Unimpaired macrophage differentiation and activation in mice lacking the zinc finger transplantation factor NGFI-A (EGR1).
The zinc finger protein NGFI-A (also called EGR1, Krox24, or zif268) is a candidate regulator of myeloid cell differentiation. Evidence supporting this hypothesis is twofold. First, NGFI-A antisense oligonucleotides prevent macrophage differentiation in HL-60 and U937 myeloid leukemia cell lines and in normal bone marrow cells. Second, enforced expression of NGFI-A blocks granulocytic differentiation and promotes macrophage differentiation in HL-60 cells and in the hematopoietic progenitor cell line 32D. We sought to determine the effect of NGFI-A deficiency on macrophage differentiation and function in vivo by examining native bone marrow cells from mice homozygous for a disrupted allele of NGFI-A derived from gene-targeted ES cells. Macrophages were observed in peripheral blood and several tissues, indicating that NGFI-A was not required for the formation of a variety of macrophage compartments. No differences in myeloid cell differentiation were observed between wild-type and NGFI-A-/- bone marrow cells cultured in the presence of macrophage, granulocyte-macrophage, or granulocyte colony-stimulating factor (M-CSF, GM-CSF, or G-CSF). Activation of NGFI-A-/- macrophages was comparable to that of wild-type macrophages as determined by nitric oxide production and increased cell surface expression of class II major histocompatibility complex molecules. Moreover, NGFI-A-/- mice showed no increased mortality or bacteria] burden when challenged with Listeria monocytogenes. Together, these results indicate that NGFI-A is not required for macrophage differentiation or activation.


Genetic instability caused by loss of MutS homologue 3 in human colorectal cancer.
Microsatellite instability (MSI) is a hallmark of mismatch repair (MMR) deficiency. High levels of MSI at mononucleotide and dinucleotide repeats in colorectal cancer (CRC) are attributed to inactivation of the MMR genes, hMLH1 and hMSH2. CRC with low levels of MSI (MSI-L) exists; however, its molecular basis is unclear. There is another type of MSI--elevated microsatellite alterations at selected tetranucleotide repeats (EMAST)--where loci containing [AAAG](n) or [ATAG](n) repeats are unstable. EMAST is frequent in non-CRCs; however, the incidence of EMAST and its cause in CRC is not known. Here, we report that MutS homologue 3 (MSH3) knockdown or MSH3-deficient cells exhibit the EMAST phenotype and low levels of mutations at dinucleotide repeats. About 60% of 117 sporadic CRC cases exhibit EMAST. All of the cases defined as MSI-H (16 cases) exhibited high levels of EMAST. Among 101 non-MSI-H cases, all 19 cases of MSI-L and 35 of 82 cases of MSS exhibited EMAST. Although non-MSI-H CRC tissues contained MSH3-negative tumor cells ranging from 2% to 50% of the total tumor cell population, the tissues exhibiting EMAST contained more MSH3-negative cells (average, 31.5%) than did the tissues not exhibiting EMAST (8.4%). Taken together, our results support the concept that MSH3 deficiency causes EMAST or EMAST with low levels of MSI at loci with dinucleotide repeats in CRC.


Impulsivity differences between bipolar and unipolar depression.
Even though particularly bipolar depression and unipolar depression seem to be similar, they show differences in terms of the etiology, phenomenology, course, and treatment process. Bipolar depression is associated with mood lability, motor retardation, and hypersomnia to a larger extent. Early age of onset, a high frequency of depressive episodes, and history of bipolar disease in the family are suggestive of bipolar disorder (BD) rather than major depression. Bipolar and unipolar disorders are also associated with increased impulsivity during illness episodes. However, there is little information about impulsivity during euthymia in these mood disorders. The aim of this study was to illustrate the difference in impulsivity in euthymic bipolar and unipolar patients. Impulsivity was evaluated by the Barratt Impulsiveness Scale (BIS-11A), in 78 interepisode BD patients, 72 interepisode unipolar disorder patients, and 70 healthy controls. The diagnosis was established by severe combined immunodeficiency. One-way between-groups ANOVA was used to compare the BIS-11A mean scores for all three groups. Impulsivity scores of the bipolar and unipolar disorder patients were significantly higher than controls on total and all subscales measures. There was no difference between the bipolar and unipolar disorder groups on total, attentional, and nonplanning impulsivity measures. However, BD patients scored significantly higher than the unipolar patients on motor impulsivity measures. Both interepisode bipolar and unipolar disorder patients had increased impulsivity compared to healthy individuals. There was no significant difference on attention and nonplanning impulsivity subscales; however, on the motor subscale, bipolar patients were more impulsive than unipolar disorder patients.


Subtle cerebellar phenotype in mice homozygous for a targeted deletion of the En-2 homeobox.
The two mouse genes, En-1 and En-2, that are homologs of the Drosophila segmentation gene engrailed, show overlapping spatially restricted patterns of expression in the neural tube during embryogenesis, suggestive of a role in regional specification. Mice homozygous for a targeted mutation that deletes the homeobox were viable and showed no obvious defects in embryonic development. This may be due to functional redundancy of En-2 and the related En-1 gene product during embryogenesis. Consistent with this hypothesis, the mutant mice showed abnormal foliation in the adult cerebellum, where En-2, and not En-1, is normally expressed.


Universal fractal scaling in stream chemistry and its implications for solute transport and water quality trend detection.
The chemical dynamics of lakes and streams affect their suitability as aquatic habitats and as water supplies for human needs. Because water quality is typically monitored only weekly or monthly, however, the higher-frequency dynamics of stream chemistry have remained largely invisible. To illuminate a wider spectrum of water quality dynamics, rainfall and streamflow were sampled in two headwater catchments at Plynlimon, Wales, at 7-h intervals for 1-2 y and weekly for over two decades, and were analyzed for 45 solutes spanning the periodic table from H(+) to U. Here we show that in streamflow, all 45 of these solutes, including nutrients, trace elements, and toxic metals, exhibit fractal 1/f(α) scaling on time scales from hours to decades (α = 1.05 ± 0.15, mean ± SD). We show that this fractal scaling can arise through dispersion of random chemical inputs distributed across a catchment. These 1/f time series are non-self-averaging: monthly, yearly, or decadal averages are approximately as variable, one from the next, as individual measurements taken hours or days apart, defying naive statistical expectations. (By contrast, stream discharge itself is nonfractal, and self-averaging on time scales of months and longer.) In the solute time series, statistically significant trends arise much more frequently, on all time scales, than one would expect from conventional t statistics. However, these same trends are poor predictors of future trends-much poorer than one would expect from their calculated uncertainties. Our results illustrate how 1/f time series pose fundamental challenges to trend analysis and change detection in environmental systems.


Microbial eukaryote communities exhibit robust biogeographical patterns along a gradient of Patagonian and Antarctic lakes.
Microbial eukaryotes play important roles in aquatic ecosystem functioning. Unravelling their distribution patterns and biogeography provides important baseline information to infer the underlying mechanisms that regulate the biodiversity and complexity of ecosystems. We studied the distribution patterns and factors driving diversity gradients in microeukaryote communities (total, abundant, uncommon and rare community composition) along a latitudinal gradient of lakes distributed from Argentinean Patagonia to Maritime Antarctica using both denaturing gradient gel electrophoresis (DGGE) and high-throughput sequencing (Illumina HiSeq). DGGE and abundant Illumina operational taxonomic units (OTUs) showed both decreasing richness with latitude and significant differences between Patagonian and Antarctic lakes communities. In contrast, total richness did not change significantly across the latitudinal gradient, although evenness and diversity indices were significantly higher in Patagonian lakes. Beta-diversity was characterized by a high species turnover, influenced by both environmental and geographical descriptors, although this pattern faded in the rare community. Our results suggest the co-existence of a 'core biosphere' containing reduced number of abundant/dominant OTUs on which classical ecological rules apply, together with a much larger seedbank of rare OTUs driven by stochastic and reduced dispersal processes. These findings shed new light on the biogeographical patterns and forces structuring inland microeukaryote composition across broad spatial scales.


Pine rosin identified as a toxic cannabis extract adulterant.
Pine rosin (colophony) has been identified as a potentially new adulterant in cannabis oil. Its inhalation toxicity poses a significant health concern to users. For example, pine rosin fumes are released during soldering, and have been cited as a causative agent of occupational asthma. Symptoms also include desquamation of bronchial epithelium, which has also been observed in e-cigarette or vaping product used-associated lung injury (EVALI) patients. The sample analyzed herein was acquired from a cannabis industry source, also contains medium chain triglycerides and oleamide, the latter of which is a hypnotic that is commonly found in the synthetic marijuana product Spice, or K2. A combination of proton nuclear magnetic resonance (1H NMR) and high pressure liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESIMS) was used to unambiguously identify major pine rosin ingredients such as abietic and other resin acids. Comparison to commercial samples of pure pine rosin confirmed the assignment.


Sexual Dimorphism in the Age of Genomics: How, When, Where.
In mammals, sex chromosomes start to program autosomal gene expression and epigenetic patterns very soon after fertilization. Yet whether the resulting sex differences are perpetuated throughout development and how they connect to the sex-specific expression patterns in adult tissues is not known. There is a dearth of information on the timing and continuity of sex biases during development. It is also unclear whether sex-specific selection operates during embryogenesis. On the other hand, there is mounting evidence that all adult tissues exhibit sex-specific expression patterns, some of which are independent of hormonal influence and due to intrinsic regulatory effects of the sex chromosome constitution. There are many diseases with origins during embryogenesis that also exhibit sex biases. Epigenetics has provided us with viable mechanisms to explain how the genome stores the memory of developmental events. We propose that some of these marks can be traced back to the sex chromosomes, which interact with the autosomes and establish sex-specific epigenetic features soon after fertilization. Sex-biased epigenetic marks that linger after reprograming may reveal themselves at the transcriptional level at later developmental stages and possibly, throughout the lifespan. Detailed molecular information on the ontogeny of sex biases would also elucidate the sex-specific selective pressures operating on embryos and how compensatory mechanisms evolved to resolve sexual conflict.


