently, there are active efforts to develop new PCVs with additional serotypes in order to provide protection against the emergent serotypes. Due to costs and ethical issues associated with performing true vaccine efficacy studies, new PCVs are being licensed based on their immunogenicity, which may be assessed with 2 in vitro assays: enzyme-linked immunosorbent assay (ELISA) for quantitating antibody level and opsonophagocytic assay (OPA) for assessing protective function. While a standardized ELISA has been developed, OPA results from different laboratories can be quite disparate, even among laboratories utilizing the same platform. In order to harmonize OPA data, a recent international collaboration assigned opsonic indices to the US Food and Drug Administration (US FDA) reference serum, 007sp, as well as a panel of US FDA calibration sera. However, due to a low number of aliquots, the availability of these calibration sera is extremely limited. Because calibration sera are critical to establish the performance characteristics of an OPA, a second calibration serum panel was created, comprised of 20 sera collected from adults immunized with the 23-valent polysaccharide vaccine, with 150 to 500 aliquots prepared for each serum. In order to establish consensus OPA values of the 20 sera for the 13 serotypes in 13-valent PCV, the sera were tested by 4 laboratories in an international collaborative OPA study. The 007sp results of 1 laboratory deviated significantly from those obtained by the other laboratories, as well as from previously assigned values. Due to these discrepancies, the consensus values for the calibration sera were determined based on the data from the remaining laboratories. Thus, we were able to create a panel of sera with consensus opsonic values that could be used by outside laboratories to calibrate pneumococcal OPAs. Our results also confirmed findings of a previous study that normalization of OPA results significantly reduces interlaboratory variation, with normalization based on 007sp reducing variation by 43% to 74%, depending on serotype.


Structure-function relationships of tachyplesins and their analogues.
Haemocytes of the horseshoe crab (Limulus) contain a new family of arthropodous peptide antibiotics, termed the tachyplesin family. These cationic peptides are composed of 17-18 amino acid residues with a C-terminal arginine alpha-amide. Tachyplesin I takes on a fairly rigid conformation constrained by two disulphide bridges and adopts a conformation consisting of an antiparallel beta-sheet connected by a beta-turn. Isopeptides of tachyplesin I with amino acid replacements, tachyplesins II and III, and polyphemusins I and II have also been found in the haemocytes of the South-East Asian species and Limulus polyphemus. These peptides are present in abundance in the small granules of the haemocytes and inhibit strongly the growth of not only Gram-negative and Gram-positive bacteria but also fungi such as Candida albicans. Tachyplesin exists in the prepro form consisting of 77 residues; this precursor is probably processed by intracellular proteases and an amidation enzyme before incorporation into the small granules of the haemocytes. We examined the mode of action of tachyplesin I on biomembranes, comparing it with that of gramicidin S. Tachyplesin caused an efflux of K+ from Staphylococcus aureus and Escherichia coli cells similar to that caused by gramicidin S. Another antimicrobial substance, anti-LPS factor, has been isolated from haemocytes.


Characterizing the cauline domatia of two newly discovered ecuadorian ant plants in piper: an example of convergent evolution.
The stems of some myrmecophytes in Piper are used as domatia by resident ant colonies. Hollow, ant-occupied stems were previously known only in four species of southern Central American Piper, all members of Section Macrostachys. Here we present two additional, unrelated, hollow-stemmed myrmecophytes from Ecuador: P. immutatum and P. pterocladum (members of sections Radula and Peltobryon, respectively). Although similar superficially, stem cavities of the Ecuadorian Piper species differ morphologically and developmentally from those of Central American taxa. The stem cavities of P. immutatum, and possibly P. pterocladum, are formed during stem development, and begin forming only a few millimeters behind the apical meristem. This mode of cavity formation differs markedly from myrmecophytes in section Macrostachys, where the stems remain solid unless excavated by the specialized ant partner Pheidole bicornis. The stems of P. immutatum and P. pterocladum do not produce wound-response tissue around the cavity, unlike the stems in section Macrostachys. The entrance holes in stems of P. immutatum are formed through apoptotic processes and are located at each node below the petiole, whereas those in section Macrostachys are excavated by the ants in the leaf axil. This study documents convergent evolution of ant-plant associations in Piper, and emphasizes the need for careful comparison of apparently homologous, ant-associated structures in specialized myrmecophytes.


