Implications of the Nagoya Protocol for genome resource banks composed of biomaterials from rare and endangered species.
The Nagoya Protocol on Access to Genetic Resources and the Fair and Equitable Sharing of Benefits Arising from their Utilisation is a multilateral legal instrument within the Convention on Biodiversity. It has now come into force, having been signed by 92 countries, 68 of which have ratified it, but notably these do not yet include the US, China, Canada and Russia. The overarching objective of the Nagoya Protocol is to prevent the unfair commercial exploitation of a country's biodiversity and it also protects traditional knowledge. Although the intentions seem reasonable and equitable, the provisions of the Nagoya Protocol will have major effects on the ability of researchers in both the commercial and non-commercial sectors to access genetic materials (which are widely defined and include almost every conceivable animal product, as well as whole animals) from around the world. It also places a heavy bureaucratic burden on researchers and their institutions, which must comply with an international standard and obtain an International Certificate of Compliance proving that all samples will be collected according to the terms of the Protocol. Herein we review of the unforeseen implications of the Nagoya Protocol in relation to biobanking and animal conservation.


Attitudes and perceptions of biomedical HIV prevention methods: voices from young men who have sex with men.
In the third decade of the HIV/AIDS epidemic in the United States, the prevalence rates of new HIV infections among young men who have sex with men (YMSM) continue to increase. As new and emerging HIV prevention methods are developed, it is important to understand the perceptions of this vulnerable population-as they may be an ideal target for these intervention methods. This pilot study provides an overview of YMSM of color's awareness and perceptions of pre-exposure prophylaxis (PrEP) and rectal microbicides (RM). A total of 6 focus groups were convened with 53 YMSM (23 Latino/Hispanic and 30 Black/African American). Findings indicate a lack of knowledge of biomedical interventions and high perceived acceptability. Concerns regarding PrEP included potential side effects, potential for misinterpretation of its use and cost. RMs were perceived to be more acceptable than PrEP, but the limited knowledge about their potential was emphasized by YMSM. Results are discussed in relation to the need for providers to continue to provide general health education about safe sexual practices. As PrEP and other biomedical interventions are introduced into community settings, caution should be taken with regards to determining the appropriate target user and sufficient education.


Marital status improves survival after orthotopic heart transplantation.
Large national registries lack information on social support, which is increasingly recognized as an important factor associated with improved outcomes after solid-organ transplantation. We examined our institutional database to identify social factors associated with improved outcomes after orthotopic heart transplantation (OHT). Outcomes of OHT patients from 1995 to 2010 at our institution were retrospectively reviewed. Clinical data and social information were extracted from medical records. Patients were stratified by marital status at time of OHT listing. The examined outcome was 5-year survival, excluding deaths within 60 days, modeled using the Kaplan-Meier method. A Cox multivariable hazard regression model was constructed to assess the effect on 5-year survival. Of 260 OHT recipients, 176 (68%) were men. Mean age was 49 ± 12 years and mean body mass index was 26.8 ± 5.0 kg/m(2). At the time of OHT listing, 175 patients (68%) were married. Before OHT, 25% were supported with ventricular assist devices and 17% were in the intensive care unit. Conditional Kaplan-Meier analysis revealed improved 5-year survival for married patients (84%) compared with unmarried patients (69%). After risk-adjustment with Cox analysis, being married improved 5-year survival (hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.23-0.97; p = 0.042) and also improved 1-year survival (p = 0.02). Other social support variables (children, grandchildren, living arrangements, education, race, employment status) were not associated with mortality. Married patients have improved survival after OHT compared with unmarried patients. Being married confers a powerful 5-year survival advantage after OHT. This benefit appears mediated by an improvement in survival during the first post-transplant year.


Changes in BOLD transients with visual stimuli across 1-44 Hz.
The dependency of positive BOLD (PBOLD) and post-stimulus undershoot (PSU) on the temporal frequency of visual stimulation was investigated using stimulation frequencies between 1 and 44 Hz. The PBOLD peak at 8 Hz in primary visual cortex was in line with previous neuroimaging studies. In addition to the 8 Hz peak, secondary peaks were observed for stimulation frequencies at 16 and 24 Hz. These additional local peaks were contrary to earlier fMRI studies which reported either a decrease or a plateau for frequencies above 8 Hz but in line with electrophysiological results obtained in animal local field potential (LFP) measurements and human steady-state visual evoked potential (SSVEP) recordings. Our results also indicate that the dependency of PSU amplitude on stimulus frequency deviates from that of PBOLD. Although their amplitudes were correlated within the 1-13 Hz range, they changed independently at stimulation frequencies between 13 and 44 Hz. The different dependency profiles of PBOLD and PSU to stimulation frequency points to different underlying neurovascular mechanisms responsible for the generation of these BOLD transients with regard to their relation to inhibitory and excitatory neuronal activity.


Interrater Reliability and Concurrent Validity of a New Rating Scale to Assess the Performance of Everyday Life Tasks in Dementia: The Core Elements Method.
Errorless learning (EL) is an instructional procedure involving error reduction during learning. Errorless learning is mostly examined by counting correctly executed task steps or by rating them using a Task Performance Scale (TPS). Here, we explore the validity and reliability of a new assessment procedure, the core elements method (CEM), which rates essential building blocks of activities rather than individual steps. Task performance was assessed in 35 patients with Alzheimer's dementia recruited from the Relearning methods on Daily Living task performance of persons with Dementia (REDALI-DEM) study using TPS and CEM independently. Results showed excellent interrater reliabilities for both measure methods (CEM: intraclass coefficient [ICC] = .85; TPS: ICC = .97). Also, both methods showed a high agreement (CEM: mean of measurement difference [MD] = -3.44, standard deviation [SD] = 14.72; TPS: MD = -0.41, SD = 7.89) and correlated highly (>.75). Based on these results, TPS and CEM are both valid for assessing task performance. However, since TPS is more complicated and time consuming, CEM may be the preferred method for future research projects.


