Large Variations in HIV-1 Viral Load Explained by Shifting-Mosaic Metapopulation Dynamics.
The viral population of HIV-1, like many pathogens that cause systemic infection, is structured and differentiated within the body. The dynamics of cellular immune trafficking through the blood and within compartments of the body has also received wide attention. Despite these advances, mathematical models, which are widely used to interpret and predict viral and immune dynamics in infection, typically treat the infected host as a well-mixed homogeneous environment. Here, we present mathematical, analytical, and computational results that demonstrate that consideration of the spatial structure of the viral population within the host radically alters predictions of previous models. We study the dynamics of virus replication and cytotoxic T lymphocytes (CTLs) within a metapopulation of spatially segregated patches, representing T cell areas connected by circulating blood and lymph. The dynamics of the system depend critically on the interaction between CTLs and infected cells at the within-patch level. We show that for a wide range of parameters, the system admits an unexpected outcome called the shifting-mosaic steady state. In this state, the whole body's viral population is stable over time, but the equilibrium results from an underlying, highly dynamic process of local infection and clearance within T-cell centers. Notably, and in contrast to previous models, this new model can explain the large differences in set-point viral load (SPVL) observed between patients and their distribution, as well as the relatively low proportion of cells infected at any one time, and alters the predicted determinants of viral load variation.


Application of humanistic learning theory in an associate degree program for occupational therapy assistants.
A humanistic education model was implemented in a 2-year associate degree curriculum for occupational therapy assistants. The goal of this model was to help students to become responsible and successful with their own lives. This prepares students with higher levels of ability to cope effectively with clients in crises. The curriculum presented here supports the framework of The American Occupational Therapy Association role delineation document (Entry-Level Role Delineation for OTRs and COTAs, approved by the Representative Assembly, AOTA, March 1981).


Protein quantity and quality in term and preterm infants: effects on urine creatinine and expression of amino acid excretion data.
The effect of dietary protein quantity and quality on the excretion of creatinine in preterm and term neonatal infants has been investigated. Whey protein predominant formulas result in increased creatinine excretion as compared with either casein protein predominant formulas or with pooled human milk in preterm infants (p less than 0.001 by ANOVA). The volume of human milk (170 versus 185 versus 200 ml/kg/day) appears to have little effect in these infants. In term infants, few differences among the feeding groups were observed, although creatinine excretion did increase with time. The pattern of creatinine excretion among feeding groups was similar regardless of whether or not the data were expressed in milligrams per deciliter or in milligrams per 24 hours. Small correlations of creatinine excretion with birth weight were observed, but these appeared to vary, depending on the type of feeding. These diet-induced differences in creatinine excretion indicate the need for caution in expressing other urinary metabolites, such as amino acids, relative to creatinine excretion.


Separating Clinical and Subclinical Depression by Big Data Informed Structural Vulnerability Index and Its impact on Cognition: ENIGMA Dot Product.
Big Data neuroimaging collaborations including Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) integrated worldwide data to identify regional brain deficits in major depressive disorder (MDD). We evaluated the sensitivity of translating ENIGMA-defined MDD deficit patterns to the individual level. We treated ENIGMA MDD deficit patterns as a vector to gauge the similarity between individual and MDD patterns by calculating ENIGMA dot product (EDP). We analyzed the sensitivity and specificity of EDP in separating subjects with (1) subclinical depressive symptoms without a diagnosis of MDD, (2) single episode MDD, (3) recurrent MDD, and (4) controls free of neuropsychiatric disorders. We compared EDP to the Quantile Regression Index (QRI; a linear alternative to the brain age metric) and the global gray matter thickness and subcortical volumes and fractional anisotropy (FA) of water diffusion. We performed this analysis in a large epidemiological sample of UK Biobank (UKBB) participants (N=17,053/19,265 M/F). Group-average increases in depressive symptoms from controls to recurrent MDD was mirrored by EDP (r2=0.85), followed by FA (r2=0.81) and QRI (r2=0.56). Subjects with MDD showed worse performance on cognitive tests than controls with deficits observed for 3 out of 9 cognitive tests administered by the UKBB. We calculated correlations of EDP and other brain indices with measures of cognitive performance in controls. The correlation pattern between EDP and cognition in controls was similar (r2=0.75) to the pattern of cognitive differences in MDD. This suggests that the elevation in EDP, even in controls, is associated with cognitive performance - specifically in the MDD-affected domains. That specificity was missing for QRI, FA or other brain imaging indices. In summary, translating anatomically informed meta-analytic indices of similarity using a linear vector approach led to better sensitivity to depressive symptoms and cognitive patterns than whole-brain imaging measurements or an index of accelerated aging.


Frailty in Young and Middle-Aged Adults: An Integrative Review.
Frailty is a public health priority resulting in poor health outcomes and early mortality in older adults. Early identification, management, and prevention of frailty may reduce frailty trajectory into later life. However, little is known about frailty in younger adults. Describe frailty prevalence, definitions, study designs, and components contributing to multidimensional frailty in 18 to 65-year-olds and impart guidance for future research, practice, and policies with potential to positively impact frail individuals. Integrative review approach was selected to explore frailty allowing for inclusion of diverse methodologies and varied persepectives while maintaining rigor and applicability to evidence-based practice initiatives. CINAHL, Embase, PsycInfo, PubMed databases were searched for studies describing frailty in adults age 18 to 65. Articles were excluded if published prior to 2010, not in English, lacked frailty focus, or non-Western culture. Twelve descriptive correlational studies were included. No intervention or qualitative studies were identified. No standard conceptual definition of frailty was discovered. Studied in participants with health disparities (n=3) and chronic conditions (n=8); HIV was most common (n=4). Frailty prevalence ranged from 3.9% (313 of 8095) to 63% (24 of 38). Many factors associated with frailty were identified among physical (18) and social (14), and fewer among psychological (11) domains. Universal frailty definition and multidimensional assessment tool is needed to generate generalizable results in future studies describing frailty in young and middle-aged adults. Early frailty identification by clinicians has potential to facilitate development and implementation of targeted interventions to prevent or mitigate frailty progression, but additional research is needed because risk factors in younger populations may be different than older adults.


Intestinal absorption of the antiepileptic drug substance vigabatrin is altered by infant formula in vitro and in vivo.
Vigabatrin is an antiepileptic drug substance mainly used in pediatric treatment of infantile spasms. The main source of nutrition for infants is breast milk and/or infant formula. Our hypothesis was that infant formula may affect the intestinal absorption of vigabatrin. The aim was therefore to investigate the potential effect of coadministration of infant formula with vigabatrin on the oral absorption in vitro and in vivo. The effect of vigabatrin given with an infant formula on the oral uptake and transepithelial transport was investigated in vitro in Caco-2 cells. In vivo effects of infant formula and selected amino acids on the pharmacokinetic profile of vigabatrin was investigated after oral coadministration to male Sprague-Dawley rats using acetaminophen as a marker for gastric emptying. The presence of infant formula significantly reduced the uptake rate and permeability of vigabatrin in Caco-2 cells. Oral coadministration of vigabatrin and infant formula significantly reduced C max and prolonged t max of vigabatrin absorption. Ligands for the proton-coupled amino acid transporter PAT1, sarcosine, and proline/l-tryptophan had similar effects on the pharmacokinetic profile of vigabatrin. The infant formula decreased the rate of gastric emptying. Here we provide experimental evidence for an in vivo role of PAT1 in the intestinal absorption of vigabatrin. The effect of infant formula on the oral absorption of vigabatrin was found to be due to delayed gastric emptying, however, it seems reasonable that infant formula may also directly affect the intestinal absorption rate of vigabatrin possibly via PAT1.


Recovery of mitogenic activity of a growth factor mutant with a nuclear translocation sequence.
Heparin-binding growth factor-1 (HBGF-1) is an angiogenic polypeptide mitogen for mesoderm- and neuroectoderm-derived cells in vitro and remains biologically active after truncation of the amino-terminal domain (HBGF-1 alpha) of the HBGF-1 beta precursor. Polymerase chain reaction mutagenesis and prokaryotic expression systems were used to prepare a mutant of HBGF-1 alpha lacking a putative nuclear translocation sequence (amino acid residues 21 to 27; HBGF-1U). Although HBGF-1U retains its ability to bind to heparin, HBGF-1U fails to induce DNA synthesis and cell proliferation at concentrations sufficient to induce intracellular receptor-mediated tyrosine phosphorylation and c-fos expression. Attachment of the nuclear translocation sequence from yeast histone 2B at the amino terminus of HBGF-1U yields a chimeric polypeptide (HBGF-1U2) with mitogenic activity in vitro and indicates that nuclear translocation is important for this biological response.


RIM determines Ca²+ channel density and vesicle docking at the presynaptic active zone.
At presynaptic active zones, neurotransmitter release is initiated by the opening of voltage-gated Ca²+ channels close to docked vesicles. The mechanisms that enrich Ca²+ channels at active zones are, however, largely unknown, possibly because of the limited presynaptic accessibility of most synapses. Here, we have established a Cre-lox based conditional knockout approach at a presynaptically accessible central nervous system synapse, the calyx of Held, to directly study the functions of RIM proteins. Removal of all RIM1/2 isoforms strongly reduced the presynaptic Ca²+ channel density, revealing a role of RIM proteins in Ca²+ channel targeting. Removal of RIMs also reduced the readily releasable pool, paralleled by a similar reduction of the number of docked vesicles, and the Ca²+ channel-vesicle coupling was decreased. Thus, RIM proteins co-ordinately regulate key functions for fast transmitter release, enabling a high presynaptic Ca²+ channel density and vesicle docking at the active zone.