Factors influencing individual variation in perceptual directional microphone benefit.
Large variations in perceptual directional microphone benefit, which far exceed the variation expected from physical performance measures of directional microphones, have been reported in the literature. The cause for the individual variation has not been systematically investigated. To determine the factors that are responsible for the individual variation in reported perceptual directional benefit. A correlational study. Physical performance measures of the directional microphones obtained after they had been fitted to individuals, cognitive abilities of individuals, and measurement errors were related to perceptual directional benefit scores. Fifty-nine hearing-impaired adults with varied degrees of hearing loss participated in the study. All participants were bilaterally fitted with a Motion behind-the-ear device (500 M, 501 SX, or 501 P) from Siemens according to the National Acoustic Laboratories' non-linear prescription, version two (NAL-NL2). Using the Bamford-Kowal-Bench (BKB) sentences, the perceptual directional benefit was obtained as the difference in speech reception threshold measured in babble noise (SRTn) with the devices in directional (fixed hypercardioid) and in omnidirectional mode. The SRTn measurements were repeated three times with each microphone mode. Physical performance measures of the directional microphone included the angle of the microphone ports to loudspeaker axis, the frequency range dominated by amplified sound, the in situ signal-to-noise ratio (SNR), and the in situ three-dimensional, articulation-index weighted directivity index (3D AI-DI). The cognitive tests included auditory selective attention, speed of processing, and working memory. Intraparticipant variation on the repeated SRTn's and the interparticipant variation on the average SRTn were used to determine the effect of measurement error. A multiple regression analysis was used to determine the effect of other factors. Measurement errors explained 52% of the variation in perceptual directional microphone benefit (95% confidence interval [CI]: 34-78%), while another 37% of variation was explained primarily by the physical performance of the directional microphones after they were fitted to individuals. The most contributing factor was the in situ 3D AI-DI measured across the low frequencies. Repeated SRTn measurements are needed to obtain a reliable indication of the perceptual directional benefit in an individual. Further, to obtain optimum benefit from directional microphones, the effectiveness of the microphones should be maximized across the low frequencies.


Citicoline and Memory Function in Healthy Older Adults: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.
Supplementation of citicoline (CDP-choline), a naturally occurring mononucleotide, has shown beneficial effects on memory function and behavior in populations with a wide range of impairments. However, few studies have investigated its effect in healthy older populations. The objective of this study was to investigate the effects of citicoline (Cognizin®), on memory in healthy elderly populations with age-associated memory impairment (AAMI). A total of 100 healthy men and women aged between 50 and 85 y with AAMI participated in this randomized, double-blind, placebo-controlled trial. Participants were randomized to receive placebo (n = 51) or citicoline (n = 49; 500 mg/d) for 12 wk. Memory function was assessed at baseline and end of the intervention (12 wk) using computerized tests (Cambridge Brain Sciences, Ontario, Canada). Safety measurements included adverse events query, body weight, blood pressure, and hematology and metabolic panel. Intent-to-treat analysis was conducted using ANCOVA for the primary and secondary outcome variables with Bonferroni correction for multiple comparisons. A total of 99 out of 100 participants completed the study in its entirety. After the 12-wk intervention, participants supplemented with citicoline showed significantly greater improvements in secondary outcomes of episodic memory (assessed by the Paired Associate test), compared with those on placebo (mean: 0.15 vs. 0.06, respectively, P = 0.0025). Composite memory (secondary outcome), calculated using the scores of 4 memory tests, also significantly improved to a greater extent following citicoline supplementation (mean: 3.78) compared with placebo (mean: 0.72, P = 0.0052). Dietary supplementation of citicoline for 12 wk improved overall memory performance, especially episodic memory, in healthy older males and females with AAMI. The findings suggest that regular consumption of citicoline may be safe and potentially beneficial against memory loss due to aging. This trial was registered at clinicaltrials.gov as NCT03369925.


The realization of a whole palette of colors in a green gap by monochromatic phosphor-converted light-emitting diodes.
A variety of efficient green, yellow, and amber monochromatic phosphor-converted light-emitting diodes (pc-LEDs) were fabricated by simply capping a long-wave pass filter (LWPF) on top of LED packing associated with each corresponding powder phosphor. In this paper, the luminous efficacy and color purity of two green, three yellow, and two amber pc-LEDs were reviewed by comparing the optical properties and current/temperature stability of each LWPF-capped pc-LED. The simple combination of LWPFs and phosphor materials in the pc-LEDs provide a simple means of addressing the low luminous efficacy problem of III-V monochromatic semiconductor LEDs in the various colors of the wavelength range between green and amber (known as the "green gap"). This technique also represents a simple approach to mitigate the sub-linearity problem of the efficacy versus the driving current occurring at a relatively low current in III-V green LEDs (known as "green droop") to the level of a blue LED. This nano-multilayered filter-capped pc-LED can open further research into developing new color-converting materials (such as powder phosphors, and/or quantum dots) to extend the color palette in the wavelength region of the "green gap" and to improve the efficacy and color purity of color pc-LEDs.


The mental health professional's concept of the normal adolescent.
This article presents empirical evidence, based on the Offer Self-Image Questionnaire, comparing the self-image of normal adolescents, psychiatrically disturbed adolescents, and juvenile delinquents, with adolescent self-image as seen by 62 mental health professionals. The latter group was asked to complete the test the way they believed a normal, mentally healthy adolescent would complete it. Similar data were gathered from graduate students in psychology. In seven of ten scales, the mental health professionals viewed the normal adolescent as significantly more disturbed than the normal adolescent views himself or herself. The professionals saw the normal adolescents as having more problems than were reported either by the psychiatrically disturbed or the delinquent adolescents. These findings are important in terms of psychodynamic theory of adolescence and diagnostic problems encountered in work with adolescents.


The blood-brain barrier and microvascular water exchange in Alzheimer's disease.
Alzheimer's disease (AD) is the most common form of dementia in the elderly. Although traditionally considered a disease of neurofibrillary tangles and amyloid plaques, structural and functional changes in the microvessels may contribute directly to the pathogenesis of the disease. Since vascular dysfunction often precedes cognitive impairment, understanding the role of the blood-brain barrier (BBB) in AD may be key to rational treatment of the disease. We propose that water regulation, a critical function of the BBB, is disturbed in AD and results in abnormal permeability and rates of water exchange across the vessel walls. In this paper, we describe some of the pathological events that may disturb microvascular water exchange in AD and examine the potential of a relatively new imaging technique, dynamic contrast-enhanced MRI, to quantify water exchange on a cellular level and thus serve as a probe of BBB integrity in AD.


Resource pulses, species interactions, and diversity maintenance in arid and semi-arid environments.
Arid environments are characterized by limited and variable rainfall that supplies resources in pulses. Resource pulsing is a special form of environmental variation, and the general theory of coexistence in variable environments suggests specific mechanisms by which rainfall variability might contribute to the maintenance of high species diversity in arid ecosystems. In this review, we discuss physiological, morphological, and life-history traits that facilitate plant survival and growth in strongly water-limited variable environments, outlining how species differences in these traits may promote diversity. Our analysis emphasizes that the variability of pulsed environments does not reduce the importance of species interactions in structuring communities, but instead provides axes of ecological differentiation between species that facilitate their coexistence. Pulses of rainfall also influence higher trophic levels and entire food webs. Better understanding of how rainfall affects the diversity, species composition, and dynamics of arid environments can contribute to solving environmental problems stemming from land use and global climate change.


Synthesis and applications of Rhodamine derivatives as fluorescent probes.
Rhodamine dyes are widely used as fluorescent probes owing to their high absorption coefficient and broad fluorescence in the visible region of electromagnetic spectrum, high fluorescence quantum yield and photostability. A great interest in the development of new synthetic procedures for preparation of Rhodamine derivatives has arisen in recent years because for most applications the probe must be covalently linked to another (bio)molecule or surface. In this critical review the strategies for modification of Rhodamine dyes and a discussion on the variety of applications of these new derivatives as fluorescent probes are given (108 references).


Coordinated function of murine cytomegalovirus genes completely inhibits CTL lysis.
Murine CMV (MCMV) encodes three viral genes that interfere with Ag presentation (VIPRs) to CD8 T cells, m04, m06, and m152. Because the functional impact of these genes during normal infection of C57BL/6 mice is surprisingly modest, we wanted to determine whether the VIPRs are equally effective against the entire spectrum of H-2(b)-restricted CD8 T cell epitopes. We also wanted to understand how the VIPRs interact at a functional level. To address these questions, we used a panel of MCMV mutants lacking each VIPR in all possible combinations, and CTL specific for 15 H-2(b)-restricted MCMV epitopes. Only expression of all three MCMV VIPRs completely inhibited killing by CTL specific for all 15 epitopes, but removal of any one VIPR enabled lysis by at least some CTL. The dominant interaction between the VIPRs was cooperation: m06 increased the inhibition of lysis achieved by either m152 or m04. However, for 1 of 15 epitopes m04 functionally antagonized m152. There was little differential impact of any of the VIPRs on K(b) vs D(b), but a surprising degree of differential impact of the three VIPRs for different epitopes. These epitope-specific differences did not correlate with functional avidity, or with timing of VIPR expression in relation to Ag expression in the virus replication cycle. Although questions remain about the molecular mechanism and in vivo role of these genes, we conclude that the coordinated function of MCMV's three VIPRs results in a powerful inhibition of lysis of infected cells by CD8 T cells.


Mapping the chemical chromatin reactivation landscape identifies BRD4-TAF1 cross-talk.
Bromodomain-containing proteins of the BET family recognize histone lysine acetylation and mediate transcriptional activation of target genes such as the MYC oncogene. Pharmacological inhibitors of BET domains promise therapeutic benefits in a variety of cancers. We performed a high-diversity chemical compound screen for agents capable of modulating BRD4-dependent heterochromatization of a generic reporter in human cells. In addition to known and new compounds targeting BRD4, we identified small molecules that mimic BRD4 inhibition without direct engagement. One such compound was a potent inhibitor of the second bromodomain of TAF1. Using this inhibitor, we discovered that TAF1 synergizes with BRD4 to control proliferation of cancer cells, making TAF1 an attractive epigenetic target in cancers driven by MYC.