Laparoscopic versus open liver resection for hepatocellular carcinoma: initial experience in Greece.
Liver resection represents the treatment of choice for a small proportion of patients with hepatocellular carcinoma (HCC), amenable to surgery. The remarkable evolution in surgical techniques during the last decades introduced laparoscopic hepatectomy in the operative management of HCC, even in the presence of liver cirrhosis. No comparative study on laparoscopic or open liver resection for HCC has been conducted in Greece yet. Patients undergoing liver resection for HCC by one senior hepatobiliary surgeon in our Institution during the period 11/2011-02/2016 were prospectively sampled and retrospectively analyzed for the purposes of this study. Statistical analysis encompassed Student's t-test, Fisher's exact test, the Kaplan-Meier method/log rank test and Cox proportional hazard regression analyses. Eleven patients underwent laparoscopic and 21 open liver resection, respectively. Statistical differences between the 2 groups were observed for tumor size (P=0.04), major resections (P=0.01), Pringle maneuver (P=0.008), intraoperative blood transfusion (P=0.03), and duration of operation (P=0.004). Resection margins, and tumor recurrence showed no statistical differences. Three-year postoperative survival after laparoscopic and open hepatectomy was 100%, and 67%, respectively (P=0.06). Regression analysis for patient survival revealed prognostic value for BCLC staging, γ-glutamyl transferase levels, laparoscopic hepatectomy, UICC stage, Dindo-Clavien classification, and hospital stay. Laparoscopic hepatectomy remained as independent predictor of survival by multivariate analysis (P=0.0142). Laparoscopic hepatectomy for HCC in chronic liver disease represents a safe and innovative treatment tool in the management of these patients under the presupposition of careful patient selection.


The use of infant seating devices in child care centers.
The purpose of this study was to compare the duration of time that infants in child care centers were placed in infant seating devices to the duration of time spent on the floor or being held by child care providers. Thirty-eight infants who were typically developing (mean age = 4.5 months) from eight child care centers were observed minute-by-minute for a consecutive 120 min, targeting the amount of time each infant spent in seating devices, on the floor, or being held by child care providers. The amount of time the infants spent in seating devices was significantly longer than on the floor (p= .0001) or being held by child care providers (p= .0001). All infants spent more time in seating devices than on the floor or being held by child care providers. Future research should explore seating device use in infants identified as at-risk or as having special needs, particularly how child care routines for these infants may influence seating device use, as well as the impact of this practice on these infants' motor development.


Effect of pregnancy as a risk factor for breast cancer in BRCA1/BRCA2 mutation carriers.
Early age at first birth and multiparity have been associated with a decrease in the risk of breast cancer in women in the general population. We examined whether this relationship is also present in women at high risk of breast cancer due to the presence of a mutation in either of the 2 breast cancer susceptibility genes, BRCA1 or BRCA2. We performed a matched case-control study of 1,260 pairs of women with known BRCA1 or BRCA2 mutations, recruited from North America, Europe and Israel. Women who had been diagnosed with breast cancer were matched with unaffected control subjects for year of birth, country of residence, and mutation (BRCA1 or BRCA2). Study subjects completed a questionnaire detailing their reproductive histories. Odds ratios (ORs) and 95% confidence intervals (CIs) were derived by conditional logistic regression. Among BRCA1 carriers, parity per se was not associated with the risk of breast cancer (OR for parous vs. nulliparous = 0.94; 95% CI = 0.75-1.19; p = 0.62). However, women with a BRCA1 mutation and 4 or more children had a 38% decrease in breast cancer risk compared to nulliparous women (OR = 0.62; 95% CI = 0.41-0.94). In contrast, among BRCA2 carriers, increasing parity was associated with an increased risk of breast cancer; women with 2 or more children were at approximately 1.5 times the risk of breast cancer as nulliparous women (OR = 1.53; 95% CI = 1.01-2.32; p = 0.05). Among women with BRCA2 mutations and who were younger than age 50, the (adjusted) risk of breast cancer increased by 17% with each additional birth (OR = 1.17; 95% CI = 1.01-1.36; p = 0.03). There was no significant increase in the risk of breast cancer among BRCA2 carriers older than 50 (OR for each additional birth = 0.97; 95% CI = 0.58-1.53; p = 0.92). In the 2-year period following a birth, the risk of breast cancer in a BRCA2 carrier was increased by 70% compared to nulliparous controls (OR = 1.70; 95% CI = 0.97-3.0). There was a much smaller increase in breast cancer risk among BRCA2 carriers whose last birth was 5 or more years in the past (OR = 1.24; 95% CI = 0.79-1.95). A modest reduction in risk of breast cancer was observed among BRCA1 carriers with 4 or more births. Among BRCA2 carriers, increasing parity was associated with a significant increase in the risk of breast cancer before age 50 and this increase was greatest in the 2-year period following a pregnancy.