Guidelines for improving entry into and retention in care and antiretroviral adherence for persons with HIV: evidence-based recommendations from an International Association of Physicians in AIDS Care panel.
After HIV diagnosis, timely entry into HIV medical care and retention in that care are essential to the provision of effective antiretroviral therapy (ART). Adherence to ART is among the key determinants of successful HIV treatment outcome and is essential to minimize the emergence of drug resistance. The International Association of Physicians in AIDS Care convened a panel to develop evidence-based recommendations to optimize entry into and retention in care and ART adherence for people with HIV. A systematic literature search was conducted to produce an evidence base restricted to randomized, controlled trials and observational studies with comparators that had at least 1 measured biological or behavioral end point. A total of 325 studies met the criteria. Two reviewers independently extracted and coded data from each study using a standardized data extraction form. Panel members drafted recommendations based on the body of evidence for each method or intervention and then graded the overall quality of the body of evidence and the strength for each recommendation. Recommendations are provided for monitoring entry into and retention in care, interventions to improve entry and retention, and monitoring of and interventions to improve ART adherence. Recommendations cover ART strategies, adherence tools, education and counseling, and health system and service delivery interventions. In addition, they cover specific issues pertaining to pregnant women, incarcerated individuals, homeless and marginally housed individuals, and children and adolescents, as well as substance use and mental health disorders. Recommendations for future research in all areas are also provided.


Reconfigurable microfluidics with integrated aptasensors for monitoring intercellular communication.
We report the development of a microsystem integrating anti-TNF-α aptasensors with vacuum-actuatable microfluidic devices that may be used to monitor intercellular communications. Actuatable chambers were used to expose to mitogen a group of ~600 cells while not stimulating another group of monocytes only 600 μm away. Co-localizing groups of cells with miniature 300 μm diameter aptamer-modified electrodes enabled monitoring of TNF-α release from each group independently. The microsystem allowed observation of the sequence of events that included 1) mitogenic activation of the first group of monocytes to produce TNF-α, 2) diffusion of TNF-α to the location of the second group of cells and 3) activation of the second group of cells resulting in the production of TNF-α by these cells. Thus, we were able to experimentally verify reciprocal paracrine crosstalk between the two groups of cells secreting the same signalling molecule. Given the prevalence of such cellular communications during injury, cancer or immune response and the dearth of available monitoring techniques, the microsystem described here is envisioned to have significant impact on cell biology.


Annual dynamics of North Sea bacterioplankton: seasonal variability superimposes short-term variation.
The dynamics of coastal marine microbial communities are driven by seasonally changing abiotic and biotic factors as well as by rapidly occurring short-term changes such as river fresh water influxes or phytoplankton blooms. We examined the variability of the free-living bacterioplankton at Helgoland Roads (German Bight, North Sea) over a period of one year with high temporal and taxonomic resolution to reveal variation patterns and main influencing factors. 16S rRNA gene tag sequencing of the bacterioplankton community hints at annual recurrence and resilience of few main taxa belonging to Alphaproteobacteria, Betaproteobacteria, Flavobacteriia, Acidimicrobiia and Thermoplasmata. Multiple regression analyses with various environmental factors revealed changes in water current patterns and resulting phytoplankton blooms as the main driving factors for short-term variation and temperature as the overlying factor for seasonal variation. Comparison of bacterioplankton successions during spring and summer phytoplankton blooms revealed the same dominating Flavobacteriia operational taxonomic units (OTUs) but shifts in Roseobacter related OTUs (Alphaproteobacteria) and SAR92 clade members (Gammaproteobacteria). Network analysis suggests that during spring and summer phytoplankton blooms temperature-dependent guilds are formed. In conclusion, our data imply that short-term bacterioplankton successions in response to phytoplankton blooms are indirectly affected by temperature, which is a major niche-defining factor in the German Bight.


The E. coli RhlE RNA helicase regulates the function of related RNA helicases during ribosome assembly.
Escherichia coli contains five members of the DEAD-box RNA helicase family, a ubiquitous class of proteins characterized by their ability to unwind RNA duplexes. Although four of these proteins have been implicated in RNA turnover or ribosome biogenesis, no cellular function for the RhlE DEAD-box protein has been described as yet. During an analysis of the cold-sensitive growth defect of a strain lacking the DeaD/CsdA RNA helicase, rhlE plasmids were identified from a chromosomal library as multicopy suppressors of the growth defect. Remarkably, when tested for allele specificity, RhlE overproduction was found to exacerbate the cold-sensitive growth defect of a strain that lacks the SrmB RNA helicase. Moreover, the absence of RhlE exacerbated or alleviated the cold-sensitive defect of deaD or srmB strains, respectively. Primer extension and ribosome analysis indicated that RhlE regulates the accumulation of immature ribosomal RNA or ribosome precursors when deaD or srmB strains are grown at low temperatures. By using an epitope-tagged version of RhlE, the majority of RhlE in cell extracts was found to cosediment with ribosome-containing fractions. Since both DeaD and SrmB have been recently shown to function in ribosome assembly, these findings suggests that rhlE genetically interacts with srmB and deaD to modulate their function during ribosome maturation. On the basis of the available evidence, I propose that RhlE is a novel ribosome assembly factor, which plays a role in the interconversion of ribosomal RNA-folding intermediates that are further processed by DeaD or SrmB during ribosome maturation.


Human SOD1 ALS Mutations in a Drosophila Knock-In Model Cause Severe Phenotypes and Reveal Dosage-Sensitive Gain- and Loss-of-Function Components.
Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset motor neuron disease and familial forms can be caused by numerous dominant mutations of the copper-zinc superoxide dismutase 1 (SOD1) gene. Substantial efforts have been invested in studying SOD1-ALS transgenic animal models; yet, the molecular mechanisms by which ALS-mutant SOD1 protein acquires toxicity are not well understood. ALS-like phenotypes in animal models are highly dependent on transgene dosage. Thus, issues of whether the ALS-like phenotypes of these models stem from overexpression of mutant alleles or from aspects of the SOD1 mutation itself are not easily deconvolved. To address concerns about levels of mutant SOD1 in disease pathogenesis, we have genetically engineered four human ALS-causing SOD1 point mutations (G37R, H48R, H71Y, and G85R) into the endogenous locus of Drosophila SOD1 (dsod) via ends-out homologous recombination and analyzed the resulting molecular, biochemical, and behavioral phenotypes. Contrary to previous transgenic models, we have recapitulated ALS-like phenotypes without overexpression of the mutant protein. Drosophila carrying homozygous mutations rendering SOD1 protein enzymatically inactive (G85R, H48R, and H71Y) exhibited neurodegeneration, locomotor deficits, and shortened life span. The mutation retaining enzymatic activity (G37R) was phenotypically indistinguishable from controls. While the observed mutant dsod phenotypes were recessive, a gain-of-function component was uncovered through dosage studies and comparisons with age-matched dsod null animals, which failed to show severe locomotor defects or nerve degeneration. We conclude that the Drosophila knock-in model captures important aspects of human SOD1-based ALS and provides a powerful and useful tool for further genetic studies.


Mass spectrometry captures biased signalling and allosteric modulation of a G-protein-coupled receptor.
G-protein-coupled receptors signal through cognate G proteins. Despite the widespread importance of these receptors, their regulatory mechanisms for G-protein selectivity are not fully understood. Here we present a native mass spectrometry-based approach to interrogate both biased signalling and allosteric modulation of the β1-adrenergic receptor in response to various ligands. By simultaneously capturing the effects of ligand binding and receptor coupling to different G proteins, we probed the relative importance of specific interactions with the receptor through systematic changes in 14 ligands, including isoprenaline derivatives, full and partial agonists, and antagonists. We observed enhanced dynamics of the intracellular loop 3 in the presence of isoprenaline, which is capable of acting as a biased agonist. We also show here that endogenous zinc ions augment the binding in receptor-Gs complexes and propose a zinc ion-binding hotspot at the TM5/TM6 intracellular interface of the receptor-Gs complex. Further interrogation led us to propose a mechanism in which zinc ions facilitate a structural transition of the intermediate complex towards the stable state.


Strong inbreeding depression in two Scandinavian populations of the self-incompatible perennial herb Arabidopsis lyrata.
Inbreeding depression is a key factor influencing mating system evolution in plants, but current understanding of its relationship with selfing rate is limited by a sampling bias with few estimates for self-incompatible species. We quantified inbreeding depression (δ) over two growing seasons in two populations of the self-incompatible perennial herb Arabidopsis lyrata ssp. petraea in Scandinavia. Inbreeding depression was strong and of similar magnitude in both populations. Inbreeding depression for overall fitness across two seasons (the product of number of seeds, offspring viability, and offspring biomass) was 81% and 78% in the two populations. Chlorophyll deficiency accounted for 81% of seedling mortality in the selfing treatment, and was not observed among offspring resulting from outcrossing. The strong reduction in both early viability and late quantitative traits suggests that inbreeding depression is due to deleterious alleles of both large and small effect, and that both populations experience strong selection against the loss of self-incompatibility. A review of available estimates suggested that inbreeding depression tends to be stronger in self-incompatible than in self-compatible highly outcrossing species, implying that undersampling of self-incompatible taxa may bias estimates of the relationship between mating system and inbreeding depression.


The frugivory network properties of a simplified ecosystem: Birds and plants in a Neotropical periurban park.
Frugivory networks exhibit a set of properties characterized by a number of network theory-derived metrics. Their structures often form deterministic patterns that can be explained by the functional roles of interacting species. Although we know lots about how these networks are organized when ecosystems are in a complete, functional condition, we know much less about how incomplete and simplified networks (such as those found in urban and periurban parks) are organized, which features are maintained, which ones are not, and why. In this paper, we examine the properties of a network between frugivorous birds and plants in a small Neotropical periurban park. We found a frugivory network composed of 29 species of birds and 23 of plants. The main roles in this network are played by four species of generalist birds (three resident, one migratory: Myiozetetes similis, Turdus grayi, Chlorospingus flavopectus, and Dumetella carolinensis) and three species of plants (one exotic, two early successional: Phoenix canariensis, Phoradendron sp., and Witheringia stramoniifolia). When compared to reference data from other locations in the Neotropics, species richness is low, one important network-level metric is maintained (modularity) whereas another one is not (nestedness). Nestedness, a metric associated with network specialists, is a feature this network lacks. Species-level metrics such as degree, species strength, and module roles, are not maintained. Our work supports modularity as the most pervasive network-level metric of altered habitats. From a successional point of view, our results suggest that properties revealed by species-level indices may be developed at a later time, lagging the acquisition of structural elements.