Coordination of cortisol response to social evaluative threat with autonomic and inflammatory responses is moderated by stress appraisals and affect.
Recent approaches to stress regulation have emphasized coordination among multiple biological systems. This study builds on evidence that hypothalamic-pituitary-adrenal (HPA) axis activity should be considered in coordination with other stress-sensitive biological systems to characterize healthy responses. Healthy African-Americans (n=115) completed the Trier Social Stress Test, and biological responses were assessed through salivary cortisol, dehydroepiandrosterone-sulfate (DHEA-S), alpha amylase (sAA), and C-reactive protein (sCRP). Multilevel modeling demonstrated that cortisol responses typically aligned with changes in DHEA-S, sAA, and sCRP across the session. At the same time, the degree of cortisol coordination with sAA and sCRP varied by participants' subjective stress following the task; participants with higher secondary stress appraisals showed greater cortisol-sAA alignment, whereas those experiencing more negative affect showed greater cortisol-sCRP alignment. Results highlight the importance of a multisystem approach to stress and suggest that positive HPA axis coordination with the autonomic response, but not with the immune/inflammatory response, may be adaptive.


Improved nutrition knowledge and practice through intensive nutrition education: a study among caregivers of mildly wasted children on Nias Island, Indonesia.
Inappropriate nutrition knowledge and feeding practices of caregivers are among several important causes of persistent malnutrition problems in young children. Thus, it is essential to provide caregivers with the necessary knowledge to help them modify their feeding practices. To examine the effectiveness of two different nutrition education methods, weekly intensive nutrition education (INE) and monthly nonintensive nutrition education (NNE), designed for caregivers of mildly wasted children (weight-for-height z-score ≥ -1.5 to < -1) aged ≥ 6 to < 60 months on Nias Island, Indonesia. To assess the impact of the two different nutrition education approaches on nutrition knowledge and practice of caregivers with their children, respondents were assigned to receive either weekly INE (n=114) or monthly NNE (n=96). The knowledge and practice levels of the mothers in each group were assessed and compared using a pretested validated questionnaire at admission and after the intervention period. At admission, the knowledge and practice levels of caregivers in both groups were not statistically significantly different. After participating in the nutrition education program, the percentage of correct answers on nutrition knowledge and practice in the INE group was significantly higher than that in the NNE group. Significant improvement in knowledge and practice scores was observed in the INE group after the intervention (p < 0.001), whereas only a significant improvement in knowledge was found in the NNE group (p < .05). In comparison with NNE, the INE approach was significantly better in bringing about a positive change in knowledge and practice of caregivers of mildly wasted children in the study area.


Absence of sperm RNA elements correlates with idiopathic male infertility.
Semen parameters are typically used to diagnose male infertility and specify clinical interventions. In idiopathic infertile couples, an unknown male factor could be the cause of infertility even when the semen parameters are normal. Next-generation sequencing of spermatozoal RNAs can provide an objective measure of the paternal contribution and may help guide the care of these couples. We assessed spermatozoal RNAs from 96 couples presenting with idiopathic infertility and identified the final reproductive outcome and sperm RNA elements (SREs) reflective of fecundity status. The absence of required SREs reduced the probability of achieving live birth by timed intercourse or intrauterine insemination from 73 to 27%. However, the absence of these same SREs does not appear to be critical when using assisted reproductive technologies such as in vitro fertilization with or without intracytoplasmic sperm injection. About 30% of the idiopathic infertile couples presented an incomplete set of required SREs, suggesting a male component as the cause of their infertility. Conversely, analysis of couples that failed to achieve a live birth despite presenting with a complete set of SREs suggested that a female factor may have been involved, and this was confirmed by their diagnosis. The data in this study suggest that SRE analysis has the potential to predict the individual success rate of different fertility treatments and reduce the time to achieve live birth.


Early expression of the receptor for advanced glycation end products in a toxic model produced by 6-hydroxydopamine in the rat striatum.
The receptor for advanced glycation end products (RAGE) is commonly involved in different neurodegenerative and inflammatory disorders. The cellular signaling associated to RAGE activation may occur upon binding to different ligands. In this study we investigated whether the toxic model produced by 6-hydroxydopamine (6-OHDA) in rats comprises early noxious responses related to RAGE-mediated signaling cascades. In order to explore a possible interaction between 6-OHDA and RAGE, affinity parameters of RAGE with 6-OHDA were estimated by different means. The possible binding sites of 6-OHDA with the VC1 homodimer for both rat and human RAGE were also modeled. Our results show that the striatal infusion of 6-OHDA recruits RAGE upregulation, as evidenced by an early expression of the receptor. 6-OHDA was also found to bind the VC1 homodimer, although its affinity was moderate when compared to other ligands. This work contributes to the understanding of the role of RAGE activation for 6-OHDA-induced neurotoxicity.


Enhanced Detection of Community-Acquired Pneumonia Pathogens With the BioFire® Pneumonia FilmArray® Panel.
Although most observational studies identify viral or bacterial pathogens in 50% or less of patients hospitalized with community-acquired pneumonia (CAP), we previously demonstrated that a multi-test bundle (MTB) detected a potential pathogen in 73% of patients. This study compares detection rates for potential pathogens with the MTB versus the Biofire® Pneumonia FilmArray® panel (BPFA) multiplex PCR platform and presents an approach for integrating BPFA results as a foundation for subsequent antibiotic stewardship (AS) activities. Between January 2017 to March 2018, all patients admitted for CAP were enrolled. Patients were considered evaluable if all elements of the MTB and the BPFA were completed, and they met other a priori inclusion criteria. The primary endpoint was the percentage of potential pathogens detected using the MTB (8 viral and 6 bacterial targets) versus the BPFA (8 viral and 18 bacterial targets). Blood and sputum cultures were performed on all patients. Two or more procalcitonin (PCT) levels assisted clinical assessments as to whether detected bacteria were invading or colonizing. Of 585 enrolled patients, 274 were evaluable. A potential viral pathogen was detected in 40.5% with MTB versus 60.9% of patients with BPFA with an odds ratio (95% CI) of 9.00 (4.12 to 23.30) p<0.01. A potential bacterial pathogen was identified in 66.4% with the MTB vs 75.5% with the BPFA odds ratio (95% CI) of 2.09 (1.24 to 3.59), p 0.003). Low PCT levels helped identify detected bacteria as colonizers.


Abundance and short-term temporal variability of fecal microbiota in healthy dogs.
Temporal variations of intestinal microorganisms have been investigated in humans, but limited information is available for other animal species. The aim of the study was to evaluate the abundance and short-term temporal variability of fecal microbiota in dogs. Two fecal samples were collected (15 days apart) from six healthy dogs. The microbiota was evaluated using fluorescence in situ hybridization (FISH) and 454-pyrosequencing targeting the 16S rRNA and its gene. Pyrosequencing revealed 15 families comprising >80% of all microbiota, over time intraindividual coefficients of variation (%CV) ranged from 2% to 141% (median: 55%). In contrast, the interindividual %CV ranged from 62% to 230% (median: 145%). Relative proportions of Faecalibacterium (important for intestinal health) and Subdoligranulum were low (two dogs harbored 4-7% of Subdoligranulum, the remaining dogs had <1% of either genus). Conversely, FISH revealed that Faecalibacterium comprised a median of 5% of total counts (range: 0-8%, probe Fprau645). A novel FISH probe (Faecali 698) was tested that, compared with Fprau645, can detect in silico a similar percentage of Faecalibacterium but higher proportions of Subdoligranulum. This probe revealed a high percentage of Faecalibacterium-Subdoligranulum (median: 16% of total counts). Future studies should consider the observed variability and discrepancies in microbial abundance between FISH and 454-pyrosequencing.


Incidence of spondyloarthropathy in patients with Crohn's disease: a population-based study.
Spondyloarthritis (SpA) is an extraintestinal manifestation of inflammatory bowel disease with significant clinical effects, although the frequency is uncertain. We assessed the cumulative incidence and clinical spectrum of SpA in patients with Crohn's disease (CD) in a population-based cohort. The medical records of a population-based cohort of Olmsted County, Minnesota, residents diagnosed with CD between 1970 and 2004 were reviewed. Patients were followed longitudinally until migration, death, or December 31, 2010. We used the European Spondylarthropathy Study Group, Assessment of Spondyloarthritis international Society (ASAS) criteria and modified New York criteria to identify patients with SpA. The Kaplan-Meier method was used to estimate the cumulative incidence of SpA following diagnosis of CD. The cohort included 311 patients with CD (49.8% females; median age 29.9 yrs, range 8-89). Thirty-two patients developed SpA based on ASAS criteria. The cumulative incidence of SpA after CD diagnosis was 6.7% (95% CI 2.5%-6.7%) at 10 years, 13.9% (95% CI 8.7%-18.8%) at 20 years, and 18.6% (95% CI 11.0%-25.5%) at 30 years. The 10-year cumulative incidence of ankylosing spondylitis was 0, while both the 20-year and 30-year cumulative incidences were 0.5% (95% CI 0-1.6%). We have for the first time defined the actual cumulative incidence of SpA in CD using complete medical record information in a population-based cohort. The cumulative incidence of all forms of SpA increased to approximately 19% by 30 years from diagnosis of CD. Our results emphasize the importance of maintaining a high level of suspicion for SpA when following patients with CD.


Sexual dimorphism and the evolution of sex-biased gene expression in the brown alga ectocarpus.
Males and females often have marked phenotypic differences, and the expression of these dissimilarities invariably involves sex differences in gene expression. Sex-biased gene expression has been well characterized in animal species, where a high proportion of the genome may be differentially regulated in males and females during development. Male-biased genes tend to evolve more rapidly than female-biased genes, implying differences in the strength of the selective forces acting on the two sexes. Analyses of sex-biased gene expression have focused on organisms that exhibit separate sexes during the diploid phase of the life cycle (diploid sexual systems), but the genetic nature of the sexual system is expected to influence the evolutionary trajectories of sex-biased genes. We analyze here the patterns of sex-biased gene expression in Ectocarpus, a brown alga with haploid sex determination (dioicy) and a low level of phenotypic sexual dimorphism. In Ectocarpus, female-biased genes were found to be evolving as rapidly as male-biased genes. Moreover, genes expressed at fertility showed faster rates of evolution than genes expressed in immature gametophytes. Both male- and female-biased genes had a greater proportion of sites experiencing positive selection, suggesting that their accelerated evolution is at least partly driven by adaptive evolution. Gene duplication appears to have played a significant role in the generation of sex-biased genes in Ectocarpus, expanding previous models that propose this mechanism for the resolution of sexual antagonism in diploid systems. The patterns of sex-biased gene expression in Ectocarpus are consistent both with predicted characteristics of UV (haploid) sexual systems and with the distinctive aspects of this organism's reproductive biology.