Whole-Body Cryotherapy in Athletes: From Therapy to Stimulation. An Updated Review of the Literature.
Nowadays, whole-body cryotherapy is a medical physical treatment widely used in sports medicine. Recovery from injuries (e.g., trauma, overuse) and after-season recovery are the main purposes for application. However, the most recent studies confirmed the anti-inflammatory, anti-analgesic, and anti-oxidant effects of this therapy by highlighting the underlying physiological responses. In addition to its therapeutic effects, whole-body cryotherapy has been demonstrated to be a preventive strategy against the deleterious effects of exercise-induced inflammation and soreness. Novel findings have stressed the importance of fat mass on cooling effectiveness and of the starting fitness level on the final result. Exposure to the cryotherapy somehow mimics exercise, since it affects myokines expression in an exercise-like fashion, thus opening another possible window on the therapeutic strategies for metabolic diseases such as obesity and type 2 diabetes. From a biochemical point of view, whole-body cryotherapy not always induces appreciable modifications, but the final clinical output (in terms of pain, soreness, stress, and post-exercise recovery) is very often improved compared to either the starting condition or the untreated matched group. Also, the number and the frequency of sessions that should be applied in order to obtain the best therapeutic results have been deeply investigated in the last years. In this article, we reviewed the most recent literature, from 2010 until present, in order to give the most updated insight into this therapeutic strategy, whose rapidly increasing use is not always based on scientific assumptions and safety standards.


Major flavonoid constituents and short-term effects of Chun Mee tea in rats.
Chun Mee tea is a kind of green tea produced in China mainly for export purposes. Foam quantity is usually used as an index for evaluating the quality of Chun Mee tea. In the current study, we compared the concentrations of total saponin and flavonoids between foamy and low-foam Chun Mee tea. Our research confirmed that the total saponin and O-glycosylated flavonoid concentrations were related to the foam quantity of Chun Mee teas. We also studied the short-term safety effects of extract supplementation with foamy and low-foam Chun Mee tea in rats by routine blood tests and analysis of liver and kidney function, and blood lipids. Our results showed that both types of tea extract supplementations did not cause any observable adverse effects or impair either liver or kidney function. Additionally, this study confirmed the beneficial effects of Chun Mee tea extract supplementation on the decrease of total plasma cholesterol.


Alternative splicing and extensive RNA editing of human TPH2 transcripts.
Brain serotonin (5-HT) neurotransmission plays a key role in the regulation of mood and has been implicated in a variety of neuropsychiatric conditions. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of 5-HT. Recently, we discovered a second TPH isoform (TPH2) in vertebrates, including man, which is predominantly expressed in brain, while the previously known TPH isoform (TPH1) is primarly a non-neuronal enzyme. Overwhelming evidence now points to TPH2 as a candidate gene for 5-HT-related psychiatric disorders. To assess the role of TPH2 gene variability in the etiology of psychiatric diseases we performed cDNA sequence analysis of TPH2 transcripts from human post mortem amygdala samples obtained from individuals with psychiatric disorders (drug abuse, schizophrenia, suicide) and controls. Here we show that TPH2 exists in two alternatively spliced variants in the coding region, denoted TPH2a and TPH2b. Moreover, we found evidence that the pre-mRNAs of both splice variants are dynamically RNA-edited in a mutually exclusive manner. Kinetic studies with cell lines expressing recombinant TPH2 variants revealed a higher activity of the novel TPH2B protein compared with the previously known TPH2A, whereas RNA editing was shown to inhibit the enzymatic activity of both TPH2 splice variants. Therefore, our results strongly suggest a complex fine-tuning of central nervous system 5-HT biosynthesis by TPH2 alternative splicing and RNA editing. Finally, we present molecular and large-scale linkage data evidencing that deregulated alternative splicing and RNA editing is involved in the etiology of psychiatric diseases, such as suicidal behaviour.


Empirical evidence for unique hues?
Red, green, blue, yellow, and white have been distinguished from other hues as unique. We present results from two experiments that undermine existing behavioral evidence to separate the unique hues from other colors. In Experiment 1 we used hue scaling, which has often been used to support the existence of unique hues, but has never been attempted with a set of non-unique primaries. Subjects were assigned to one of two experimental conditions. In the "unique" condition, they rated the proportions of red, yellow, blue, and green that they perceived in each of a series of test stimuli. In the "intermediate" condition, they rated the proportions of teal, purple, orange, and lime. We found, surprisingly, that results from the two conditions were largely equivalent. In Experiment 2, we investigated the effect of instruction on subjects' settings of unique hues. We found that altering the color terms given in the instructions to include intermediate hues led to significant shifts in the hue that subjects identified as unique. The results of both experiments question subjects' abilities to identify certain hues as unique.