From struggles to resource gains in interprofessional service networks: Key findings from a multiple case study.
In interprofessional service networks, employees cross professional boundaries to collaborate with colleagues and clients with expertise and values different from their own. It can be a struggle to adopt shared work practices and deal with "multivoicedness." At the same time, networks allow members to engage in meaningful service provision, gain a broader understanding of the service provided, and obtain social support. Intertwined network struggles and resource gains have received limited attention in the interprofessional care literature to date. The aim of the study was to investigate the learning potential of the co-existing struggles and resource gains. This article reports findings from two interprofessional networks. Interviews were conducted with 19 employees and thematically analysed. Three types of struggles and six types of resource gains of networking were identified. The struggles relate, first, to the assumptions of networking following similar practices to those in a home organisation; second, to the challenges of dealing with the multivoicedness of networking; and, third, to the experienced gap between the networking ideals and the reality of cooperation. At the same time, the network members experience gains in emotional resources (e.g., stronger sense of meaningfulness at work), cognitive resources (e.g., understanding the customer needs from alternative perspectives), and social resources (e.g., being able to rely on other professionals' competence). Learning potential emerged from the dynamics between coexisting struggles and resource gains.


The effect of high-intensity versus low-level laser therapy in the management of plantar fasciitis: a randomized clinical trial.
We aimed to compare the efficacy of low-level laser therapy (LLLT) and high-intensity laser therapy (HILT) in the treatment of plantar fasciitis (PF). Seventy patients were randomized into either the LLLT (8 men, 27 women; mean age 48.65 ± 10.81 years) or HILT (7 men, 28 women; mean age 48.73 ± 11.41 years) groups. LLLT (904 nm) and HILT (1064 nm) were performed three times per week, over a period of 3 weeks. Each treatment combined with silicone insole and stretching exercises. Patients' pain and functional status were evaluated with Visual Analog Scale, Heel Tenderness Index, and Foot and Ankle Outcome Score before and after treatment. A chi-square test was performed to compare demographic and clinical characteristics. Within-group and between-group differences were also investigated. Paired samples t test was used to analyze the differences between baseline and after treatment values, while independent samples t test was used to compare the two groups. Both groups contained similar demographic characteristics including age, sex, and body mass index (all p > 0.05). Three and two patients in the HILT and LLLT group, respectively, were lost to follow-up. At the study onset, there were no statistically significant differences between the two groups in the Visual Analog Scale, Heel Tenderness Index, and Foot And Ankle Outcome Scores. Three weeks later, both groups showed significant improvement in all parameters (p < 0.05). The HILT group demonstrated better improvement in all parameters than the LLLT group. Although both treatments improved the pain levels, function, and quality of life in patients with PF, HILT had a more significant effect than LLLT.


Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.
As a part of our cDNA project for deducing the coding sequence of unidentified human genes, we newly determined the sequences of 100 cDNA clones from a set of size-fractionated human brain cDNA libraries, and predicted the coding sequences of the corresponding genes, named KIAA0919 to KIAA1018. The sequencing of these clones revealed that the average sizes of the inserts and corresponding open reading frames were 4.9 kb and 2.6 kb (882 amino acid residues), respectively. A computer search of the sequences against the public databases indicated that predicted coding sequences of 87 genes contained sequences similar to known genes, 53% of which (46 genes) were categorized as proteins relating to cell signaling/communication, cell structure/motility and nucleic acid management. The chromosomal locations of the genes were determined by using human-rodent hybrid panels unless their mapping data were already available in the public databases. The expression profiles of all the genes among 10 human tissues, 8 brain regions (amygdala, corpus callosum, cerebellum, caudate nucleus, hippocampus, substania nigra, subthalamic nucleus, and thalamus), spinal cord, fetal brain and fetal liver were also examined by reverse transcription-coupled polymerase chain reaction, products of which were quantified by enzyme-linked immunosorbent assay.


Self-mortification and the stigma of leprosy in northern India.
This article examines the biocultural dynamics of social discrimination and physical disfigurement among people with leprosy, or Hansen's disease (HD), in Banaras, northern India. Based on the narratives and observations ofpeople living in colony and street settings, I trace three destructive processes by which the social stigmata of leprosy become physically expressed. First, strategies of concealment further the progression and spread of HD through late detection and undertreatment. Second, the internalization of stigma can lead to bodily dissociation and injury through self-neglect. Finally, some people intentionally seek injuries under conditions of desperate poverty. As a result of such mortification processes, these people came to embody, quite literally, the prejudices that exacerbated their condition in the first place.


Verbal memory is associated with structural hippocampal changes in newly diagnosed Parkinson's disease.
Cognitive impairment, including impairment of episodic memory, is frequently found in newly diagnosed Parkinson's disease (PD). In this longitudinal observational study we investigated whether performance in memory encoding, retention, recognition and free recall is associated with reduced hippocampal radial distance. We analysed baseline T1-weighted brain MRI data from 114 PD subjects without cognitive impairment, 29 PD subjects with mild cognitive impairment and 99 normal controls from the ParkWest study. Age- and education-predicted scores for the California Verbal Learning Test 2 (CVLT-2) and tests of executive function were regressed against hippocampal radial distance while adjusting for imaging centre. There was no association between encoding or performance on executive tests and hippocampal atrophy in the PD group. In the full PD sample we found bilaterally significant associations between lower delayed free recall scores and hippocampal atrophy in the CA1, CA3 and subiculum area (left, p=0.0013; right, p=0.0082). CVLT-2 short delay free recall scores were associated with bilateral hippocampal CA1 and subicular atrophy in the full PD sample (left, p=0.013; right, p=0.047). CVLT-2 recognition scores showed a significant association with right-sided subicular and CA1 atrophy in the full PD sample (p=0.043). At the time of PD diagnosis, subjects' verbal memory performance in recall and recognition are associated with atrophy of the hippocampus, while encoding is not associated with hippocampal radial distance. We postulate that impaired recall and recognition might reflect deficient memory consolidation at least partly due to structural hippocampal changes.


Review: evaluating information systems in nursing.
To review existing nursing research on inpatient hospitals' information technology (IT) systems in order to explore new approaches for evaluation research on nursing informatics to guide further design and implementation of effective IT systems. There has been an increase in the use of IT and information systems in nursing in recent years. However, there has been little evaluation of these systems and little guidance on how they might be evaluated. A literature review was conducted between 1995 and 2005 inclusive using CINAHL and Medline and the search terms 'nursing information systems', 'clinical information systems', 'hospital information systems', 'documentation', 'nursing records', 'charting'. Research in nursing information systems was analysed and some deficiencies and contradictory results were identified which impede a comprehensive understanding of effective implementation. There is a need for IT systems to be understood from a wider perspective that includes aspects related to the context where they are implemented. Social and organizational aspects need to be considered in evaluation studies and realistic evaluation can provide a framework for the evaluation of information systems in nursing. The rapid introduction of IT systems for clinical practice urges evaluation of already implemented systems examining how and in what circumstances they work to guide effective further development and implementation of IT systems to enhance clinical practice. Evaluation involves more factors than just involving technologies such as changing attitudes, cultures and healthcare practices. Realistic evaluation could provide configurations of context-mechanism-outcomes that explain the underlying relationships to understand why and how a programme or intervention works.


Headache and major depression: is the association specific to migraine?
To examine the relationship between migraine and major depression, by estimating the risk for first-onset major depression associated with prior migraine and the risk for first migraine associated with prior major depression. We also examined the extent to which comorbidity with major depression is specific to migraine or is observed in other severe headaches. Representative samples of persons 25 to 55 years of age with migraine or other severe headaches (i.e., disabling headaches without migraine features) and controls with no history of severe headaches were identified by a telephone survey and later interviewed in person to ascertain history of common psychiatric disorders. Lifetime prevalence of major depression was approximately three times higher in persons with migraine and in persons with severe headaches compared with controls. Significant bidirectional relationships were observed between major depression and migraine, with migraine predicting first-onset depression and depression predicting first-onset migraine. In contrast, persons with severe headaches had a higher incidence of first-onset major depression (hazard ratio = 3.6), but major depression did not predict a significantly increased incidence of other severe headaches (hazard ratio = 1.6). The contrasting results regarding the relationship of major depression with migraine versus other severe headaches suggest that different causes may underlie the co-occurrence of major depression in persons with migraine compared with persons with other severe headaches.


Exercise prevents weight gain and alters the gut microbiota in a mouse model of high fat diet-induced obesity.
Diet-induced obesity (DIO) is a significant health concern which has been linked to structural and functional changes in the gut microbiota. Exercise (Ex) is effective in preventing obesity, but whether Ex alters the gut microbiota during development with high fat (HF) feeding is unknown. Determine the effects of voluntary Ex on the gastrointestinal microbiota in LF-fed mice and in HF-DIO. Male C57BL/6 littermates (5 weeks) were distributed equally into 4 groups: low fat (LF) sedentary (Sed) LF/Sed, LF/Ex, HF/Sed and HF/Ex. Mice were individually housed and LF/Ex and HF/Ex cages were equipped with a wheel and odometer to record Ex. Fecal samples were collected at baseline, 6 weeks and 12 weeks and used for bacterial DNA isolation. DNA was subjected both to quantitative PCR using primers specific to the 16S rRNA encoding genes for Bacteroidetes and Firmicutes and to sequencing for lower taxonomic identification using the Illumina MiSeq platform. Data were analyzed using a one or two-way ANOVA or Pearson correlation. HF diet resulted in significantly greater body weight and adiposity as well as decreased glucose tolerance that were prevented by voluntary Ex (p<0.05). Visualization of Unifrac distance data with principal coordinates analysis indicated clustering by both diet and Ex at week 12. Sequencing demonstrated Ex-induced changes in the percentage of major bacterial phyla at 12 weeks. A correlation between total Ex distance and the ΔCt Bacteroidetes: ΔCt Firmicutes ratio from qPCR demonstrated a significant inverse correlation (r2 = 0.35, p = 0.043). Ex induces a unique shift in the gut microbiota that is different from dietary effects. Microbiota changes may play a role in Ex prevention of HF-DIO.