Investigation of genotoxic effect of taxol plus radiation on mice bone marrow cells.
In this study, we investigated the genotoxic effect of taxol, radiation, or taxol plus radiation on highly proliferative normal tissue-bone marrow cells of Swiss albino mice. Swiss-albino mice, 3-4 months old, were used in this study. Taxol was administered bolus intravenously through the tail vein. Radiation was given by using a linear accelerator. There were four treatment categories, which had a total of 34 groups. Each group consisted of five animals. The first was the control category that had one group (n = 5). The second treatment category was taxol alone, which had three groups as per taxol dose alone (n = 15). The third treatment category was radiation alone, which had three groups as per the radiation dose (n = 15). The fourth treatment category was taxol plus radiation, which had 27 groups as per combined radiation dose plus taxol dose concentration and as per pre-treatment timing sequence of taxol before radiation (n = 135). Mice were sacrificed 24 h after taxol or radiation or combined administration using ether anesthesia. The cells were then dropped on two labeled slides, flamed, air dried, and stained in 7% Giemsa; 20-30 well-spread mitotic metaphases were analyzed for each animal; the cells with chromosome breaks, acentric fragments, and rearrangements were evaluated on x1,000 magnification with light microscope (Zeiss axioplan). The mitotic index was determined by counting the number of mitotic cells among 1,000 cells per animal. Differences between groups were evaluated with Student's t-test statistically. Taxol caused a dose-dependent increase in chromosomal aberrations (P = 0.027). Similarly, radiation caused a dose-dependent increase in chromosomal aberrations (P = 0.003) and decreased mitotic index (P = 0.002). In combination, there were a small enhancements at the 40 mg/kg taxol dose level and at 0.25 and 0.5 Gy radiation doses in the 48 h group. However, an increase in chromosomal aberrations was observed after 48 hours of taxol exposure when compared 12 or 24 h of taxol exposure (P = 0.001 and P = 0.019). These findings suggest that taxol at the high doses with low dose radiation caused radiosensitizing effect in bone marrow cells. Forty-eight-hour pretreatment of taxol exposure followed by radiation caused significant induction of chromosomal aberrations and a reduction of mitotic index when compared to other taxol timing sequence.


Developments in continuous therapy and maintenance treatment approaches for patients with newly diagnosed multiple myeloma.
The evolving paradigm of continuous therapy and maintenance treatment approaches in multiple myeloma (MM) offers prolonged disease control and improved outcomes compared to traditional fixed-duration approaches. Potential benefits of long-term strategies include sustained control of disease symptoms, as well as continued cytoreduction and clonal control, leading to unmeasurable residual disease and the possibility of transforming MM into a chronic or functionally curable condition. "Continuous therapy" commonly refers to administering a doublet or triplet regimen until disease progression, whereas maintenance approaches typically involve single-agent or doublet treatment following more intensive prior therapy with autologous stem cell transplant (ASCT) or doublet, triplet, or even quadruplet induction therapy. However, the requirements for agents and regimens within these contexts are similar: treatments must be tolerable for a prolonged period of time, should not be associated with cumulative or chronic toxicity, should not adversely affect patients' quality of life, should ideally be convenient with a minimal treatment burden for patients, and should not impact the feasibility or efficacy of subsequent treatment at relapse. Multiple agents have been and are being investigated as long-term options in the treatment of newly diagnosed MM (NDMM), including the immunomodulatory drugs lenalidomide and thalidomide, the proteasome inhibitors bortezomib, carfilzomib, and ixazomib, and the monoclonal antibodies daratumumab, elotuzumab, and isatuximab. Here we review the latest results with long-term therapy approaches in three different settings in NDMM: (1) maintenance treatment post ASCT; (2) continuous frontline therapy in nontransplant patients; (3) maintenance treatment post-frontline therapy in the nontransplant setting. We also discuss evidence from key phase 3 trials. Our review demonstrates how the paradigm of long-term treatment is increasingly well-established across NDMM treatment settings, potentially resulting in further improvements in patient outcomes, and highlights key clinical issues that will need to be addressed in order to provide optimal benefit.


Natural killer cells and malignant haemopathies: a model for the interaction of cancer with innate immunity.
Despite recent progress in the therapeutic approach of malignant haemopathies, their prognoses remain frequently poor. Immunotherapy offers an alternative of great interest in this context but defect or abnormal expression of human leukocyte antigens (HLA), frequently observed in cancer cells, limits its efficiency. Natural killer (NK) cells, which are able to kill target cells in a HLA-independent way, represent a novel tool in the treatment of haematological malignancies. Abnormal NK cytolytic function is observed in all the haematological malignancies studied, such as acute leukaemia, myelodysplastic syndromes or chronic myeloid/lymphoid leukaemia. Several mechanisms are involved in the alterations of NK cytotoxicity: decreased expression of activating receptors, increased expression of inhibitory receptors or defective expression of NK ligands on target cells. Further studies are needed to identify how each type of haematological malignancy escapes from the innate immune response. Attempts to increase the expression of activating receptors, to counteract inhibitory receptors expression, or to increase NK cell cytotoxic capacities could overcome tumour escape from innate immunity. These therapies are based on monoclonal antibodies or culture of NK cells in presence of cytokines or dendritic cells. Moreover, many novel drugs used in haematological malignancies [tyrosine kinase inhibitors, IMIDs(®), proteasome inhibitors, demethylating agents, histone deacetylase inhibitors (HDACis), histamine dihydrochloride] display interesting immunomodulatory properties that affect NK cells. These data suggest that combined modalities associating cytotoxic drugs with innate immunity modulators may represent a major breakthrough in tumour eradication.


Psychometric testing of the McGill Ingestive Skills Assessment.
The goal of this study was to determine the psychometric properties of the McGill Ingestive Skills Assessment. Interrater and intrarater reliability and score stability were tested using repeated administration of this test. The Functional Independence Measure and Modified Mini-Mental State Examination, as well as patient characteristics, were used to determine the validity of the assessment. One hundred and two persons with ingestive skill loss of neurologic origin were evaluated. Intraclass correlations for interrater, intrarater reliability and stability reached or surpassed 0.80 for most subscales. In validity testing, significant relationships were found between McGill Ingestive scores and Functional Independence Measure and Mini-Mental scores, as well as with patient characteristics. It is concluded that the McGill Ingestive Skills Assessment approaches or meets levels of reliability necessary for assessing patients and is valid for adults with neurogenic feeding difficulties residing in tertiary care facilities.


Genetic map of the calicivirus rabbit hemorrhagic disease virus as deduced from in vitro translation studies.
The 7.5-kb plus-stranded genomic RNA of rabbit hemorrhagic disease virus contains two open reading frames of 7 kb (ORF1) and 351 nucleotides (ORF2) that cover nearly 99% of the genome. The aim of the present study was to identify the proteins encoded in these open reading frames. To this end, a panel of region-specific antisera was generated by immunization of rabbits with bacterially expressed fusion proteins that encompass in total 95% of the ORF1 polyprotein and almost the complete ORF2 polypeptide. The antisera were used to analyze the in vitro translation products of purified virion RNA of rabbit hemorrhagic disease virus. Our studies show that the N-terminal half of the ORF1 polyprotein is proteolytically cleaved to yield three nonstructural proteins of 16, 23, and 37 kDa (p16, p23, and p37, respectively). In addition, a cleavage product of 41 kDa which is composed of VPg and a putative nonstructural protein of approximately 30 kDa was identified. Together with the results of previous studies which identified a trypsin-like cysteine protease (TCP) of 15 kDa, a putative RNA polymerase (pol) of 58 kDa, and the major capsid protein VP60, our data establish the following gene order in ORF1: NH2-p16-p23-p37 (helicase)-p30-VPg-TCP-pol-VP60-COOH. Immunoblot analyses showed that a minor structural protein of 10 kDa is encoded in ORF2. The data provide the first complete genetic map of a calicivirus. The map reveals a remarkable similarity between caliciviruses and picornaviruses with regard to the number and order of the genes that encode the nonstructural proteins.


Investigation of cream and ointment on antimicrobial activity of Mangifera indica extract.
Medicinal plants have curative properties due to the presence of various complex chemical substance of different composition, which are found as secondary plant metabolites in one or more parts of these plants. Mangifera indica Linn (MI L.) is a species of mango in the Anacardiaceae family. Phytoconstituents in the seed extracts may be responsible for the antimicrobial activity of the plant. The purpose of the study was to formulate and evaluate the antimicrobial herbal ointment and cream from extracts of the seeds of mango (MI L.) The formulated ointments containing oleaginous-based showed the best formulation compared to the emulsion water in oil type, the ointment and cream bases in different concentration 1%, 5% and 10%. The formulated ointment and cream of MI L. were subjected to evaluation of Uniformity of Weight, measurement of pH, viscosity, Spreadability, Acute skin irritation study, stability study and antimicrobial activity. Our study shows that MI has high potential as an antimicrobial agent when formulated as ointment and creams for topical use. Thus, the present study concludes that the formulated formulations of the MI are safe and efficient carriers, with potent antimicrobial activity.


Cone spacing and waveguide properties from cone directionality measurements.
Reflectometric techniques estimate the directionality of the retinal cones by measuring the distribution of light at the pupil plane of light reflected off the bleached retina. The waveguide-scattering model of Marcos et al. [J. Opt. Soc. Am. A 15, 2012 (1998)] predicts that the shape of this intensity distribution is determined by both the waveguide properties of the cone photoreceptors and the topography of the cone mosaic (cone spacing). We have performed two types of cone directionality measurement. In the first type, cone directionality estimates are obtained by measuring the spatial distribution of light returning from the retina with a single-entry pupil position (single-entry measurements). In the second type, estimates are obtained by measuring the total amount of light guided back through the pupil as a function of entry pupil position (multiple-entry measurements). As predicted by the model, single-entry measurements provide narrower distributions than the multiple-entry measurements, since the former are affected by both waveguides and scattering and the latter are affected primarily by waveguides. Measurements at different retinal eccentricities and at two different wavelengths are consistent with the model. We show that the broader multiple-entry measurements are not accounted for by cone disarray. Results of multiple-entry measurements are closer to results from measurements of the psychophysical Stiles-Crawford effect (although still narrower), and the variation with retinal eccentricity and wavelength is similar. By combining single- and multiple-entry measurements, we can estimate cone spacing. The estimates at 0- and 2-deg retinal eccentricities are in good agreement with published anatomical data.