Relationship between the ability of sunscreens containing 2-ethylhexyl-4'-methoxycinnamate to protect against UVR-induced inflammation, depletion of epidermal Langerhans (Ia+) cells and suppression of alloactivating capacity of murine skin in vivo.
The UVB sunscreen 2-ethylhexyl-4'-methoxycinnamate was evaluated in hairless albino mouse skin for its ability to inhibit UVR-induced (i) oedema, (ii) epidermal Langerhans cell (Ia+) depletion and (iii) suppression of the alloactivating capacity of epidermal cells (mixed epidermal cell-lymphocyte reaction, MECLR). The sunscreen, prepared at 9% in ethanol or a cosmetic lotion, was applied prior to UVB/UVA irradiation. In some experiments there was a second application halfway through the irradiation. Single applications in both vehicles gave varying degrees of protection from oedema and Langerhans cell depletion but afforded no protection from suppression of MECLR. When the sunscreens were applied twice there was improved protection from oedema and Langerhans cell depletion and complete protection was afforded from suppression of MECLR. There was a clear linear relationship between Langerhans cell numbers and oedema with and without sunscreen application. The relationship between Langerhans cell numbers and MECLR was more complex. These data confirm published discrepancies between protection from oedema (a model for human erythema) and endpoints with immunological significance, but show that 2-ethylhexyl-4'-methoxycinnamate can afford complete immunoprotection, although protection is dependent on the application rate and vehicle.


Aging faces and aging perceivers: young and older adults are less sensitive to deviations from normality in older than in young adult faces.
Past studies examining the other-age effect, the phenomenon in which own-age faces are recognized more accurately than other-age faces, are limited in number and report inconsistent results. Here we examine whether the perceptual system is preferentially tuned to differences among young adult faces. In experiment 1 young (18-25 years) and older adult (63-87 years) participants were shown young and older face pairs in which one member of each pair was undistorted and the other had compressed or expanded features. Participants indicated which member of each pair was more normal and which was more expanded. Both age groups were more accurate when tested with young compared with older faces-but only when judging normality. In experiment 2 we tested a separate group of young adults on the same two tasks but with upright and inverted face pairs to examine the differential pattern of results between the normality and discrimination tasks. Inversion impaired performance on the normality task but not the discrimination task and eliminated the young adult advantage in the normality task. Collectively, these results suggest that the face processing system is optimized for young adult faces and that abundant experience with older faces later in life does not reverse this perceptual tuning.


Outgassed Water on Mars: Constraints from Melt Inclusions in SNC Meteorites.
The SNC (shergottite-nakhlite-chassignite) meteorites, thought to be igneous rocks from Mars, contain melt inclusions trapped at depth in early-formed crystals. Determination of the pre-eruptive water contents of SNC parental magmas from calculations of the solidification histories of these amphibole-bearing inclusions indicates that martian magmas commonly contained 1.4 percent water by weight. When combined with an estimate of the volume of igneous materials on Mars, this information suggests that the total amount of water outgassed since 3.9 billion years ago corresponds to global depths on the order of 200 meters. This value is significantly higher than previous geochemical estimates but lower than estimates based on erosion by floods. These results imply a wetter Mars interior than has been previously thought and support suggestions of significant outgassing before formation of a stable crust or heterogeneous accretion of a veneer of cometary matter.


Black Carbon Emissions from Associated Natural Gas Flaring.
Approximately 150 billion cubic meters (BCM) of natural gas is flared and vented in the world annually, emitting greenhouse gases and other pollutants with no energy benefit. About 7 BCM per year is flared in the United States, and half is from North Dakota alone. There are few emission measurements from associated gas flares and limited black carbon (BC) emission factors have been previously reported from the field. Emission plumes from 26 individual flares in the Bakken formation in North Dakota were sampled. Methane, carbon dioxide, and BC were measured simultaneously, allowing the calculation of BC mass emission factors using the carbon balance method. Particle optical absorption was measured using a three-wavelength particle soot absorption photometer (PSAP) and BC particle number and mass concentrations were measured with a single particle soot photometer. The BC emission factors varied over 2 orders of magnitude, with an average and uncertainty range of 0.14 ± 0.12 g/kg hydrocarbons in associated gas and a median of 0.07 g/kg which represents a lower bound on these measurements. An estimation of the BC emission factor derived from PSAP absorption provides an upper bound at 3.1 g/kg. These results are lower than previous estimations and laboratory measurements. The BC mass absorption cross section was 16 ± 12 m(2)/g BC at 530 nm. The average absorption Ångström exponent was 1.2 ± 0.8, suggesting that most of the light absorbing aerosol measured was black carbon and the contribution of light absorbing organic carbon was small.


Conformational changes induced by ATP-hydrolysis in an ABC transporter: a molecular dynamics study of the Sav1866 exporter.
ATP-Binding Cassette (ABC) transporters are ubiquitous membrane proteins that use energy from ATP binding or/and hydrolysis to actively transport allocrites across membranes. In this study, we identify ATP-hydrolysis induced conformational changes in a complete ABC exporter (Sav1866) from Staphylococcus aureaus, using molecular dynamics (MD) simulations. By performing MD simulations on the ATP and ADP+IP bound states, we identify the conformational consequences of hydrolysis, showing that the major rearrangements are not restricted to the NBDs, but extend to the transmembrane domains (TMDs) external regions. For the first time, to our knowledge, we see, within the context of a complete transporter, NBD dimer opening in the ADP+IP state in contrast with all ATP-bound states. This opening results from the dissociation of the ABC signature motif from the nucleotide. In addition, in both states, we observe the opening of a gate entrance in the intracellular loop region leading to the exposure of the TMDs internal cavity to the cytoplasm. To see if this opening was large enough to allow allocrite transport, the adiabatic energy profile for doxorubicin passage was determined. For both states, this profile, although an approximation, is overall downhill from the cytoplasmatic to the extracellular side, and the local energy barriers along the TMDs are relatively small, evidencing the exporter nature of Sav1866. The major difference between states is an energy barrier located in the cytoplasmic gate region, which becomes reduced upon hydrolysis, suggesting that allocrite passage is facilitated, and evidencing a possible molecular mechanism for the active transport in these proteins.