Coclustering of human cancer microarrays using Minimum Sum-Squared Residue coclustering.
It is a consensus in microarray analysis that identifying potential local patterns, characterized by coherent groups of genes and conditions, may shed light on the discovery of previously undetectable biological cellular processes of genes as well as macroscopic phenotypes of related samples. In order to simultaneously cluster genes and conditions, we have previously developed a fast co-clustering algorithm, Minimum Sum-Squared Residue Co-clustering (MSSRCC), which employs an alternating minimization scheme and generates what we call co-clusters in a checkerboard structure. In this paper, we propose specific strategies that enable MSSRCC to escape poor local minima and resolve the degeneracy problem in partitional clustering algorithms. The strategies include binormalization, deterministic spectral initialization, and incremental local search. We assess the effects of various strategies on both synthetic gene expression datasets and real human cancer microarrays and provide empirical evidence that MSSRCC with the proposed strategies performs better than existing co-clustering and clustering algorithms. In particular, the combination of all the three strategies leads to the best performance. Furthermore, we illustrate coherence of the resulting co-clusters in a checkerboard structure, where genes in a co-cluster manifest the phenotype structure of corresponding specific samples, and evaluate the enrichment of functional annotations in Gene Ontology (GO).


The acid-base-nucleophile catalytic triad in ABH-fold enzymes is coordinated by a set of structural elements.
The alpha/beta-Hydrolases (ABH) are a structural class of proteins that are found widespread in nature and includes enzymes that can catalyze various reactions in different substrates. The catalytic versatility of the ABH fold enzymes, which has been a valuable property in protein engineering applications, is based on a similar acid-base-nucleophile catalytic mechanism. In our research, we are concerned with the structure that surrounds the key units of the catalytic machinery, and we have previously found conserved structural organizations that coordinate the catalytic acid, the catalytic nucleophile and the residues of the oxyanion hole. Here, we explore the architecture that surrounds the catalytic histidine at the active sites of enzymes from 40 ABH fold families, where we have identified six conserved interactions that coordinate the catalytic histidine next to the catalytic acid and the catalytic nucleophile. Specifically, the catalytic nucleophile is coordinated next to the catalytic histidine by two weak hydrogen bonds, while the catalytic acid is directly involved in the coordination of the catalytic histidine through by two weak hydrogen bonds. The imidazole ring of the catalytic histidine is coordinated by a CH-π contact and a hydrophobic interaction. Moreover, the catalytic triad residues are connected with a residue that is located at the core of the active site of ABH fold, which is suggested to be the fourth member of a "structural catalytic tetrad". Besides their role in the stability of the catalytic mechanism, the conserved elements of the catalytic site are actively involved in ligand binding and affect other properties of the catalytic activity, such as substrate specificity, enantioselectivity, pH optimum and thermostability of ABH fold enzymes. These properties are regularly targeted in protein engineering applications, and thus, the identified conserved structural elements can serve as potential modification sites in order to develop ABH fold enzymes with altered activities.


Home telehealth for chronic disease management: a systematic review and an analysis of economic evaluations.
The research objectives were two-fold: first, to systematically review the literature on the cost-effectiveness of home telehealth for chronic diseases, and second to develop a framework for the conduct of economic evaluation of home telehealth projects for patients with chronic diseases. A comprehensive literature search identified twenty-two studies (n = 4,871 patients) on home telehealth for chronic diseases published between 1998 and 2008. Studies were reviewed in terms of their methodological quality and their conclusions. Home telehealth was found to be cost saving from the healthcare system and insurance provider perspectives in all but two studies, but the quality of the studies was generally low. An evaluative framework was developed which provides a basis to improve the quality of future studies to facilitate improved healthcare decision making, and an application of the framework is illustrated using data from an existing program evaluation of a home telehealth program. Current evidence suggests that home telehealth has the potential to reduce costs, but its impact from a societal perspective remains uncertain until higher quality studies become available.


Systematic identification of single amino acid variants in glioma stem-cell-derived chromosome 19 proteins.
Novel proteoforms with single amino acid variations represent proteins that often have altered biological functions but are less explored in the human proteome. We have developed an approach, searching high quality shotgun proteomic data against an extended protein database, to identify expressed mutant proteoforms in glioma stem cell (GSC) lines. The systematic search of MS/MS spectra using PEAKS 7.0 as the search engine has recognized 17 chromosome 19 proteins in GSCs with altered amino acid sequences. The results were further verified by manual spectral examination, validating 19 proteoforms. One of the novel findings, a mutant form of branched-chain aminotransferase 2 (p.Thr186Arg), was verified at the transcript level and by targeted proteomics in several glioma stem cell lines. The structure of this proteoform was examined by molecular modeling in order to estimate conformational changes due to mutation that might lead to functional modifications potentially linked to glioma. Based on our initial findings, we believe that our approach presented could contribute to construct a more complete map of the human functional proteome.


Blind prediction of noncanonical RNA structure at atomic accuracy.
Prediction of RNA structure from nucleotide sequence remains an unsolved grand challenge of biochemistry and requires distinct concepts from protein structure prediction. Despite extensive algorithmic development in recent years, modeling of noncanonical base pairs of new RNA structural motifs has not been achieved in blind challenges. We report a stepwise Monte Carlo (SWM) method with a unique add-and-delete move set that enables predictions of noncanonical base pairs of complex RNA structures. A benchmark of 82 diverse motifs establishes the method's general ability to recover noncanonical pairs ab initio, including multistrand motifs that have been refractory to prior approaches. In a blind challenge, SWM models predicted nucleotide-resolution chemical mapping and compensatory mutagenesis experiments for three in vitro selected tetraloop/receptors with previously unsolved structures (C7.2, C7.10, and R1). As a final test, SWM blindly and correctly predicted all noncanonical pairs of a Zika virus double pseudoknot during a recent community-wide RNA-Puzzle. Stepwise structure formation, as encoded in the SWM method, enables modeling of noncanonical RNA structure in a variety of previously intractable problems.


slender rice, a constitutive gibberellin response mutant, is caused by a null mutation of the SLR1 gene, an ortholog of the height-regulating gene GAI/RGA/RHT/D8.
The rice slender mutant (slr1-1) is caused by a single recessive mutation and results in a constitutive gibberellin (GA) response phenotype. The mutant elongates as if saturated with GAs. In this mutant, (1) elongation was unaffected by an inhibitor of GA biosynthesis, (2) GA-inducible alpha-amylase was produced by the aleurone layers without gibberellic acid application, and (3) endogenous GA content was lower than in the wild-type plant. These results indicate that the product of the SLR1 gene is an intermediate of the GA signal transduction pathway. SLR1 maps to OsGAI in rice and has significant homology with height-regulating genes, such as RHT-1Da in wheat, D8 in maize, and GAI and RGA in Arabidopsis. The GAI gene family is likely to encode transcriptional factors belonging to the GRAS gene superfamily. DNA sequence analysis revealed that the slr1-1 mutation is a single basepair deletion of the nuclear localization signal domain, resulting in a frameshift mutation that abolishes protein production. Furthermore, introduction of a 6-kb genomic DNA fragment containing the wild-type SLR1 gene into the slr1-1 mutant restored GA sensitivity to normal. These results indicate that the slr1-1 mutant is caused by a loss-of-function mutation of the SLR1 gene, which is an ortholog of GAI, RGA, RHT, and D8. We also succeeded in producing GA-insensitive dwarf rice by transforming wild-type rice with a modified SLR1 gene construct that has a 17-amino acid deletion affecting the DELLA region. Thus, we demonstrate opposite GA response phenotypes depending on the type of mutations in SLR1.


A mixed methods approach to adapting and evaluating the functional assessment of HIV infection (FAHI), Swahili version, for use with low literacy populations.
Despite bearing the largest HIV-related burden, little is known of the Health-Related Quality of Life (HRQoL) among people living with HIV in sub-Saharan Africa. One of the factors contributing to this gap in knowledge is the lack of culturally adapted and validated measures of HRQoL that are relevant for this setting. We set out to adapt the Functional Assessment of HIV Infection (FAHI) Questionnaire, an HIV-specific measure of HRQoL, and evaluate its internal consistency and validity. The three phase mixed-methods study took place in a rural setting at the Kenyan Coast. Phase one involved a scoping review to describe the evidence base of the reliability and validity of FAHI as well as the geographical contexts in which it has been administered. Phase two involved in-depth interviews (n = 38) to explore the content validity, and initial piloting for face validation of the adapted FAHI. Phase three was quantitative (n = 103) and evaluated the internal consistency, convergent and construct validities of the adapted interviewer-administered questionnaire. In the first phase of the study, we identified 16 studies that have used the FAHI. Most (82%) were conducted in North America. Only seven (44%) of the reviewed studies reported on the psychometric properties of the FAHI. In the second phase, most of the participants (37 out of 38) reported satisfaction with word clarity and content coverage whereas 34 (89%) reported satisfaction with relevance of the items, confirming the face validity of the adapted questionnaire during initial piloting. Our participants indicated that HIV impacted on their physical, functional, emotional, and social wellbeing. Their responses overlapped with items in four of the five subscales of the FAHI Questionnaire establishing its content validity. In the third phase, the internal consistency of the scale was found to be satisfactory with subscale Cronbach's α ranging from 0.55 to 0.78. The construct and convergent validity of the tool were supported by acceptable factor loadings for most of the items on the respective sub-scales and confirmation of expected significant correlations of the FAHI subscale scores with scores of a measure of common mental disorders. The adapted interviewer-administered Swahili version of FAHI questionnaire showed initial strong evidence of good psychometric properties with satisfactory internal consistency and acceptable validity (content, face, and convergent validity). It gives impetus for further validation work, especially construct validity, in similar settings before it can be used for research and clinical purposes in the entire East African region.