Impact of Single Combination Inhaler versus Multiple Inhalers to Deliver the Same Medications for Patients with Asthma or COPD: A Systematic Literature Review.
With increasing choice of medications and devices for asthma and chronic obstructive pulmonary disease (COPD) treatment, comparative evidence may inform treatment decisions. This systematic literature review assessed clinical and economic evidence for using a single combination inhaler versus multiple inhalers to deliver the same medication for patients with asthma or COPD. In 2016, Embase, PubMed and the Cochrane library were searched for publications reporting studies in asthma or COPD comparing a single-inhaler combination medicine with multiple inhalers delivering the same medication. Publications included English-language articles published since 1996 and congress abstracts since 2013. Clinical, economic and adherence endpoints were assessed. Of 2031 abstracts screened, 18 randomized controlled trials (RCTs) in asthma and four in COPD, nine retrospective and three prospective observational studies in asthma, and four observational studies in COPD were identified. Of these, five retrospective and one prospective study in asthma, and two retrospective studies in COPD reported greater adherence with a single inhaler than multiple inhalers. Nine observational studies reported significantly (n=7) or numerically (n=2) higher rates of adherence with single- versus multiple-inhaler therapy. Economic analyses from retrospective and prospective studies showed that use of single-inhaler therapies was associated with reduced healthcare resource use (n=6) and was cost-effective (n=5) compared with multiple-inhaler therapies. Findings in 18 asthma RCTs and one prospective study reporting lung function, and six RCTs reporting exacerbation rates, showed no significant differences between a single inhaler and multiple inhalers. This was in contrast to several observational studies reporting reductions in healthcare resource use or exacerbation events with single-inhaler treatment, compared with multiple inhalers. Retrospective and prospective studies showed that single-inhaler use was associated with decreased healthcare resource utilization and improved cost-effectiveness compared with multiple inhalers. Lung function and exacerbation rates were mostly comparable in the RCTs, possibly due to study design.


Monitoring a widespread bacterial group: in situ detection of planctomycetes with 16S rRNA-targeted probes.
The group of planctomycetes represents a separate line of descent within the domain Bacteria. Two phylum-specific 16S rRNA-targeted oligonucleotide probes for planctomycetes have been designed, optimized for in situ hybridization and used in different habitats to detect members of the group in situ. The probes, named PLA46 and PLA886, are targeting all or nearly all members of the planctomycete line of descent. Planctomycetes could be detected in almost all samples examined, e.g. a brackish water lagoon, activated sludge, and other wastewater habitats. In situ probing revealed quite uniform morphology and spatial arrangement of the detected cells but profound differences in abundance ranging from less than 0.1% to several percentage of the total cells. Single coccoid cells with diameters between 1 and 2.5 microm were dominating in most samples with the exception of the lagoon, in which rosettes of pear-shaped cells were abundant. The planctomycetes showed generally no hybridization signals with the bacterial probe EUB338, which is in accordance with base changes in their 165 rRNA sequences. A discrete ultrastructure of planctomycete cells was suggested by double staining with rRNA-targeted probes and the DNA-binding dye 4',6-diamidino-2-phenylindole (DAPI). The probe-conferred fluorescence was distributed in a ring-shaped manner around a central DAPI spot. The two probes developed extend the existing set of group-specific rRNA-targeted probes and help to elucidate the basic composition of bacterial communities in a first step of differential analysis. In situ hybridization of environmental samples indicated widespread presence of planctomycetes in different ecosystems.


A bespoke smoking cessation service compared with treatment as usual for people with severe mental ill health: the SCIMITAR+ RCT.
There is a high prevalence of smoking among people with severe mental ill health (SMI). Helping people with SMI to quit smoking could improve their health and longevity, and reduce health inequalities. However, those with SMI are less likely to access and engage with routine smoking cessation services than the general population. To compare the clinical effectiveness and cost-effectiveness of a bespoke smoking cessation (BSC) intervention with usual stop smoking services for people with SMI. A pragmatic, two-arm, individually randomised controlled trial. Primary care and secondary care mental health services in England. Smokers aged ≥ 18 years with SMI who would like to cut down on or quit smoking. A BSC intervention delivered by mental health specialists trained to deliver evidence-supported smoking cessation interventions compared with usual care. The primary outcome was self-reported, CO-verified smoking cessation at 12 months. Smoking-related secondary outcomes were self-reported smoking cessation, the number of cigarettes smoked per day, the Fagerström Test for Nicotine Dependence and the Motivation to Quit questionnaire. Other secondary outcomes were Patient Health Questionnaire-9 items, Generalised Anxiety Disorder Assessment-7 items and 12-Item Short-Form Health Survey, to assess mental health and body mass index measured at 6 and 12 months post randomisation. The trial randomised 526 people (265 to the intervention group, 261 to the usual-care group) aged 19 to 72 years (mean 46 years). About 60% of participants were male. Participants smoked between 3 and 100 cigarettes per day (mean 25 cigarettes per day) at baseline. The intervention group had a higher rate of exhaled CO-verified smoking cessation at 6 and 12 months than the usual-care group [adjusted odds ratio (OR) 12 months: 1.6, 95% confidence interval (CI) 0.9 to 2.8; adjusted OR 6 months: 2.4, 95% CI 1.2 to 4.7]. This was not statistically significant at 12 months (p = 0.12) but was statistically significant at 6 months (p = 0.01). In total, 111 serious adverse events were reported (69 in the BSC group and 42 in the usual-care group); the majority were unplanned hospitalisations due to a deterioration in mental health (n = 98). The intervention is likely (57%) to be less costly but more effective than usual care; however, this result was not necessarily associated with participants' smoking status. Follow-up was not blind to treatment allocation. However, the primary outcome included a biochemically verified end point, less susceptible to observer biases. Some participants experienced difficulties in accessing nicotine replacement therapy because of changes in service provision. Efforts were made to help participants access nicotine replacement therapy, but this may have affected participants' quit attempt. People with SMI who received the intervention were more likely to have stopped smoking at 6 months. Although more people who received the intervention had stopped smoking at 12 months, this was not statistically significant. Further research is needed to establish how quitting can be sustained among people with SMI. Current Controlled Trials ISRCTN72955454. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 50. See the NIHR Journals Library website for further project information.


The Shp-1 and Shp-2, tyrosine phosphatases, are recruited on cell membrane in two distinct molecular complexes including Ret oncogenes.
The Shp-2 and Shp-1 non-transmembrane tyrosine phosphatases display different and even opposing effects on downstream signaling events initiated by Ret activation. By using rat pheochromocytoma-derived PC12 cells, here we studied the interactions of Shp-2 and Shp-1 with two activated mutants of Ret receptor, Ret(C634Y) and Ret(M918T). Each of these mutated receptors causes inheritance of distinct cancer syndromes, multiple endocrine neoplasia (MEN) type 2A and type 2B, respectively. We show that: (i) both Shp-1 and Shp-2 are associated to a multiprotein complex that includes Ret mutants; (ii) the Shp-1-Ret complexes are distinct from Shp-2-Ret complexes, and these complexes are differently distributed inside and outside lipid rafts; (iii) constitutively activated Ret proteins neither directly bind to nor are substrates of these phosphatases. Our results well support the evidence that Ret complexes within and outside rafts mediate distinct biological functions, and indicate that the presence of either Shps participates to determine such functions.


Short-term predictive ability of selected cardiovascular risk prediction models in a rural Bangladeshi population: a case-cohort study.
Prediction of absolute risk of cardiovascular diseases (CVDs) has important clinical and public health significance, but the predictive ability of the available tools has not yet been tested in the rural Bangladeshi population. The present study was undertaken to test the hypothesis that both laboratory-based (Framingham equation and WHO/ISH laboratory-based charts) and non-laboratory-based tools may be used to predict CVDs on a short-term basis. Data from a case-cohort study (52989 cohort and 439 sub-cohort participants), conducted on a rural Bangladeshi population, were analysed using modified Cox PH model with a maximum follow-up of 2.5 years. The outcome variable, coronary heart diseases (CHDs), was assessed in 2014 using electrocardiography, and it was used as a surrogate marker for CVDs in Bangladesh. The predictive power of the models was assessed by calculating C-statistics and generating ROC curves with other measures of diagnostic tests. All the models showed high negative prediction values (NPVs, 84 % to 92 %) and these did not differ between models or gender. The sensitivity of the models substantially changed based on the risk prediction thresholds (between 5-30 %); however, the NPVs and PPVs were relatively stable at various threshold levels. Hypertension and dyslipidaemia were significantly associated with CHD outcome in males and ABSI (a body shape index) in females. All models showed similar C-statistics (0.611-0.685, in both genders). Overall, the non-laboratory-based model showed better performance (0.685) in women but equal performance in men. Existing CVD risk prediction tools may identify future CHD cases with fairly good confidence on a short-term basis. The non-laboratory-based tool, using ABSI as a predictor, may provide better predictive accuracy among women.