Amyloid-beta42 interacts mainly with insoluble prion protein in the Alzheimer brain.
The prion protein (PrP) is best known for its association with prion diseases. However, a controversial new role for PrP in Alzheimer disease (AD) has recently emerged. In vitro studies and mouse models of AD suggest that PrP may be involved in AD pathogenesis through a highly specific interaction with amyloid-β (Aβ42) oligomers. Immobilized recombinant human PrP (huPrP) also exhibited high affinity and specificity for Aβ42 oligomers. Here we report the novel finding that aggregated forms of huPrP and Aβ42 are co-purified from AD brain extracts. Moreover, an anti-PrP antibody and an agent that specifically binds to insoluble PrP (iPrP) co-precipitate insoluble Aβ from human AD brain. Finally, using peptide membrane arrays of 99 13-mer peptides that span the entire sequence of mature huPrP, two distinct types of Aβ binding sites on huPrP are identified in vitro. One specifically binds to Aβ42 and the other binds to both Aβ42 and Aβ40. Notably, Aβ42-specific binding sites are localized predominantly in the octapeptide repeat region, whereas sites that bind both Aβ40 and Aβ42 are mainly in the extreme N-terminal or C-terminal domains of PrP. Our study suggests that iPrP is the major PrP species that interacts with insoluble Aβ42 in vivo. Although this work indicated the interaction of Aβ42 with huPrP in the AD brain, the pathophysiological relevance of the iPrP/Aβ42 interaction remains to be established.


Determining individual variation in growth and its implication for life-history and population processes using the empirical Bayes method.
The differences in demographic and life-history processes between organisms living in the same population have important consequences for ecological and evolutionary dynamics. Modern statistical and computational methods allow the investigation of individual and shared (among homogeneous groups) determinants of the observed variation in growth. We use an Empirical Bayes approach to estimate individual and shared variation in somatic growth using a von Bertalanffy growth model with random effects. To illustrate the power and generality of the method, we consider two populations of marble trout Salmo marmoratus living in Slovenian streams, where individually tagged fish have been sampled for more than 15 years. We use year-of-birth cohort, population density during the first year of life, and individual random effects as potential predictors of the von Bertalanffy growth function's parameters k (rate of growth) and L∞ (asymptotic size). Our results showed that size ranks were largely maintained throughout marble trout lifetime in both populations. According to the Akaike Information Criterion (AIC), the best models showed different growth patterns for year-of-birth cohorts as well as the existence of substantial individual variation in growth trajectories after accounting for the cohort effect. For both populations, models including density during the first year of life showed that growth tended to decrease with increasing population density early in life. Model validation showed that predictions of individual growth trajectories using the random-effects model were more accurate than predictions based on mean size-at-age of fish.


Sediment chronologies of As, Bi, and Ga in Sweden--impact of industrialisation.
The acid-leachable amount and pore water concentration of As, Bi and Ga in sediment cores from four remote lakes in a south to north transect in Sweden were used to recapitulate the pollution history of the elements. The diagenetic impact on the element distribution was elucidated from their solid/solution partition and relationships to elements indicative for diagenesis. Dating was made by their acid-leachable lead content in combination with the 206Pb/207Pb ratio. In one of the lakes this approach was validated against dating with 210Pb. The impact of diagenesis on the sediment distribution of theses elements was found to be low enough for a chronological interpretation of the sediment profiles, as evidenced by their ratios to elements indicative of the geological background. A closer examination of the diagenetic impact would however be required if a more detailed chronology is desired. This study has demonstrated that atmospheric deposition of arsenic, bismuth and gallium contributes to the sediment inventory of these elements. The major part of the deposition of arsenic and bismuth took place after the Second World War. For gallium no concentrations exceeding background were detected before circa 1930. Increased levels of arsenic are traceable to circa 1850. For bismuth increased levels are concluded to extend before 1790, i.e., background concentrations were not reached in the present cores. For all elements the atmospheric deposition has been lower towards the north.


Heterotaxy and complex structural heart defects in a mutant mouse model of primary ciliary dyskinesia.
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder associated with ciliary defects and situs inversus totalis, the complete mirror image reversal of internal organ situs (positioning). A variable incidence of heterotaxy, or irregular organ situs, also has been reported in PCD patients, but it is not known whether this is elicited by the PCD-causing genetic lesion. We studied a mouse model of PCD with a recessive mutation in Dnahc5, a dynein gene commonly mutated in PCD. Analysis of homozygous mutant embryos from 18 litters yielded 25% with normal organ situs, 35% with situs inversus totalis, and 40% with heterotaxy. Embryos with heterotaxy had complex structural heart defects that included discordant atrioventricular and ventricular outflow situs and atrial/pulmonary isomerisms. Variable combinations of a distinct set of cardiovascular anomalies were observed, including superior-inferior ventricles, great artery alignment defects, and interrupted inferior vena cava with azygos continuation. The surprisingly high incidence of heterotaxy led us to evaluate the diagnosis of PCD. PCD was confirmed by EM, which revealed missing outer dynein arms in the respiratory cilia. Ciliary dyskinesia was observed by videomicroscopy. These findings show that Dnahc5 is required for the specification of left-right asymmetry and suggest that the PCD-causing Dnahc5 mutation may also be associated with heterotaxy.