Fracture resistance of structurally compromised and normal endodontically treated teeth restored with different post systems: An in vitro study.
With the aim of developing methods that could increase the fracture resistance of structurally compromised endodontically treated teeth, this study was conducted to compare the effect of three esthetic post systems on the fracture resistance and failure modes of structurally compromised and normal roots. Forty five extracted and endodontically treated maxillary central teeth were assigned to 5 experimental groups (n=9). In two groups, the post spaces were prepared with the corresponding drills of the post systems to be restored with double taper light posts (DT.Light-Post) (group DT.N) and zirconia posts (Cosmopost) (group Zr.N). In other 3 groups thin wall canals were simulated to be restored with Double taper Light posts (DT.W), double taper Light posts and Ribbond fibers (DT+R.W) and Zirconia posts (Zr.W). After access cavity restoration and thermocycling, compressive load was applied and the fracture strength values and failure modes were evaluated. Data were analyzed using two-way ANOVA, Tukey and Fisher exact tests (P<0.05). The mean failure loads (N) were 678.56, 638.22, 732.44, 603.44 and 573.67 for groups DT.N, Zr.N, DT.W, DT+R.W and Zr.w respectively. Group DT+R.W exhibited significantly higher resistance to fracture compared to groups Zr.N, DT.W and Zr.w (P<0.05). A significant difference was detected between groups DT.N and Zr.W (P=0.027). Zirconia posts showed significantly higher root fracture compared to fiber posts (P=0.004). The structurally compromised teeth restored with double taper light posts and Ribbond fibers showed the most fracture resistance and their strengths were comparable to those of normal roots restored with double taper light posts. More desirable fracture patterns were observed in teeth restored with fiber posts.


Epidemiology and outcome of invasive fungal diseases in patients with chronic granulomatous disease: a multicenter study in France.
Chronic granulomatous disease (CGD) is a rare inherited phagocytic disorder resulting in an increased susceptibility to infections including invasive fungal diseases (IFDs) and inflammatory complications. This study is aimed at assessing the incidence, prevalence, and outcome of IFDs among CGD patients followed in France. CGD patients were identified through the French national registry for primary immunodeficiencies (PID) held by the French national reference Centre of PID (Centre de Référence Déficits Immunitaires Héréditaires), which comprises a total of 3083 patients including 155 with CGD followed between 1976 and 2008. A questionnaire was filled out for each episode of IFD. Information retrieved included a description of the IFD using the 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group IFD definition criteria. Of CGD patients, 42.6% (66/155) developed at least 1 episode of IFD. Overall incidence of IFD was 0.040/patient-years (1862 patient-years of total follow-up). IFD incidence was found to be significant while receiving itraconazole prophylaxis compared with no prophylaxis (0.027 vs. 0.053 IFD/patient-years; P < 0.01). Median age at IFD diagnosis was 6.5 years (3.3-11.3). The most common fungal genus was Aspergillus sp. accounting for 40% of all IFDs. Of the IFDs, 42.5% were proven, 30.0% probable, and 27.5% possible. Of all IFD episodes, 52.5% were treated by antifungal monotherapy, mostly by amphotericin B. Survival was reduced in IFD patients compared with those without it (log-rank 0.04). IFDs are a frequent and life-threatening complication in CGD patients. Itraconazole significantly reduces its incidence and should be recommended in absence of better alternatives.


Evaluation of the rSP03B sero-strip, a newly proposed rapid test for canine exposure to Phlebotomus perniciosus, vector of Leishmania infantum.
Canine leishmaniasis (CanL) is a zoonotic disease, caused by Leishmania infantum and transmitted by Phlebotomus perniciosus in the Mediterranean basin. Previously, an ELISA based on the P. perniciosus salivary protein SP03B was proposed as a valid tool to screen for canine exposure to sand fly bites across regions endemic for CanL. Although this approach is useful in laboratory settings, a practical tool for immediate application in the field is needed. In this study we propose the rSP03B sero-strip, the first immunochromatographic test (ICT) in the field of vector exposure able to rapidly screen dogs living in endemic areas for the presence of P. perniciosus and to aid in the evaluation of vector control programs. The ICT was prepared using the bacterially expressed recombinant protein rSP03B as antigen. For test optimization, pre-immune sera from non-bitten laboratory-bred Beagles were used as negative controls. In order to validate the test, sera from laboratory-bred Beagles experimentally exposed to P. perniciosus bites were used as positive controls. Additionally, all samples were tested by ELISA using whole salivary gland homogenate (SGH) and the rSP03B protein as antigen. An almost perfect degree of agreement was found between the ICT and the SGH-ELISA. Furthermore, the newly proposed rSP03B sero-strip showed a sensitivity of 100% and a specificity of 86.79%. We developed a simple and rapid ICT based on the P. perniciosus rSP03B salivary protein, able to replace the standard ELISA used in previous studies. Our rSP03B sero-strip showed to be highly sensitive and specific in the detection of antibodies (IgG) against P. perniciosus saliva. In the future, this test can be employed during large-scale epidemiological studies of CanL in the Mediterranean area to evaluate the efficacy of vector control programs.


Transformation of yeast with linearized plasmid DNA. Formation of inverted dimers and recombinant plasmid products.
The molecular products of DNA double strand break repair were investigated after transformation of yeast (Saccharomyces cerevisiae) with linearized plasmid DNA. DNA of an autonomous yeast plasmid cleaved to generate free ends lacking homology with the yeast genome, when used in transformation along with sonicated non-homologous carrier DNA, gave rise to transformants with high frequency. Most of these transformants were found to harbor a head-to-head (inverted) dimer of the linearized plasmid. This outcome of transformation contrasts with that observed when the carrier DNA is not present. Transformants occur at a much reduced frequency and harbor either the parent plasmid or a plasmid with deletion at the site of the cleavage. When the linearized plasmid is introduced along with sonicated carrier DNA and a homologous DNA restriction fragment that spans the site of plasmid cleavage, homologous recombination restores the plasmid to its original circular form. Inverted dimer plasmids are not detected. This relationship between homologous recombination and a novel DNA transaction that yields rearrangement could be important to the cell, as the latter could lead to a loss of gene function and lethality.


Silica, silicosis, and lung cancer.
Evidence that crystalline silica is associated with an increased rate of lung cancer led the International Agency for Research on Cancer to conclude in 1997 that crystalline silica is a known human carcinogen. In Israel too, crystalline silica is considered as such. The decision raised a debate in the scientific arena, and a few scientists have questioned the basis upon which causality was determined. We review the literature regarding the level of evidence of crystalline silica carcinogenicity.


Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial.
In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting. In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment. Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months [IQR 13·4-36·3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35·6-not estimable] vs 26·6 months [22·1-33·4]; hazard ratio [HR] 0·66 [95% CI 0·54-0·80], p<0·0001), progression-free survival (median 8·2 months [95% CI 6·9-10·0] vs 8·3 months [7·0-8·8]; HR 0·77 [95% CI 0·65-0·90], p=0·0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0·0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37·9 months [32·2-not estimable]; HR 0·71 [95% CI 0·59-0·86], p=0·0003), progression-free survival (median 9·7 months [95% CI 8·1-11·1] vs 9·7 months [8·3-11·1]; HR 0·85 [95% CI 0·73-0·98], p=0·027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0·015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related. The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories. Bristol-Myers Squibb and ONO Pharmaceutical.


Anti-inflammatory effect of purified dietary anthocyanin in adults with hypercholesterolemia: a randomized controlled trial.
Atherosclerosis is a chronic inflammatory disease and previous studies have demonstrated that anthocyanin inhibits atherosclerosis. In the present study, we explored the effects of anthocyanins on inflammatory cytokines in hypercholesterolemic adults and cell lines. A total of 150 subjects with hypercholesterolemia consumed a purified anthocyanin mixture (320 mg/d) or a placebo twice a day for 24 weeks in a randomized, double-blind trial. Anthocyanin consumption significantly decreased the levels of serum high sensitivity C-reactive protein (hsCRP) (-21.6% vs. -2.5%, P = 0.001), soluble vascular cell adhesion molecule-1 (sVCAM-1) (-12.3% vs. 0.4%, P = 0.005) and plasma IL-1β (-12.8% vs. -1.3%, P = 0.019) compared to the placebo. We also found a significant difference in the LDL-cholesterol (-10.4% vs. 0.3%, P = 0.030) and HDL-cholesterol level changes (14.0% vs. -0.9%, P = 0.036) between the two groups. In cell culture assays in vitro, purified anthocyanin mixture, delphinidin-3-Ο-β-glucoside (Dp-3g) and cyanidin-3-Ο-β-glucoside (Cy-3g) inhibited IL-6 and IL-1β-induced CRP production (P < 0.05) in HepG2 cell line and LPS-induced VCAM-1 secretion (P < 0.05) in porcine iliac artery endothelial cell line respectively in a dose-dependent manner. In addition, the reduction of inflammatory cytokines associated with anthocyanin mixture was stronger when compared with the effects of Dp-3g and Cy-3g separately (P < 0.05). Anthocyanin mixture reduced the inflammatory response in hypercholesterolemic subjects. In addition, different anthocyanin compounds were found to have additive or synergistic effects in mediating anti-inflammatory responses in vitro cell culture assays.