Addition of Docetaxel to Oral Fluoropyrimidine Improves Efficacy in Patients With Stage III Gastric Cancer: Interim Analysis of JACCRO GC-07, a Randomized Controlled Trial.
S-1 is a standard postoperative adjuvant chemotherapy for patients with stage II or III gastric cancer in Asia. Neoadjuvant or perioperative strategies dominate in Western countries, and docetaxel has recently shown significant survival benefits when combined with other standard regimens in advanced cancer and perioperative settings. This randomized phase III study was designed to prove the superiority of postoperative S-1 plus docetaxel over S-1 alone for R0 resection of pathologic stage III gastric cancer. The sample size of 1,100 patients was necessary to detect a 7% increase in 3-year relapse-free survival as the primary end point (hazard ratio, 0.78; 2-sided α = .05; β = .2). The second interim analysis was conducted when the number of events reached 216 among 915 enrolled patients (median follow-up, 12.5 months). Analysis demonstrated the superiority of S-1 plus docetaxel (66%) to S-1 (50%) for 3-year relapse-free survival (hazard ratio, 0.632; 99.99% CI, 0.400 to 0.998; stratified log-rank test, P < .001), and enrollment was terminated as recommended by the independent data and safety monitoring committee. Incidences of grade 3 or greater adverse events, particularly neutropenia and leukopenia, were higher in the S-1 plus docetaxel group, but all events were manageable. Addition of docetaxel to S-1 is effective with few safety concerns in patients with stage III gastric cancer. The present findings may also be applicable in countries in which perioperative adjuvant chemotherapy or chemoradiation is not standard.


Distinguishing subcortical and cortical influences in visual attention. Subcortical attentional processing.
The purpose of the study was to investigate the role of subcortical processing in human visual attention. The midbrain contribution to visual attention is unclear. Although evidence exists for a subcortical attentional advantage in ocular motor tasks, such an advantage has not been shown in perceptual tasks. Because retinotectal projections arise predominantly from nasal retina (i.e., temporal hemifield), subcortical attention should be distributed asymmetrically for monocular viewing conditions with an advantage to the temporal hemifield. To test for a subcortical attentional effect, the authors compared the results of binocular and monocular viewing conditions using the split priming motion induction paradigm. In this perceptual attention paradigm, priming cues are presented to the left and right of fixation followed by an instantaneously presented horizontal bar. As a result of attention to the priming cues, motion is perceived within the bar as it appears to draw in from the two lateral cues toward a central collision point. Asymmetrically distributed attention results in an asymmetry in the perception of motion within the bar, and thus the perceived collision point will be shifted away from the center. In two separate studies, one with and one without control of eye movements, the authors found significant differences between the results for monocular and binocular presentation. When the stimulus configuration is presented to the left eye, the perceived collision point is shifted toward the center consistent with a subcortical attentional effect. However, presentation of the stimulus configuration to the right eye yields the same results as those of binocular presentation. This pattern of results can be explained by a separate and additive interaction between cortical and subcortical attentional effects in the visual field. Dominance of the left visual field for cortical attention and dominance of the temporal visual field for subcortical attention act together when the initial priming cue occurs in the temporal (left) visual field of the left eye. However, these influences compete when the same stimulus configuration is presented to the right eye, where cortical attention predominates in the left visual field and subcortical attention predominates in the temporal (right) visual field.


Health-related quality of life of African-American female breast cancer survivors, survivors of other cancers, and those without cancer.
The purpose of this study was to compare differences in health-related quality of life (HRQOL) between African-American female breast cancer survivors, African-American female survivors of other cancers, and African-American women with no history of cancer. Using data from the 2010 National Health Interview Survey (NHIS), the HRQOL of African-American women aged 35 years or older was compared by cancer status. Physical and mental health items from the Patient-Reported Outcomes Measurement Information System (PROMIS) global health scale were used to assess differences in HRQOL. For summary physical and mental health measures, no significant differences were found between breast cancer survivors and women with no history of cancer; survivors of other cancers reported poorer physical and mental health than did women with no history of cancer. Similar differences were found at the item level. When we examined the two African-American female cancer survivor groups, we found that cancer survivors whose cancer was being treated reported substantially poorer physical health and mental health than did those whose cancer was not being treated. Survivors who had private insurance and were cancer free reported better physical and mental health than did those who did not have private insurance and those who were not cancer free. Breast cancer survivors reported slightly better physical and mental health than did survivors of other cancers. Our findings highlight the need for public health agencies to adopt practices to improve the mental and physical health of African-American female survivors of cancer.


Geographic Differences in Endovascular Treatment and Retreatment of Cerebral Aneurysms.
Comparing outcomes between endovascular aneurysm coiling trials can be difficult because of heterogeneity in patients and end points. We sought to understand the impact of geography on aneurysm retreatment in patients enrolled in the Matrix and Platinum Science Trial. Post hoc analysis was performed on data from the Matrix and Platinum Science trial. Patients were stratified as either North American or international. Baseline patient demographics, comorbidities, aneurysm characteristics, procedural complications, and clinical and angiographic outcomes were compared. We evaluated 407 patients from 28 North American sites and 219 patients from 15 international sites. Patient demographics differed significantly between North American and international sites. Aneurysms were well occluded postprocedure more often at international than North American sites (P < .001). Stents were used significantly more often at North American sites (32.7% [133 of 407]) compared with international sites (10.0% [22 of 219]; P < .001). At 455 days, there was no difference in the proportion of patients alive and free of disability (P = .56) or with residual aneurysm filling (P = .10). Ruptured aneurysms were significantly more likely to have been retreated at North American sites within the first year (P < .001) and at 2 years (P < .001). Among all patients for whom the treating physician believed there to be Raymond 3 aneurysm filling at follow-up, absolute rates of retreatment at international and North American sites were similar by 2-year follow-up. Data from the Matrix and Platinum Science Trial demonstrate that aneurysm retreatment occurs with different frequency and at different times in different regions of the world. This trend has critical value when interpreting trials reporting short-term outcomes, especially when judgment-based metrics such as retreatment are primary end points that may or may not take place within the defined study follow-up period. Though these variations can be controlled for and balanced within a given randomized trial, such differences in practice patterns must be accounted for in any attempt to compare outcomes between different trials. Despite these differences, endovascular-treated intracranial aneurysms around the world have similar clinical outcomes.


Fetal growth retardation and lack of hypotaurine in ezrin knockout mice.
Ezrin is a membrane-associated cytoplasmic protein that serves to link cell-membrane proteins with the actin-based cytoskeleton, and also plays a role in regulation of the functional activities of some transmembrane proteins. It is expressed in placental trophoblasts. We hypothesized that placental ezrin is involved in the supply of nutrients from mother to fetus, thereby influencing fetal growth. The aim of this study was firstly to clarify the effect of ezrin on fetal growth and secondly to determine whether knockout of ezrin is associated with decreased concentrations of serum and placental nutrients. Ezrin knockout mice (Ez(-/-)) were confirmed to exhibit fetal growth retardation. Metabolome analysis of fetal serum and placental extract of ezrin knockout mice by means of capillary electrophoresis-time-of-flight mass spectrometry revealed a markedly decreased concentration of hypotaurine, a precursor of taurine. However, placental levels of cysteine and cysteine sulfinic acid (precursors of hypotaurine) and taurine were not affected. Lack of hypotaurine in Ez(-/-) mice was confirmed by liquid chromatography with tandem mass spectrometry. Administration of hypotaurine to heterogenous dams significantly decreased the placenta-to-maternal plasma ratio of hypotaurine in wild-type fetuses but only slightly decreased it in ezrin knockout fetuses, indicating that the uptake of hypotaurine from mother to placenta is saturable and that disruption of ezrin impairs the uptake of hypotaurine by placental trophoblasts. These results indicate that ezrin is required for uptake of hypotaurine from maternal serum by placental trophoblasts, and plays an important role in fetal growth.


Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation.
The retinoblastoma protein (pRb) inhibits progression through the cell cycle. Although pRb is phosphorylated when G1 cyclin-dependent kinases (Cdks) are active, the mechanisms underlying pRb regulation are unknown. In vitro phosphorylation by cyclin D1/Cdk4 leads to inactivation of pRb in a microinjection-based in vivo cell cycle assay. In contrast, phosphorylation of pRb by Cdk2 or Cdk3 in complexes with A- or E-type cyclins is not sufficient to inactivate pRb function in this assay, despite extensive phosphorylation and conversion to a slowly migrating "hyperphosphorylated form." The differential effects of phosphorylation on pRb function coincide with modification of distinct sets of sites. Serine 795 is phosphorylated efficiently by Cdk4, even in the absence of an intact LXCXE motif in cyclin D, but not by Cdk2 or Cdk3. Mutation of serine 795 to alanine prevents pRb inactivation by Cdk4 phosphorylation in the microinjection assay. This study identifies a residue whose phosphorylation is critical for inactivation of pRb-mediated growth suppression, and it indicates that hyperphosphorylation and inactivation of pRb are not necessarily synonymous.


Fiber fractions, multielemental and isotopic composition of a tropical C4 grass grown under elevated atmospheric carbon dioxide.
Brazil has the largest commercial herd of ruminants with approximately 211 million head, representing 15% of world's beef production, in an area of 170 million hectares of grasslands, mostly cultivated with Brachiaria spp. Although nutrient reduction due to increased atmospheric carbon dioxide (CO2) concentration has already been verified in important crops, studies evaluating its effects on fiber fractions and elemental composition of this grass genus are still scarce. Therefore, a better understanding of the effects of elevated CO2 on forage quality can elucidate the interaction between forage and livestock production and possible adaptations for a climate change scenario. The objective of this study was to evaluate the effects of contrasting atmospheric CO2 concentrations on biomass production, morphological characteristics, fiber fractions, and elemental composition of Brachiaria decumbens (cv. Basilisk). A total of 12 octagonal rings with 10 m diameter were distributed in a seven-ha coffee plantation and inside each of them, two plots of 0.25 m2 were seeded with B. decumbens (cv. Basilisk) in a free air carbon dioxide enrichment facility. Six rings were kept under natural conditions (≈390 μmol mol-1 CO2; Control) and other six under pure CO2 flux to achieve a higher concentration (≈550 μmol mol-1 CO2; Elevated CO2). After 30 months under contrasting atmospheric CO2 concentration, grass samples were collected, and then splitted into two portions: in the first, whole forage was kept intact and in the second portion, the leaf, true stem, inflorescence and senescence fractions were manually separated to determine their proportions (%). All samples were then analyzed to determine the fiber fractions (NDF, hemicellulose, ADF, cellulose, and Lignin), carbon (C), nitrogen (N), potassium (K), calcium (Ca), sulfur (S), phosphorus (P), iron (Fe), and manganese (Mn) contents and N isotopic composition. Elevated atmospheric CO2 concentration did not influence biomass productivity, average height, leaf, stem, senescence and inflorescence proportions, and fiber fractions (p > 0.05). Calcium content of the leaf and senescence portion of B. decumbens were reduced under elevated atmospheric CO2 (p < 0.05). Despite no effect on total C and N (p > 0.05), lower C:N ratio was observed in the whole forage grown under elevated CO2 (p < 0.05). The isotopic composition was also affected by elevated CO2, with higher values of δ15N in the leaf and stem portions of B. decumbens (p < 0.05). Productivity and fiber fractions of B. decumbens were not influenced by CO2 enrichment. However, elevated CO2 resulted in decreased forage Ca content which could affect livestock production under a climate change scenario.