Allelic variation in the contiguous loci encoding Candida albicans ALS5, ALS1 and ALS9.
The ALS gene family of Candida albicans consists of eight genes (ALS1 to ALS7 and ALS9) that encode cell-wall glycoproteins involved in adhesion to host surfaces. Considerable allelic sequence variability has been documented for regions of ALS genes encoding repeated sequences. Although regions of ALS genes encoding non-repeated sequences tend to be more conserved, some sequence divergence has been noted, particularly for alleles of ALS5. Data from the C. albicans genome sequencing project provided the first indication that strain SC5314 encoded two divergent ALS9-like sequences and that three of the ALS genes (ALS5, ALS1 and ALS9) were contiguous on chromosome 6. Data from PCR analysis and construction of both single and double deletion mutants indicated that the divergent sequences were alleles of ALS9, and located downstream of ALS5 and ALS1. Sequences within the 5' domain of ALS9-1 and ALS9-2 varied by 11 %. Within the 3' domain of each allele, extra nucleotides were present in two regions of ALS9-2, designated Variable Block 1 (VB1) and Variable Block 2 (VB2). Analysis of strains from the five major C. albicans genetic clades showed that both ALS9 alleles are widespread among these strains, that the sequences of ALS9-1 and ALS9-2 are conserved among diverse strains and that recombinant ALS9 alleles have been generated during C. albicans evolution. Phylogenetic analysis showed that, although divergent in sequence, ALS9 alleles are more similar to each other than to any other ALS genes. The degree of sequence divergence for ALS9 greatly exceeds that observed previously for other ALS genes and may result in functional differences for the proteins encoded by the two alleles.


Preparation of Tc99m-Labeled Pseudomonas Bacteriophage without Adversely Impacting Infectivity or Biodistribution.
Bacteriophages (phages) are ubiquitous viruses which have adapted to infect and replicate within target bacteria, their only known hosts, in a strain specific fashion with minimal cross infectivity. The recent steep rise in antibiotic resistance throughout the world has renewed interest in adapting phages for the imaging and treatment of bacterial infection in humans. In this article, we describe the current limitations surrounding the radiolabeling of phage for the imaging and treatment of bacterial infection and methods to overcome these difficulties. Specifically, we examined the effects of hydrazinonicotinamide conjugation and removal of bacterial DNA on the infectivity, biodistribution, and radionuclide imaging of a phage lytic for a clinically relevant strain of Pseudomonas aeruginosa, a common Gram-negative bacterial pathogen often resistant to multiple antibiotics. We found that all but the briefest reaction of concentrated phage with hydrazinonicotinamide (≤3 min) resulted in nearly complete loss of infectivity. Furthermore, we determined that digestion and removal of bacterial DNA was needed to avoid high nonspecific uptake of hydrazinonicotinamide-labeled phage within the liver and spleen as well as prolonged circulation in the blood. We also demonstrate the surprisingly wide soft tissue and organ biodistribution and rapid pharmacokinetics of 99mTc-hydrazinonicotinamide-labeled phage in normal mice as well as its imaging characteristics and efficacy in wounded mice infected with bioluminescent Pseudomonas aeruginosa. In conclusion, the preservation of phage infectivity and removal of all bacterial containments including DNA are critical methodologic considerations in the labeling of phages for imaging and therapy.


Fluoride occurrence in the lower East African Rift System, Southern Malawi.
Countries located on the East African Rift System (EARS) are vulnerable to fluoride in their groundwater; a vulnerability for the developing country of Malawi at the southern rift periphery that is not well characterised. Groundwater fluoride occurrence in Malawi is documented here to better understand and manage fluoride risks posed. Available literature and Gov't of Malawi archive fluoride data spanning some fifty years have been collated and augmented by our own 2016-18 surveys of groundwater quality in Southern Malawi, targeting deep-sourced springs. In total, fluoride data for 1365 borehole, spring and hot spring samples were assembled. Statistically, 83% of samples were below the 1.5 mg/l WHO limit, concentrations in the 1.5-6 mg/l range between former (pre-1993) and current WHO guidelines at 14%, and those with fluoride above the current Malawi (former WHO) 6 mg/l guideline, at 3%. A lower occurrence than in other zones of the EARS, but indicative of a need for a Malawi Gov't management policy revision and associated management strategies endorsed by several documented incidences of dental fluorosis in proximity to high fluoride groundwater. Increased fluoride is related to increased groundwater temperatures signifying the importance of geothermal groundwater provenance. Temperature data may indeed be used as a proxy indicator of fluoride risk; samples with a temperature >32 °C, contained >6 mg/l fluoride. Structural geological controls appear to allow deep geothermal groundwaters to come to the near surface, as evidenced by increased fluoride in springs and boreholes close to faulted areas. Hydrochemical evaluation shows that fluoride concentrations are influenced by fluorite equilibration and sensitivity to calcium and pH. Recommendations are made to further document the occurrence of fluoride and enhance management of risks due to fluoride in drinking water in Malawi. With fluoride as a key indicator within Sustainable Development Goal number 6, the current Malawi standard and waters with concentration between 1.5 and 6 mg/l will come under increased scrutiny and pose a key challenge to assessment and management efforts.