The influence of handedness on hemispheric interaction during word production: insights from effective connectivity analysis.
Overt picture naming causes activation in both left and right hemispheres as demonstrated by functional magnetic resonance imaging (fMRI) studies. Unexpectedly, a previous experiment revealed that there was no difference in brain lateralization related to handedness. To understand the mechanisms behind this phenomenon and to investigate the influence that each hemisphere exerts over the other in more detail, we analyzed the effective connectivity in the naming network. More specifically, we examined the impact of handedness on hemispheric interactions. Four brain regions activated for correct naming in the previous fMRI experiment served as volumes of interest: Bilateral fusiform gyrus (FG) related to visual-semantic processing and bilateral Brodmann's area (BA) 44 related to phonological processing. We defined three dynamic causal models (DCMs) representing different symmetrical connectivity patterns, compared them using Bayesian model selection, and considered differential connection strengths. For the majority of 31 participants, the same model featuring early integration of visual-semantic processing and independent phonological processing was optimal. This also held true if right-handers, left-handers, and ambidexters were considered as independent groups. For left-handers, the connection of right FG and right BA 44 was significantly stronger compared with the other two groups, and it was significantly stronger than its left-hemisphere equivalent. In right-handers, the according left-hemisphere connection was significant, but connectivities were rather symmetrical. These findings reveal significant and unique right-hemisphere contributions to word production.


Molecular mechanism of calcium channel regulation in the fight-or-flight response.
During the fight-or-flight response, the sympathetic nervous system stimulates L-type calcium ion (Ca2+) currents conducted by Ca(V)1 channels through activation of β-adrenergic receptors, adenylyl cyclase, and phosphorylation by adenosine 3',5'-monophosphate-dependent protein kinase [also known as protein kinase A (PKA)], increasing contractility of skeletal and cardiac muscles. We reconstituted this regulation of cardiac Ca(V)1.2 channels in non-muscle cells by forming an autoinhibitory signaling complex composed of Ca(V)1.2Δ1800 (a form of the channel truncated at the in vivo site of proteolytic processing), its noncovalently associated distal carboxyl-terminal domain, the auxiliary α₂δ₁ and β(2b) subunits, and A-kinase anchoring protein 15 (AKAP15). A factor of 3.6 range of Ca(V)1.2 channel activity was observed from a minimum in the presence of protein kinase inhibitors to a maximum upon activation of adenylyl cyclase. Basal Ca(V)1.2 channel activity in unstimulated cells was regulated by phosphorylation of serine-1700 and threonine-1704, two residues located at the interface between the distal and the proximal carboxyl-terminal regulatory domains, whereas further stimulation of channel activity through the PKA signaling pathway only required phosphorylation of serine-1700. Our results define a conceptual framework for Ca(V)1.2 channel regulation and identify sites of phosphorylation that regulate channel activity.


Characteristics and indications of hydrogen and oxygen isotopes distribution in lake ice body.
Stable isotopes have been used to identify the characteristics of precipitation, evaporation, basin hydrology, and residence times. However, lakes in the cold regions are usually covered by ice for 5-6 months. To get a better understanding of stable isotopes characteristics and indications in lake ice bodies, ice and water were sampled during the icebound season in both the ice and water bodies in Dali Lake, and deuterium, oxygen-18 total nitrogen (TN), and the major ions were analyzed. The results showed that deuterium and oxygen-18 compositions (δD-δ¹⁸O) compositions in the ice body were greater than in the water body beneath, scattered on a straight line, and deviating downward from the global meteoric water line in the top right. The ice profile showed that the δD-δ¹⁸O compositions increased from the ice surface downward and decreased near to the bottom. In contrast, the TN and the major ions in the ice decreased from the ice surface downward and increased near to the bottom, meaning that the concentrations of δ¹⁸O had a negative correlation with the concentrations of TN and major ions. These indicated that stable isotopes can be used for tracing the nutriment and ion transport processes in the ice body.