A global to local genomics analysis of Clostridioides difficile ST1/RT027 identifies cryptic transmission events in a northern Arizona healthcare network.
Clostridioides difficile is a ubiquitous, diarrhoeagenic pathogen often associated with healthcare-acquired infections that can cause a range of symptoms from mild, self-limiting disease to toxic megacolon and death. Since the early 2000s, a large proportion of C. difficile cases have been attributed to the ribotype 027 (RT027) lineage, which is associated with sequence type 1 (ST1) in the C. difficile multilocus sequence typing scheme. The spread of ST1 has been attributed, in part, to resistance to fluoroquinolones used to treat unrelated infections, which creates conditions ideal for C. difficile colonization and proliferation. In this study, we analysed 27 isolates from a healthcare network in northern Arizona, USA, and 1352 publicly available ST1 genomes to place locally sampled isolates into a global context. Whole genome, single nucleotide polymorphism analysis demonstrated that at least six separate introductions of ST1 were observed in healthcare facilities in northern Arizona over an 18-month sampling period. A reconstruction of transmission networks identified potential nosocomial transmission of isolates, which were only identified via whole genome sequence analysis. Antibiotic resistance heterogeneity was observed among ST1 genomes, including variability in resistance profiles among locally sampled ST1 isolates. To investigate why ST1 genomes are so common globally and in northern Arizona, we compared all high-quality C. difficile genomes and identified that ST1 genomes have gained and lost a number of genomic regions compared to all other C. difficile genomes; analyses of other toxigenic C. difficile sequence types demonstrate that this loss may be anomalous and could be related to niche specialization. These results suggest that a combination of antimicrobial resistance and gain and loss of specific genes may explain the prominent association of this sequence type with C. difficile infection cases worldwide. The degree of genetic variability in ST1 suggests that classifying all ST1 genomes into a quinolone-resistant hypervirulent clone category may not be appropriate. Whole genome sequencing of clinical C. difficile isolates provides a high-resolution surveillance strategy for monitoring persistence and transmission of C. difficile and for assessing the performance of infection prevention and control strategies.


Negative and positive illness representations of rheumatoid arthritis: a latent profile analysis.
This study extends previous work to consider whether individuals with rheumatoid arthritis (RA) can be categorised into groups with similar illness representations. Data from 227 RA patients attending outpatient clinics were collected prospectively at two time points, 6 months apart. The optimal number of illness representation groups at the baseline assessment was identified using latent profile analysis. Two groups of individuals sharing similar illness perception profiles were identified. The smaller group (43%), characterised by a negative representation of their illness, attributed more symptoms to their condition and reported stronger perceptions of the consequences, chronicity and cyclicality of their condition, and lower control compared to the positive representation group (57%). Cross-sectionally, membership of the negative representation group was associated with higher levels of pain and functional disability and, longitudinally, with increases in levels of pain, functional disability and distress. These data highlight the central role of illness perceptions in RA and suggest that individuals with RA can be categorised into groups with similar illness representations.


Morphology of the uvula in obstructive sleep apnea.
Alterations in pharyngeal structure and function are considered fundamental in the pathogenesis of obstructive sleep apnea (OSA). However, little is known about morphologic features of the pharynx in patients with OSA. We therefore studied the tissue composition of the uvula (midsagittal section) in patients with OSA, using a quantitative, morphometric point-counting technique. Uvula tissue was obtained by uvulopalatopharyngoplasty (UPPP) in 33 patients (mean number of apneas per hour of sleep = 32.7 +/- 5.2) and by autopsy in 22 normal subjects not known to have OSA. All statistical comparisons were controlled for differences caused by age and body mass index. Patients with OSA had a significantly greater percentage of muscle in the uvula (18.1 +/- 1.9% versus 9.3 +/- 2.1%, p = 0.02) than did normal subjects. A significant difference in fat content was also found (9.5 +/- 1.4% in patients versus 4.0 +/- 1.0% in normal subjects, p less than 0.02). These differences between patients with OSA and control subjects could not be accounted for by anthropometric or sex differences. The percentage of uvula fat tissue was significantly related to the frequency of apneas and hypopneas in sleep (r = 0.43, p less than 0.01). Uvula morphology in 6 nonapneic snorers undergoing UPPP was similar to that of patients with OSA. We conclude that the uvula in patients with OSA contains more muscle and fat than the uvula in control subjects, possibly contributing to pharyngeal narrowing in OSA.


The Acridine Orange test: determining the relationship between sperm morphology and fertilization in vitro.
The prediction of human fertilization is an important aspect of research protocols dealing with male fertility. Sperm DNA has been reported to be an indicator of human sperm fertility potential. The Acridine Orange test for evaluation of sperm DNA has been employed during the present study to determine its relationship with human sperm morphology and fertilization in vitro. Seventy-six patients from the in-vitro fertilization (IVF) and/or gamete intra-Fallopian transfer (GIFT) programme were randomly selected for the study. All patients had a routine semen analysis, sperm DNA evaluation and underwent standard IVF procedures at the time of the study. The results indicated a moderate positive correlation (r = 0.38, P = 0.0006) between results of the Acridine Orange test and normal sperm morphology. Patients with an Acridine Orange test value exceeding 24% had significantly higher oocyte fertilization rates than patients with lower values, for metaphase I (74 versus 51%, P = 0.0008) and for metaphase II oocytes (88 versus 60%, P = 0.0001). Sperm morphology, however, proved to be a more significant predictor of fertilization in vitro compared to the Acridine Orange test.


Tobacco Retail Density and Initiation of Alternative Tobacco Product Use Among Teens.
The rise of noncigarette, alternative tobacco product (ATP) use among adolescents may be due in part to an increase in retail availability of ATPs. We examined whether proximity and density of tobacco retailers near students' homes are associated with a higher likelihood of initiating ATP use over time. Using data from 728 adolescents (aged 13-19 years at baseline) residing in 191 different neighborhoods and attending 10 different California high schools, longitudinal multilevel and cross-classified random effect models evaluated individual-level, neighborhood-level, and school-level risk factors for ATP initiation after 1 year. Covariates were obtained from the American Community Survey and the California Department of Education. The sample was predominantly female (63.5%) and was racially and ethnically diverse. Approximately one third of participants (32.5%) reported ever ATP use at baseline, with 106 (14.5%) initiating ATP use within 1 year. The mean number of tobacco retailers per square mile within a tract was 5.66 (standard deviation = 6.3), and the average distance from each participant's residence to the nearest tobacco retailer was .61 miles (standard deviation = .4). Living in neighborhoods with greater tobacco retailer density at baseline was associated with higher odds of ATP initiation (odds ratio = 1.22, 95% confidence interval = 1.07-2.12), controlling for individual and school factors. Tobacco retailers clustered in students' home neighborhood may be an environmental influence on adolescents' ATP use. Policy efforts to reduce adolescent ATP use should aim to reduce the density of tobacco retailers and limit the proximity of tobacco retailers near adolescents' homes and schools.


Frontoparietal activity with minimal decision and control in the awake macaque at 7 T.
Previous imaging work has identified a frontoparietal network in the human brain involved in many different cognitive functions, as well as in simple updates of attended information. To determine whether a similar network is present in the monkey brain and direct future electrophysiological recordings, we examined the activation of frontoparietal areas during visual stimulation in the awake, fixating monkey. We measured activity with BOLD fMRI in three animals and analyzed the data individually for each animal and at group level. We found reliable activations in lateral prefrontal and parietal areas, even though task-related decision making was minimal, as a response to simple update of visual information. These activations were significant for each individual animal, as well as at group level. Similar to human imaging results the update of visual input was enough to activate an extensive network of frontoparietal cortex in the macaque brain, a network which is normally associated with complex cognitive control processes.


The C. elegans cGMP-dependent protein kinase EGL-4 regulates nociceptive behavioral sensitivity.
Signaling levels within sensory neurons must be tightly regulated to allow cells to integrate information from multiple signaling inputs and to respond to new stimuli. Herein we report a new role for the cGMP-dependent protein kinase EGL-4 in the negative regulation of G protein-coupled nociceptive chemosensory signaling. C. elegans lacking EGL-4 function are hypersensitive in their behavioral response to low concentrations of the bitter tastant quinine and exhibit an elevated calcium flux in the ASH sensory neurons in response to quinine. We provide the first direct evidence for cGMP/PKG function in ASH and propose that ODR-1, GCY-27, GCY-33 and GCY-34 act in a non-cell-autonomous manner to provide cGMP for EGL-4 function in ASH. Our data suggest that activated EGL-4 dampens quinine sensitivity via phosphorylation and activation of the regulator of G protein signaling (RGS) proteins RGS-2 and RGS-3, which in turn downregulate Gα signaling and behavioral sensitivity.


Direct binding of MEK1 and MEK2 to AKT induces Foxo1 phosphorylation, cellular migration and metastasis.
Crosstalk between the ERK cascade and other signaling pathways is one of the means by which it acquires its signaling specificity. Here we identified a direct interaction of both MEK1 and MEK2 with AKT. The interaction is mediated by the proline rich domain of MEK1/2 and regulated by phosphorylation of Ser298 in MEK1, or Ser306 in MEK2, which we identified here as a novel regulatory site. We further developed a blocking peptide, which inhibits the interaction between MEK and AKT, and when applied to cells, affects migration and adhesion, but not proliferation. The specific mechanism of action of the MEK-AKT complex involves phosphorylation of the migration-related transcription factor FoxO1. Importantly, prevention of the interaction results in a decreased metastasis formation in a breast cancer mouse model. Thus, the identified interaction both sheds light on how signaling specificity is determined, and represents a possible new therapeutic target for metastatic cancer.