SheppHeartCABG trial-comprehensive early rehabilitation after coronary artery bypass grafting: a protocol for a randomised clinical trial.
Patients undergoing coronary artery bypass graft surgery often experience a range of symptoms. Studies indicate that non-pharmacological interventions such as exercise training and psychoeducation have a positive physiological and psychological effect in early outpatient rehabilitation. The SheppHeartCABG trial will investigate the effect of early comprehensive rehabilitation in early phase rehabilitation versus usual care. The aim of this paper is to present the protocol for the SheppHeartCABG trial. SheppHeartCABG is an investigator-initiated randomised clinical superiority trial with blinded outcome assessment, employing 1:1 central randomisation to rehabilitation plus usual care versus usual care alone. On the basis of a sample size calculation, 326 patients undergoing coronary artery bypass grafting will be included from two clinical sites. All patients receive usual care and patients allocated to the experimental intervention follow 4 weeks rehabilitation consisting of an exercise programme, psycho-educative consultations and a compact mindfulness programme. The primary outcome is physical function measured by the 6-min walk test. The secondary outcomes are mental health and physical activity measured by the Medical Outcome Study Short Form (SF-12), anxiety and depression measured by the Hospital Anxiety and Depression Scale questionnaire, physical, emotional and global scores by the HeartQoL questionnaire, sleep measured by the Pittsburgh Sleep Quality Index, pain measured by the Örebro Musculoskeletal Screening Questionnaire and muscle endurance measured by the sit-to-stand test. A number of explorative analyses will also be conducted. SheppHeartCABG is approved by the regional ethics committee (no. H-4-2014-109) and the Danish Data Protection Agency (no. 30-1309) and is performed in accordance with good clinical practice and the Declaration of Helsinki in its latest form. Positive, neutral and negative results of the trial will be submitted to international peer-reviewed journals. Furthermore, results will be presented at national and international conferences relevant to the subject fields. NCT02290262; pre-results.


Emotional maltreatment in Canada: prevalence, reporting and child welfare responses (CIS2).
To determine the prevalence and characteristics of reports of emotional maltreatment (EMT) in Canada, as well as changes in these reports between 1998 and 2003. This study is based on a secondary analysis of data collected in the first and second Canadian Incidence Study. Emotional maltreatment (excluding exposure to intimate partner violence) investigations were categorized into six groups: emotional abuse, emotional neglect, and other maltreatment as the only investigated form of maltreatment, and these same three groups were examined when they co-occurred with another form of maltreatment. Both the rate of emotional-abuse-only investigations and emotional-neglect-only investigations increased almost threefold from 1998 to 2003. Substantiated emotional neglect investigations had the highest rate of transfer to ongoing services. Half of the investigations involving single forms of emotional maltreatment occurred for six months or more. Finally, emotional neglect cases (in single form and when it co-occurs with another form of maltreatment) were more likely to be associated with emotional harm and longer duration of maltreatment. In 2003, EMT represented a significant increasing form of maltreatment and is detected nearly twice as often in situations in which abuse or neglect are also reported. Reports of emotional abuse are two and a half times more frequent than reports of emotional neglect. Nevertheless, lack of emotional engagement may also be difficult to identify, since an omission is more difficult to detect. Reports of EMT often reveal situations of chronic victimization that have been the subject of previous reports and are associated with greater emotional impact.


SUPPORT Tools for evidence-informed health Policymaking (STP) 8: Deciding how much confidence to place in a systematic review.
This article is part of a series written for people responsible for making decisions about health policies and programmes and for those who support these decision makers. The reliability of systematic reviews of the effects of health interventions is variable. Consequently, policymakers and others need to assess how much confidence can be placed in such evidence. The use of systematic and transparent processes to determine such decisions can help to prevent the introduction of errors and bias in these judgements. In this article, we suggest five questions that can be considered when deciding how much confidence to place in the findings of a systematic review of the effects of an intervention. These are: 1. Did the review explicitly address an appropriate policy or management question? 2. Were appropriate criteria used when considering studies for the review? 3. Was the search for relevant studies detailed and reasonably comprehensive? 4. Were assessments of the studies' relevance to the review topic and of their risk of bias reproducible? 5. Were the results similar from study to study?


Autonomic correlates at rest and during evoked attention in children with attention-deficit/hyperactivity disorder and effects of methylphenidate.
The aim of this study was to assess autonomic nervous system functioning in children with attention-deficit/hyperactivity disorder (ADHD) and to examine the effects of methylphenidate and focussed attention. Children with ADHD (n = 19) were tested while they were stimulant free and during a period in which they were on stimulants. On both occasions, autonomic nervous system functioning was tested at baseline and during focussed attention. Autonomic nervous system functioning of control subjects was also tested at baseline and during focussed attention. Autonomic nervous system activity was determined by means of heart rate variability (HRV) and skin conductivity analyses. Attention was evoked by means of the BioGraph Infiniti biofeedback apparatus. HRV was determined by time domain, frequency domain and Poincaré analysis of RR interval data. Skin conductivity was determined by the BioGraph Infiniti biofeedback apparatus. The main findings of this study were (a) that stimulant-free children with ADHD showed a sympathetic underarousal and parasympathetic overarousal of the sympathovagal balance relative to control subjects; (b) methylphenidate shifted the autonomic balance of children with ADHD towards normal levels; however, a normal autonomic balance was not reached, and (c) stimulant-free children with ADHD exhibited a shift in the sympathovagal balance towards the sympathetic nervous system from baseline to focussed attention; however, methylphenidate appeared to abolish this shift. Stimulant-free children with ADHD have a parasympathetic dominance of the autonomic balance, relative to control subjects. Methylphenidate attempts to restore the normal autonomic balance in children with ADHD, but inhibits the normal autonomic nervous system response to a cognitive challenge. These results indicate that methylphenidate may have a suppressive effect on the normal stress response. Although this may be of benefit to those who interact with children who suffer from ADHD, the implications for the physiological and psychological well-being of the children themselves are debatable. Further research is needed. Only 19 children with ADHD and 18 control subjects were tested. Further studies should include prior testing in order to exclude children with possible co-existing learning disabilities. Cognitive function and emotional responses of children with ADHD were not tested.