Risk Reclassification With Coronary Computed Tomography Angiography-Visualized Nonobstructive Coronary Artery Disease According to 2018 American College of Cardiology/American Heart Association Cholesterol Guidelines (from the Coronary Computed Tomography Angiography Evaluation for Clinical Outcomes : An International Multicenter Registry [CONFIRM]).
The 2018 American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guideline recommends risk enhancers in the borderline-risk and statin recommended/intermediate-risk groups. We determined the risk reclassification by the presence and severity of coronary computed tomography angiography (CCTA)-visualized coronary artery disease (CAD) according to statin eligibility groups. Of 35,281 individuals who underwent CCTA, 1,303 asymptomatic patients (age 59, 65% male) were identified. Patients were categorized as low risk, borderline risk, statin recommended/intermediate risk or statin recommended/high risk according to the guideline. CCTA-visualized CAD was categorized as no CAD, nonobstructive, or obstructive. Major adverse cardiovascular events (MACE) were defined as a composite outcome of all-cause mortality, nonfatal myocardial infarction, and late coronary revascularization (>90 days). We tested a reclassification wherein no CAD reclassifies downward, and the presence of any CAD reclassifies upward. During a median follow-up of 2.9 years, 93 MACE events (7.1%) were observed. Among the borderline-risk and statin-recommended/intermediate-risk groups eligible for risk enhancers, the presence or absence of any CCTA-visualized CAD led to a net increase of 2.3% of cases and 22.4% of controls correctly classified (net reclassification index [NRI] 0.27, 95% CI 0.13 to 0.41, p = 0.0002). The NRI was not significant among low- or statin-recommended/high-risk patients (all p >0.05). The presence or absence of CCTA-visualized CAD, including both obstructive and nonobstructive CAD, significantly improves reclassification in patients eligible for risk enhancers in 2018 ACC/AHA guidelines. Patients in low- and high-risk groups derive no significant improvement in risk reclassification from CCTA.


Differential-damper topologies for actuators in rehabilitation robotics.
Differential-damper (DD) elements can provide a high bandwidth means for decoupling a high inertia, high friction, non-backdrivable actuator from its output and can enable high fidelity force control. In this paper, a port-based decomposition is used to analyze the energetic behavior of such actuators in various physical domains. The general concepts are then applied to a prototype DD actuator for illustration and discussion. It is shown that, within physical bounds, the output torque from a DD actuator can be controlled independently from the input speed. This concept holds the potential to be scaled up and integrated in a compact and lightweight package powerful enough for incorporation with a portable lower limb orthotic or prosthetic device.


Low-frequency noise effect on terahertz tomography using thermal detectors.
In this paper, the impact of low-frequency noise on terahertz-computed tomography (THz-CT) is analyzed for several measurement configurations and pyroelectric detectors. We acquire real noise data from a continuous millimeter-wave tomographic scanner in order to figure out its impact on reconstructed images. Second, noise characteristics are quantified according to two distinct acquisition methods by (i) extrapolating from experimental acquisitions a sinogram for different noise backgrounds and (ii) reconstructing the corresponding spatial distributions in a slice using a CT reconstruction algorithm. Then we describe the low-frequency noise fingerprint and its influence on reconstructed images. Thanks to the observations, we demonstrate that some experimental choices can dramatically affect the 3D rendering of reconstructions. Thus, we propose some experimental methodologies optimizing the resulting quality and accuracy of the 3D reconstructions, with respect to the low-frequency noise characteristics observed during acquisitions.