Adaptation of a counseling intervention to address multiple cancer risk factors among overweight/obese Latino smokers.
More than 60% of cancer-related deaths in the United States are attributable to tobacco use, poor nutrition, and physical inactivity, and these risk factors tend to cluster together. Thus, strategies for cancer risk reduction would benefit from addressing multiple health risk behaviors. We adapted an evidence-based intervention grounded in social cognitive theory and principles of motivational interviewing originally developed for smoking cessation to also address physical activity and fruit/vegetable consumption among Latinos exhibiting multiple health risk behaviors. Literature reviews, focus groups, expert consultation, pretesting, and pilot testing were used to inform adaptation decisions. We identified common mechanisms underlying change in smoking, physical activity, and diet used as treatment targets; identified practical models of patient-centered cross-cultural service provision; and identified that family preferences and support as particularly strong concerns among the priority population. Adaptations made to the original intervention are described. The current study is a practical example of how an intervention can be adapted to maximize relevance and acceptability and also maintain the core elements of the original evidence-based intervention. The intervention has significant potential to influence cancer prevention efforts among Latinos in the United States and is being evaluated in a sample of 400 Latino overweight/obese smokers.


Milk fat globule-epidermal growth factor-factor VIII downregulates interleukin-17 expression in sepsis by modulating STAT3 activation.
Milk fat globule-epidermal growth factor-factor VIII (MFG-E8) is a secretory glycoprotein with a known role in inflammation. In sepsis, interleukin (IL)-17 acts as a proinflammatory cytokine to exaggerate systemic inflammation. We hypothesize that MFG-E8 downregulates IL-17 expression in sepsis. Sepsis was induced in 8-week-old male C57BL/6 mice by cecal ligation and puncture (CLP). Recombinant mouse MFG-E8 (rmMFG-E8) at a dosage of 20 μg/kg body weight or phosphate-buffered saline was concurrently injected. After 10 hours, blood and spleen samples were harvested for analysis. For in vitro studies, splenocytes isolated from healthy mice pretreated with rmMFG-E8 and splenocytes from MFG-E8 knockout (mfge8(-/-)) mice were stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin, followed by measurement of IL-17 expression with either quantitative PCR or enzyme-linked immunosorbent assay. At 10 hours after CLP, rmMFG-E8 inhibited the elevated levels of IL-17 protein in serum by 31%, compared with the vehicle. In the spleen, rmMFG-E8 reduced the upregulated IL-17 mRNA and protein levels by 81% and 51%, respectively. This correlated with a significant reduction in organ injury markers AST and ALT in sepsis after administration of rmMFG-E8. In vitro treatment of splenocytes isolated from healthy mice with rmMFG-E8 showed significant downregulation in PMA/ionomycin-induced IL-17 expression. In contrast, CD4 T-cells from mfge8(-/-) mice showed significant upregulation of IL-17 compared with wild-type mice. The phosphorylated level of signal transducer and activator of transcription 3 (STAT3) was downregulated in spleen tissue of septic mice treated with rmMFG-E8. Conversely, mfge8(-/-) mice showed increased phosphorylated STAT3 compared with wild-type mice after sepsis. Our findings demonstrate MFG-E8-mediated downregulation of IL-17 expression, implicating its potential as a novel therapeutic agent against sepsis.


Polycyclic aromatic hydrocarbons in frying oils and snacks.
The high incidence of lung cancer observed among Chinese women has been associated with exposure to fumes from cooking oil. Polycyclic aromatic hydrocarbons (PAHs) are a class of potentially mutagenic substances emitted from cooking oils heated at high temperatures. The objective of this study was to investigate whether deep frying with different oils under different conditions leads to the development of PAHs either in the oil or in the fried product (snacks). PAH analysis was carried out with solid-phase extraction followed by reverse-phase high-performance liquid chromatography and spectrofluorometric detection. Different oils were used to fry chips and extruded snacks in different industrial plants (continuous frying) at temperatures between 170 and 205 degrees C, and peanut oil was used to fry French fries and fish (discontinuous frying) at temperatures between 160 and 185 degrees C. No appreciable differences in PAH load was observed in the same oil before and after frying. Both before and after frying, the benzo[a]pyrene concentration in oils ranged from trace to 0.7 ppb. All the analyzed samples, including oils from fried snacks, had benzo[a]pyrene concentrations well below the 2 ppb limit recently proposed by the European Community.


Tax incentives and the demand for private health insurance.
We analyze the effect of an individual insurance mandate (Medicare Levy Surcharge) on the demand for private health insurance (PHI) in Australia. With administrative income tax return data, we show that the mandate has several distinct effects on taxpayers' behavior. First, despite the large tax penalty for not having PHI coverage relative to the cost of the cheapest eligible insurance policy, compliance with mandate is relatively low: the proportion of the population with PHI coverage increases by 6.5 percentage points (15.6%) at the income threshold where the tax penalty starts to apply. This effect is most pronounced for young taxpayers, while the middle aged seem to be least responsive to this specific tax incentive. Second, the discontinuous increase in the average tax rate at the income threshold created by the policy generates a strong incentive for tax avoidance which manifests itself through bunching in the taxable income distribution below the threshold. Finally, after imposing some plausible assumptions, we extrapolate the effect of the policy to other income levels and show that this policy has not had a significant impact on the overall demand for private health insurance in Australia.


Does recession reduce global health aid? Evidence from 15 high-income countries, 1975-2007.
To test the hypothesis that economic recessions lead to reduced global development assistance for health (DAH). Data obtained from the Creditor Reporting System of the Organisation for Economic Co-operation and Development (OECD) for 15 OECD countries were used to model the percentage change (relative difference) in commitments and disbursements for DAH as a function of three measures of economic recession: recessionary year (as a dummy variable with 0 for no recession and 1 for recession), percentage change in per capita gross domestic product and percentage point change in unemployment rate for recessionary cycles from 1975 through 2007. We looked for an association both during the concurrent recessionary year and one and two years later. No statistically significant association was found in the short or long run between measures of economic recession and the amount of official DAH committed or disbursed. Any important decrease in overall DAH following the current economic recession would have little historical precedent and claims of inevitability would be unjustifiable.


Extracting and Benchmarking Emerging Adverse Outcome Pathway Knowledge.
As the community of toxicological researchers, risk assessors, and risk managers adopt the adverse outcome pathway (AOP) framework for organizing toxicological knowledge, the number and diversity of AOPs in the online AOP knowledgebase (KB) continues to grow. To track and investigate this growth, AOPs in the AOP-KB were assembled into a single network. Summary measures on the current state of the AOP-KB and the overall connectivity and structural features of the resulting network were calculated. Our results show that networking the 187 user-defined AOPs currently described in the AOP-KB resulted in the emergence of 9405 unique, previously undescribed, linear AOPs (LAOPs). To investigate patterns in this emerging knowledge, we assembled the AOP-KB network retrospectively by sequentially adding each of the 187 user-defined AOPs and found that the creation of new AOPs that borrowed components from previously existing AOPs in the KB most described emergence of new LAOPs. However, the introduction of nonadjacent key event relationships and cycles among KEs also play key roles in emergent LAOPs. We provide examples of how to identify application-specific critical paths from this large number of LAOPs. Our research shows that the global AOP network may have considerable value as a source of emergent toxicological knowledge. These findings are not only helpful for understanding the nature of this emergent information but can also be used to manage and guide future development of the AOP-KB, and how to tailor this wealth of information to specific applications.


WE-E-BRB-04: Quantitative Dose Tracking Enabled Through a Novel Deformable 3D Dosimeter.
To evaluate and investigate the feasibility of a new method for validating dose tracking algorithms in deforming tissues using a novel deformable 3D dosimeter. A novel deformable 3D Presage dosimeter is reported consisting of a stretchy polyurethane matrix doped with radiochromic leuco-dye. Two deformable cylindrical dosimeters (6 cm diameter, 5 cm long) were manufactured and irradiated with a checkerboard arrangement of 5 mm square pencil beams created by MLC fields. One dosimeter was irradiated under lateral compression by 33% (6 cm down to 4 cm diameter) to simulate a deformed organ. A second control dosimeter was irradiated with the same checkerboard pattern but without deformation applied. High-resolution 3D dose distributions (isotropic 1 mm resolution) were obtained by optical-CT imaging. Physical dose deformation was quantified by comparing checkerboard pencil beam shapes and positions in the deformed and control dosimeters. Deformation of dose in the deformed dosimeter was clearly visible in all 3 dimensions. The deformed checkerboard dose pattern showed expansion of 16% - 46% along the axis of compression, with higher expansion observed in the central regions of the dosimeter. Perpendicular to the compression axis, the dose pattern contracted by 7% - 13%. Peak dose changes of -6% and +30% were observed parallel and perpendicular to the compression axis respectively. Dose response was linear from 0-8 Gy. Dose tracking was successfully quantified in a novel deforming 3D dosimeter. This capability has potential as a powerful new method for validating deformable dose tracking and registration algorithms. NCI R01CA100835.


Fluctuations in phenylalanine concentrations in phenylketonuria: a review of possible relationships with outcomes.
Fluctuations in blood phenylalanine concentrations may be an important determinant of intellectual outcome in patients with early and continuously treated phenylketonuria (PKU). This review evaluates the studies on phenylalanine fluctuations, factors affecting fluctuations, and if stabilizing phenylalanine concentrations affects outcomes, particularly neurocognitive outcome. Electronic literature searches of Embase and PubMed were performed for English-language publications, and the bibliographies of identified publications were also searched. In patients with PKU, phenylalanine concentrations are highest in the morning. Factors that can affect phenylalanine fluctuations include age, diet, timing and dosing of protein substitute and energy intake, dietary adherence, phenylalanine hydroxylase genotype, changes in dietary phenylalanine intake and protein metabolism, illness, and growth rate. Even distribution of phenylalanine-free protein substitute intake throughout 24h may reduce blood phenylalanine fluctuations. Patients responsive to and treated with 6R-tetrahydrobiopterin seem to have less fluctuation in their blood phenylalanine concentrations than controls. An increase in blood phenylalanine concentration may result in increased brain and cerebrospinal fluid phenylalanine concentrations within hours. Although some evidence suggests that stabilization of blood phenylalanine concentrations may have benefits in patients with PKU, more studies are needed to distinguish the effects of blood phenylalanine fluctuations from those of poor metabolic control.