Presynaptically localized cyclic GMP-dependent protein kinase 1 is a key determinant of spinal synaptic potentiation and pain hypersensitivity.
Synaptic long-term potentiation (LTP) at spinal neurons directly communicating pain-specific inputs from the periphery to the brain has been proposed to serve as a trigger for pain hypersensitivity in pathological states. Previous studies have functionally implicated the NMDA receptor-NO pathway and the downstream second messenger, cGMP, in these processes. Because cGMP can broadly influence diverse ion-channels, kinases, and phosphodiesterases, pre- as well as post-synaptically, the precise identity of cGMP targets mediating spinal LTP, their mechanisms of action, and their locus in the spinal circuitry are still unclear. Here, we found that Protein Kinase G1 (PKG-I) localized presynaptically in nociceptor terminals plays an essential role in the expression of spinal LTP. Using the Cre-lox P system, we generated nociceptor-specific knockout mice lacking PKG-I specifically in presynaptic terminals of nociceptors in the spinal cord, but not in post-synaptic neurons or elsewhere (SNS-PKG-I(-/-) mice). Patch clamp recordings showed that activity-induced LTP at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey (PAG) was completely abolished in SNS-PKG-I(-/-) mice, although basal synaptic transmission was not affected. Analyses of synaptic failure rates and paired-pulse ratios indicated a role for presynaptic PKG-I in regulating the probability of neurotransmitter release. Inositol 1,4,5-triphosphate receptor 1 and myosin light chain kinase were recruited as key phosphorylation targets of presynaptic PKG-I in nociceptive neurons. Finally, behavioural analyses in vivo showed marked defects in SNS-PKG-I(-/-) mice in several models of activity-induced nociceptive hypersensitivity, and pharmacological studies identified a clear contribution of PKG-I expressed in spinal terminals of nociceptors. Our results thus indicate that presynaptic mechanisms involving an increase in release probability from nociceptors are operational in the expression of synaptic LTP on spinal-PAG projection neurons and that PKG-I localized in presynaptic nociceptor terminals plays an essential role in this process to regulate pain sensitivity.


The potential and limitations of opportunistic screening: data from a computer simulation of a general practice screening programme.
Given the continuing emphasis on preventive medicine in general practice, there is considerable interest in the relative effectiveness of different ways of inviting patients to attend for screening. Recently, opportunistic methods have been advocated as being particularly useful but these methods often fail to reach a high proportion of the target population. Many patients do not consult and when they do they are not always invited to attend for screening. In this study a computer simulation model has been used to examine the effects of these variables in more detail. The notes of a random sample of 190 patients (97 women, 93 men) aged 30-50 years, registered with one general practitioner, were used to provide data for the model. The simulation model showed that increasing the number of screening appointments available each week has only a small effect on screening rates and that a ceiling is reached when 25 appointments per 1000 patients are available. In contrast, increasing the proportion of eligible consulting patients who are invited has a substantial effect such that it could take nearly 12 years to screen 90% of a target population if only one out of every four patients were invited compared with under four years if three out of every four patients were invited. The results suggest therefore that opportunistic screening methods are unlikely to achieve desired screening rates within acceptable time limits. It is argued that to achieve target levels of screening, practices will need to combine opportunistic methods with more formal methods of invitation.


Effects of amphetamine on carrier-mediated and electrically stimulated dopamine release in slices of rat caudate putamen and nucleus accumbens.
The effects of (+)-amphetamine on carrier-mediated and electrically stimulated dopamine release were investigated using fast cyclic voltammetry in rat brain slices incorporating the nucleus accumbens, and in the caudate putamen. In the caudate putamen, dopamine release either increased with increasing frequency of local electrical stimulation (hot spots) or did not increase significantly (cold spots); dopamine release increased with increasing frequency of electrical stimulation in the nucleus accumbens. Local pressure application of (+)-amphetamine from a micropipette caused dopamine efflux at all sites examined, and this was not affected by sulpiride, indicating that efflux of dopamine caused by (+)-amphetamine is not regulated by dopamine D2 autoreceptors. (+)-Amphetamine reduced single-pulse electrically stimulated dopamine release at all sites; sulpiride reversed this decrease, indicating that endogenous dopamine released by (+)-amphetamine activates dopamine D2 autoreceptors. In nucleus accumbens and hot spots, (+)-amphetamine did not affect 20-pulse 50-Hz-stimulated dopamine release, whereas in cold spots it potentiated 20-pulse 50-Hz-stimulated dopamine release. We conclude that (+)-amphetamine modifies electrically stimulated dopamine release by uptake inhibition or by indirect activation of D2 autoreceptors; the precise mechanism is determined by site and duration of electrical stimulation.


Transdermal hormone therapy and the risk of stroke and venous thrombosis.
Recent case-control and cohort studies have indicated that the transdermal administration of postmenopausal estrogen therapy is not associated with an increased risk of cardiovascular complications, specifically stroke and venous thrombosis. These studies have prompted the clinical promotion of transdermal treatment as 'safer'. There are reasons, however, to be cautious regarding postmenopausal transdermal hormone therapy, especially in regard to stroke. Previous reports linking postmenopausal estrogen therapy and the risk of stroke have not yielded consistent results, finding it difficult to adjust for all confounding factors, including compliance with treatment. Age of the population studies may be a critical issue. Notably, the risk of stroke with oral estrogen was not increased in the Women's Health Initiative when women with prior cardiovascular disease or those older than 60 years were excluded. There does appear to be a dose-response relationship with stroke, similar to that observed with estrogen-progestin contraceptives, and this may be a problem when studying standard doses of transdermal treatment, in that many women receiving transdermal estrogen display lower estrogen blood levels when compared with oral treatment. Clinicians should administer low doses of estrogen to women with risk factors for stroke, and the transdermal route of administration is indicated for women at high risk for venous thrombosis and for older postmenopausal women, especially for women with stroke risk factors. In a recent study, Renoux and colleagues from McGill University in Montreal performed a nested case-control study deriving the data from a cohort of women in the UK General Practice Research Database (GPRD). Current use of oral and transdermal hormone therapy, based on recorded prescriptions, was compared to no use in 15 710 cases and 59 958 controls. The adjusted rate ratio (RR) for stroke for current use of transdermal estrogens, with or without a progestin, was not increased (RR 0.95; 95% confidence interval (CI) 0.75-1.20) compared with a significant increase associated with oral estrogen, with or without a progestin (RR 1.28; 95% CI 1.15-1.42). This would amount to an attributal risk of 0.8 additional strokes per 1000 women per year. There was an indication of a dose-response relationship; a significant increase in risk was observed with transdermal estrogen doses greater than 50 microg. The case-control study by Renoux and colleagues is the first major analysis to compare transdermal and oral hormone therapy and conclude that, compared with an increased risk of stroke with oral therapy, there was no increased risk with transdermal treatment at a dose of 50 microg or less. This report is about as strong an observational study as can be achieved. Large numbers of cases (15 710) and controls (59 958) were available for analysis using the well-known UK GPRD. The use of this computerized database precludes selection bias by the investigators and recall bias by the women in the study. The results support the growing conventional wisdom that transdermal therapy at standard doses is free of the cardiovascular risks associated with oral therapy.


Using Elicited Choice Probabilities in Hypothetical Elections to Study Decisions to Vote.
This paper demonstrates the feasibility and usefulness of survey research asking respondents to report voting probabilities in hypothetical election scenarios. Posing scenarios enriches the data available for studies of voting decisions, as a researcher can pose many more and varied scenarios than the elections that persons actually face. Multiple scenarios were presented to over 4,000 participants in the American Life Panel (ALP). Each described a hypothetical presidential election, giving characteristics measuring candidate preference, closeness of the election, and the time cost of voting. Persons were asked the probability that they would vote in this election and were willing and able to respond. We analyzed the data through direct study of the variation of voting probabilities with election characteristics and through estimation of a random utility model of voting. Voting time and election closeness were notable determinants of decisions to vote, but not candidate preference. Most findings were corroborated through estimation of a model fit to ALP data on respondents' actual voting behavior in the 2012 election.


Investigation of peripheral photoplethysmographic morphology changes induced during a hand-elevation study.
A hand-elevation study was carried out in the laboratory in order to alter peripheral blood flow with the aim of increasing understanding of factors affecting the morphology of peripheral photoplethysmographic signals. Photoplethysmographic (PPG) signals were recorded from twenty healthy volunteer subjects during a hand-elevation study in which the right hand was raised and lowered relative to heart level, while the left hand remained static. Red and infrared (IR) PPG signals were obtained from the right and left index fingers using a custom-made PPG processing system. PPG features were identified using a feature-detection algorithm based on the first derivative of the PPG signal. The systolic PPG amplitude, the reflection index, crest time, pulse width at half height, and delta T were calculated from 20 s IR PPG signals from three positions of the right hand with respect to heart level (-50, 0, +50 cm) in 19 volunteers. PPG features were found to change with hand elevation. On lowering the hand to 50 cm below heart level, ac systolic PPG amplitudes from the finger decreased by 68.32 %, while raising the arm increased the systolic amplitude by 69.99 %. These changes in amplitude were attributed to changes in hydrostatic pressure and the veno-arterial reflex. Other morphological variables, such as crest time, were found to be statistically significantly different across hand positions, indicating increased vascular resistance on arm elevation than on dependency. It was hypothesized that these morphological PPG changes were influenced by changes in downstream venous resistance, rather than arterial, or arteriolar, resistance. Changes in hand position relative to heart level can significantly affect the morphology of the peripheral ac PPG waveform. These alterations are due to a combination of physical effects and physiological responses to changes in hand position, which alter vascular resistance. Care should be taken when interpreting morphological data derived from PPG signals and methods should be standardized to take these effects into account.


A DNA sequence-based study of the Schistosoma indicum (Trematoda: Digenea) group: population phylogeny, taxonomy and historical biogeography.
Partial (DNA) sequences were collected for 2 mitochondrial loci (Srrna and Lrrna, the rrnS and rrnL rRNA genes respectively) for Schistosoma indicum group species from 4 Southeast Asian countries. The samples included 7 populations, 4 of which were previously unstudied. In 11 cases the combination of locus and population was new. The aim of the study was to provide a phylogeny based on new independent data and multiple populations (earlier studies had mostly used a common set of field samples or laboratory lines) and to examine interrelationships and phylogeography within this species group. Paraphyly of the S. indicum group was confirmed, as was the basal position of Schistosoma incognitum in the Schistosoma phylogeny. Southeast Asian Schistosoma spindale and S. incognitum populations were shown to fall into their respective con-specific cohesive groupings. Estimated divergence times for these taxa were shown to be related to Pleistocene changes in sea level and the radiation of definitive host groups. A revised phylogeographical model is proposed in the light of these findings.


Variation in the biomolecular interactions of nickel(II) hydrazone complexes upon tuning the hydrazide fragment.
Three new bivalent nickel hydrazone complexes have been synthesised from the reactions of [NiCl(2)(PPh(3))(2)] with H(2)L {L = dianion of the hydrazones derived from the condensation of o-hydroxynaphthaldehyde with furoic acid hydrazide (H(2)L(1)) (1)/thiophene-2-acid hydrazide (H(2)L(2)) (2)/isonicotinic acid hydrazide (H(2)L(3)) (3)} and formulated as [Ni(L(1))(PPh(3))] (4), [Ni(L(2))(PPh(3))] (5) and [Ni(L(3))(PPh(3))] (6). Structural characterization of these compounds 4-6 were accomplished by using various physico-chemical techniques. Single crystal X-ray diffraction data of complexes 4 and 5 proved their distorted square planar geometry. In order to ascertain the potential of the above synthesised compounds towards biomolecular interactions, additional experiments involving interaction with calf thymus DNA (CT DNA) and bovine serum albumin (BSA) were carried out. All the ligands and corresponding nickel(ii) chelates have been screened for their scavenging effect towards O(2)(-), OH and NO radicals. The efficiency of complexes 4-6 to arrest the growth of HeLa, HepG-2 and A431 tumour cell lines has been studied along with the cell viability test against the non-cancerous NIH 3T3 cells under in vitro conditions.


National and subnational size estimation of female sex workers in Ghana 2020: Comparing 3-source capture-recapture with other approaches.
Key Population size estimation (PSE) is instrumental for HIV/STI preventive, treatment and care services planning, implementation and delivery. The objective was to estimate the overall population of female sex workers (FSW) in all the 16 regions of Ghana using different PSE methods. Mapping of venues and complete enumeration of seaters was conducted at the formative stage prior to the bio-behavioral survey (BBS). Three PSE methods were used to derive the size estimates of FSW in the 16 regions. These include: Capture-recapture (CRC), service multiplier and three-source capture recapture (3SCRC) methods. The final choice of the estimation method used to estimate the roamer population was 3SCRC. This method was chosen because of its perfect record-linkage-hierarchic combination of three names that minimizes overmatching as well as the addition of an interaction term in the model which corrects for the dependencies in CRC. The total population size estimate of the female sex workers in the country obtained for roamers using capture re-capture was 41,746 (95% CI: 41,488-41,932). Using the service multiplier, the total population for both the roamers and seaters was 41,153 (95% CI: 37,242-45,984). The 3-source capture re-capture yielded 55,686 roamers FSW (95% CI: 47,686-63,686). The seater population was 4,363 FSW based on census/complete enumeration. The total population size estimate of FSW (seaters and roamers) in Ghana was 60,049 when 3SCRC and census were added. This represents about 0.76% of all estimated adult females aged 15-49yrs in Ghana. We report population size estimates (PSE) for FSW in Ghana. These estimates are the results of 3SCRC. These findings provide a valid and reliable source of information that should be referenced by government officials and policymakers to plan, implement and provide HIV/STI preventive, treatment, and care services for FSW in Ghana.


Exploring the Protein Folding Pathway with High-Pressure NMR: Steady-State and Kinetics Studies.
Defining the physical-chemical determinants of protein folding and stability, under normal and pathological conditions has constituted a major subfield in biophysical chemistry for over 50 years. Although a great deal of progress has been made in recent years towards this goal, a number of important questions remain. These include characterizing the structural, thermodynamic and dynamic properties of the barriers between conformational states on the protein energy landscape, understanding the sequence dependence of folding cooperativity, defining more clearly the role of solvation in controlling protein stability and dynamics and probing the high energy thermodynamic states in the native state basin and their role in misfolding and aggregation. Fundamental to the elucidation of these questions is a complete thermodynamic parameterization of protein folding determinants. In this chapter, we describe the use of high-pressure coupled to Nuclear Magnetic Resonance (NMR) spectroscopy to reveal unprecedented details on the folding energy landscape of proteins.


Non-ST-Elevation Myocardial Infarction with Non-significant Coronary Artery Disease as a Symptom of Occult or New Malignancy.
Malignancy is a known risk factor for venous thromboembolism; however, the association with arterial thromboembolic events remains unclear. To examine the association between non-ST-elevation myocardial infarction (NSTEMI) and non-significant coronary artery disease (CAD) and the presence of new or occult malignancy. An observational cohort, single-center study was performed 2010-2015. Adult patients with NSTEMI, who underwent coronary angiography and had no significant coronary lesion, were included. Using propensity score matching, we created a 2:1 matched control group of adults with NSTEMI, and significant coronary artery disease. Risk factors for new or occult malignancy were assessed using multivariate backward stepwise logistic regression analysis. The primary outcome was new or occult malignancy, defined as any malignancy diagnosed in the 3 months prior and 6 months following the myocardial infarction (MI). During the study period, 174 patients who presented with MI with non-obstructive coronary arteries were identified. The matched control group included 348 patients. There was no significant difference in the group demographics, past medical history, or clinical presentation. The incidence of new or occult malignancy in the study group was significantly higher (7/174, 4% vs. 3/348, 0.9%, P = 0.019). NSTEMI with non-significant CAD was an independent risk factor for occult malignancy (odds ratio [OR] 4.6, 95% confidence interval [95%CI] 1.1-18.7). Other risk factors included active smoking (OR 11.2, 95%CI 2.5-49.1) and age (OR 1.1, 95%CI 1.03-1.17). NSTEMI with non-significant CAD may be a presenting or early marker of malignancy and warrants further investigation.


Gambian cultural preferences in the use of insecticide-impregnated bed nets.
In field trials of permethrin-treated bed nets in a large Mandinka village, 95% of people were already sleeping under locally-made nets. They lasted about 6 years and cost about US$9.00 ($1.50 per year). Two permethrin dips per year added a further $0.60 per year (1985 prices). Non-immune children slept in beds shared with adults, and people wanted nets for many reasons, not just malaria protection. Fifty-eight per cent of people preferred opaque sheeting to open netting; sheeting gave more privacy, lasted longer, gave better protection from very small insects, dust, rats, etc. White was the colour preferred by 90% of interviewees. Comparing Mandinka with Wolof and Fula, there were ethnic differences in net owning and the proportion of children sleeping in beds with a mattress.


[Who is who in Brazilian environmental health? Identification and characterization of academic groups and civil society organizations].
In this paper we present the results of the first phase of the project Who is Who in Brazilian Environmental Health. The aim of this project is to identify and characterize the Academic Groups and Civil Society Organizations acting on the field of environmental health that are able to contribute both to the strengthening of its technical and scientific basis, and to the dialogue with organized civil society. The identification took place through the data source available at CNPq (Research Groups Directory), ABONG (Brazilian Association of Non-Governmental Organizations), FBOMS (Brazilian Forum of NGOs and Social Movements for Environment and Sustainable Development) and RBJA (Brazilian Network for Environmental Justice). The results were presented and discussed based on time evolution, geographic distribution and areas of research and action. Final considerations point to the great potential for dialogue between experts and non experts, governmental and non-governmental, in order to create the foundation for a extended peer community capable of combining policies, knowledge, technologies and actions, seeking the comprehension and search of solutions to the establishment of health as a prerequisite and X a result of well being and full life.


Long-term stability of return to work after a workplace-oriented intervention for patients on sick leave for burnout.
The period from the mid-1990s to the mid-2000s saw a rapid increase in long-term sick leave in Sweden, primarily due to mental illness and often related to job burnout. This led to an urge for effective treatment programs that could prevent the often long sick leaves. In 2010 we presented a newly developed work-place intervention method, showing that 89% of the intervention group had returned to work at a 1.5 year follow-up, compared to 73% of the control group. The main aim of this study was to assess the long-term stability of these promising results. Sick leave registry data from the Regional Social Insurance Office were analyzed for an additional year (50 weeks) beyond the original 1.5 year period (80 weeks). Data from 68 matched pairs of intervention participants (IP) and controls were available. The proportions of participants being on full-time sick leave versus having returned to work to any extent were computed for every 10th week. Generalized estimating equations were used with GROUP (IP versus controls) as between-subjects factor, WEEKS and AGE as covariates, and return-to-work (RTW) as dependent variable. Significant differences (Wald χ2 with α ≤ .05) was followed up with polynomial contrasts. Individual relapses to higher degrees of sick leave (e.g. from 50% to 100%) and whether partial RTW led to later full-time RTW, were also analyzed. The omnibus test over all 130 weeks showed a GROUP*WEEKS interaction effect (p = .02), indicating differential group developments in RTW, though similarly high at week 130 in both groups with 82.4% of the IP and 77.9% of the controls having RTW (p = .22; χ2-test). A significant interaction with age led to separate analyses of the younger and older subgroups, indicating a stable pattern of superior RTW only among younger IP (week 130: 88.6% vs. 69.7%, p = .054; χ2-test). There was no group difference in relapses into increased degree of sick leave. Part-time sick leave did not predict a later stable full-time RTW. The previously reported improvement in RTW with the newly developed workplace-oriented intervention showed a long-term stability only among younger participants.