VEGF-A not Ang2 mediates endothelial-like differentiation of immature DCs by ERK1/2 signaling in the microenvironment of human colon adenocarcinoma.
Endothelial-like differentiation of dendritic cells (DCs) is an interesting and significant phenomenon, which is worth further investigation. Here, we show that the tumor microenvironment derived from the supernatant of the SW620 human colon adenocarcinoma cell line and colon adenocarcinoma tissue homogenate can promote immature DCs (iDCs) to differentiate from the DC pathway toward endothelial cells, while the peri-carcinoma homogenate supernatant does not have this role. Inhibition of angiopoietin-2 (Ang2) in the supernatant by its antibody has no obvious influence on the endothelial-like differentiation. In contrast, inhibition of vascular endothelial growth factor-A (VEGF-A) blocked the differentiation. During the course of differentiation, a sustained activation of ERK1/2 was detected. PD98059 blocked the phosphorylation of ERK1/2 as well as the endothelial-like differentiation of iDCs. Inhibition of VEGF-A also blocked the phosphorylation of ERK1/2. These data suggest that VEGF-A not Ang2 mediates endothelial-like differentiation of iDCs by ERK1/2 signaling in the microenvironment of human colon adenocarcinoma.


Relationship between Legionella pneumophila and Acanthamoeba polyphaga: physiological status and susceptibility to chemical inactivation.
Survival studies were conducted on Legionella pneumophila cells that had been grown intracellularly in Acanthamoeba polyphaga and then exposed to polyhexamethylene biguanide (PHMB), benzisothiazolone (BIT), and 5-chloro-N-methylisothiazolone (CMIT). Susceptibilities were also determined for L. pneumophila grown under iron-sufficient and iron-depleted conditions. BIT was relatively ineffective against cells grown under iron depletion; in contrast, iron-depleted conditions increased the susceptibilities of cells to PHMB and CMIT. The activities of all three biocides were greatly reduced against L. pneumophila grown in amoebae. PHMB (1 x MIC) gave 99.99% reductions in viability for cultures grown in broth within 6 h and no detectable survivors at 24 h but only 90 and 99.9% killing at 6 h and 24 h, respectively, for cells grown in amoebae. The antimicrobial properties of the three biocides against A. polyphaga were also determined. The majority of amoebae recovered from BIT treatment, but few, if any, survived CMIT treatment or exposure to PHMB. This study not only shows the profound effect that intra-amoebal growth has on the physiological status and antimicrobial susceptibility of L. pneumophila but also reveals PHMB to be a potential biocide for effective water treatment. In this respect, PHMB has significant activity, below its recommended use concentrations, against both the host amoeba and L. pneumophila.


Lizard Tail Autotomy: Function and Energetics of Postautotomy Tail Movement in Scincella lateralis.
Handling of autotomized, thrashing and autotomized, exhausted tails of the lizard Scincella lateralis by mammals and snakes was tested to examine the function of postautotomy tail movement. Tail movement attracted a mammal's attack to the tail, permitting the lizard to escape and increased the time required for a snake to subdue a tail before swallowing it, increasing the lizard's escape time by 40 percent. Lactate concentrations of autotomized tails after movement were compared to those of intact tails after rest in S. lateralis, a species with a high rate of autotomized tail thrashing, and Anolis carolinensis, a species with a low rate of thrashing. Postautotomy movement increased tail lactate concentration in both species, but mean tail lactate concentration in S. lateralis was 60 percent higher than that in A. carolinensis, and a third higher than that reportedfor whole-body lactate content of the very mobile lizard Dipsosaurus dorsalis.


Metabolic effects of oestrogens: impact of the route of administration.
To investigate whether oestrogen modulates GH secretion and action in adult life, we studied the impact of oestrogen replacement on circulating GH and IGF-I levels in post-menopausal women. Since the liver is the major source of circulating IGF-I and the oral route of oestrogen delivery causes non-physiologic effects on hepatic proteins, we compared the effects of oral and transdermal route of delivery. Oral ethinyl oestradiol administration resulted in a significant fall in mean IGF-I levels and a 3-fold increase in mean 24h GH. Transdermal administration of 17beta oestradiol resulted in a slight increase in serum IGF-I but no change in mean 24h GH levels. To determine whether differences in oestrogen type rather than in the route of delivery caused the different effects on the GH/IGF-I axis, we compared the effects of three oral oestrogen formulations. Ethinyl oestradiol, conjugated equine oestrogen and oestradiol valerate each induced a fall in IGF-I and a rise of mean 24h GH levels in post-menopausal women. To determine the metabolic significance of oestrogen-induced changes on GH/ IGF-I, we compared the effects of 24 weeks each of oral and transdermal oestrogen on energy metabolism and body composition in 18 post menopausal women in an open-label randomised cross-over study. When compared to the transdermal route, oral oestrogen reduced lipid oxidation, increased fat mass and reduced lean body mass. Oestrogen causes distinct, route dependent effects on the somatotrophic axis. The dissociation of the GH/IGF-I axis by the oral route is likely to arise from impaired hepatic IGF-I production which causes increased GH secretion through reduced feedback inhibition. The route of oestrogen therapy confers divergent effects on substrate oxidation and body composition. The suppression of lipid oxidation during oral oestrogen therapy may increase fat mass while the fall in IGF-I may lead to a loss of lean body mass. The route dependent changes in body composition observed during oestrogen replacement therapy may have important implications for post-menopausal health and oestrogen use in general.


The long-term effects of labor market entry in a recession: Evidence from the Asian financial crisis.
This study investigates the long-term effects of initial labor market conditions by comparing cohorts who graduated from college before, during, and after the 1997-1998 Asian financial crisis in South Korea. We measure the overall welfare effect by examining their labor market activities, family formation, and household finances. Using data from 20 waves of the Korean Labor and Income Panel Study, we find a substantial and persistent reduction in employment, earnings, marriage, fertility, and asset building among men who graduated during the recession. For women, limited job opportunities at graduation resulted in an increase in childbearing. We also find evidence that family provides a risk-sharing mechanism for recession graduates. Our results suggest that labor market entry in a large-scale recession has prolonged effects on a young worker's life course even after the penalties in the labor market have disappeared.


Understanding pathways for scaling up health services through the lens of complex adaptive systems.
Despite increased prominence and funding of global health initiatives, efforts to scale up health services in developing countries are falling short of the expectations of the Millennium Development Goals. Arguing that the dominant assumptions for scaling up are inadequate, we propose that interpreting change in health systems through the lens of complex adaptive systems (CAS) provides better models of pathways for scaling up. Based on an understanding of CAS behaviours, we describe how phenomena such as path dependence, feedback loops, scale-free networks, emergent behaviour and phase transitions can uncover relevant lessons for the design and implementation of health policy and programmes in the context of scaling up health services. The implications include paying more attention to local context, incentives and institutions, as well as anticipating certain types of unintended consequences that can undermine scaling up efforts, and developing and implementing programmes that engage key actors through transparent use of data for ongoing problem-solving and adaptation. We propose that future efforts to scale up should adapt and apply the models and methodologies which have been used in other fields that study CAS, yet are underused in public health. This can help policy makers, planners, implementers and researchers to explore different and innovative approaches for reaching populations in need with effective, equitable and efficient health services. The old assumptions have led to disappointed expectations about how to scale up health services, and offer little insight on how to scale up effective interventions in the future. The alternative perspectives offered by CAS may better reflect the complex and changing nature of health systems, and create new opportunities for understanding and scaling up health services.


Field efficacy of pyrethroid treated plastic sheeting (durable lining) in combination with long lasting insecticidal nets against malaria vectors.
Insecticide treated plastic sheeting (ITPS), sometimes known as durable lining, has potential as a long-lasting insecticidal surface for malaria vector control when used as lining for interior walls and ceilings inside the home. Against a backdrop of increasing long lasting net (LN) coverage, we examined the effect of combining permethrin-treated plastic sheeting (ITPS) with LNs in Burkina Faso. A verandah trap experimental hut trial of ITPS with or without Olyset LN was conducted in the Vallée du Kou near Bobo-Dioulasso, where the two molecular forms of Anopheles gambiae s.s., S (frequency 65%) and M (frequency 35%), occur. The S form is mostly pyrethroid resistant (Fkdr = 92%) owing to the kdr mechanism, and the M form is mostly kdr susceptible (Fkdr = 7%). The treatment arms included ITPS, Olyset, ITPS plus Olyset, ITPS plus untreated net (with or without holes), and untreated control. ITPS was significantly inferior to Olyset LN in terms of mortality (37% vs 63%), blood feeding inhibition (20% vs 81%) and deterrence (0 vs 42%) effects, and hence altogether inferior as a means of personal protection (16% vs 89%). The addition of ITPS to Olyset did not improve mortality (62%), blood feeding inhibition (75%), deterrence (50%) or personal protection (88%) over that of Olyset used alone. Use of untreated nets - both holed and intact - with ITPS provided greater protection from blood-feeding. The intact net/ITPS combination killed more mosquitoes than ITPS on its own. Although ITPS has a potential role for community control of malaria, at low coverage it is unlikely to be as good as Olyset LNs for household protection. The combination of pyrethroid IRS and pyrethroid LN - as practiced in some countries - is unlikely to be additive except, perhaps, at high levels of IRS coverage. A combination of LN and ITPS treated with an alternative insecticide is likely to be more effective, particularly in areas of pyrethroid resistance.