Exposure to bisphenols and phthalates and association with oxidant stress, insulin resistance, and endothelial dysfunction in children.
The health effects of bisphenol A (BPA) and di-(2-ethylhexyl) phthalate (DEHP) have been studied extensively in children. The impact of other chemicals in these two classes has not been investigated as fully. We conducted a cross-sectional pilot study of 10-13 y old healthy children. We assessed descriptive, univariable, and multivariable associations of urinary metabolites of bisphenols and phthalates with oxidant stress, insulin resistance, body mass, and endothelial dysfunction. Possible associations with brachial artery distensibility, pulse wave velocity (markers of vascular stiffness), and serum endothelial cell-derived microparticle levels were also assessed. We enrolled 41 participants, 12.1 ± 1.0 y, most of whom were Mexican Americans (42%) or other Hispanics (34%). Increased BPA levels were associated with increased levels of F2-isoprostane (ng/ml) (P = 0.02), with a similar trend for DEHP metabolites. Each log unit increase of high molecular weight (HMW) phthalate metabolites was associated with a 0.550 increase in Homeostatic Model Assessment of insulin resistance (HOMA-IR) units (P = 0.019) and altered circulating levels of activated endothelial cell-derived microparticles (% per ml) (P = 0.026). Bisphenol S (BPS), a replacement for BPA, was associated with increased albumin (mg):creatinine (g) ratio (P = 0.04). Metabolites of HMW phthalates were also associated with decreased brachial artery distensibility (P = 0.047). Exposure to bisphenols and phthalates, including a BPA replacement, is associated with increased oxidant stress, insulin resistance, albuminuria, as well as disturbances in vascular function in healthy children.


Individual differences in the effects of mobile phone exposure on human sleep: rethinking the problem.
Mobile phone exposure-related effects on the human electroencephalogram (EEG) have been shown during both waking and sleep states, albeit with slight differences in the frequency affected. This discrepancy, combined with studies that failed to find effects, has led many to conclude that no consistent effects exist. We hypothesised that these differences might partly be due to individual variability in response, and that mobile phone emissions may in fact have large but differential effects on human brain activity. Twenty volunteers from our previous study underwent an adaptation night followed by two experimental nights in which they were randomly exposed to two conditions (Active and Sham), followed by a full-night sleep episode. The EEG spectral power was increased in the sleep spindle frequency range in the first 30 min of non-rapid eye movement (non-REM) sleep following Active exposure. This increase was more prominent in the participants that showed an increase in the original study. These results confirm previous findings of mobile phone-like emissions affecting the EEG during non-REM sleep. Importantly, this low-level effect was also shown to be sensitive to individual variability. Furthermore, this indicates that previous negative results are not strong evidence for a lack of an effect and, given the far-reaching implications of mobile phone research, we may need to rethink the interpretation of results and the manner in which research is conducted in this field.


Quality at the centre of universal health coverage.
The last decade of the MDG era witnessed substantial focus on reaching the bottom economic quintiles in low and middle income countries. However, the inordinate focus on reducing financial risk burden and increasing coverage without sufficient focus on expanding quality of services may account for slow progress of the MDGs in many countries. Human Resources for Health underlie quality and service delivery improvements, yet remains under-addressed in many national strategies to achieve Universal Health Coverage. Without adequate investments in improving and expanding health professional education, making and sustaining gains will be unlikely. The transition from the Millennium Development Goals (MDG) to the Sustainable Development Goals (SDG), with exciting new financing initiatives such as the Global Financing Facility brings the potential to enact substantial gains in the quality of services delivered and upgrading human health resources. This focus should ensure effective methodologies to improve health worker competencies and change practice are employed and ineffective and harmful ones eliminated (including undue influence of commercial interests).


Discontinuation of adalimumab after attaining disease activity score 28-erythrocyte sedimentation rate remission in patients with rheumatoid arthritis (HONOR study): an observational study.
Evidences of biologics-free disease control after discontinuing adalimumab (ADA) in rheumatoid arthritis (RA) patients in clinical practice have not been sufficiently investigated. Purpose of this study is to investigate whether disease activity score 28 (DAS28)- erythrocyte sedimentation rate (ESR) remission was preserved after discontinuation of ADA in patients with RA. This is an observational but not a randomized controlled study. Among 197 RA patients who initiated with combination of ADA with concomitant MTX, 69 (35%) acquired DAS28 (ESR) < 2.6 for at least 24 weeks. Of those 69 patients, 51 went on ADA discontinuation with their consent, and finally 50 of those with follow-up of > 24 weeks were evaluated. The effect of discontinuing ADA on clinical disease activity, functional disability and radiographic progression were evaluated by DAS28 (ESR), the clinical disease activity index (CDAI) and the simplified disease activity index (SDAI), by a health assessment questionnaire-disability index (HAQ-DI) and by the modified total Sharp score (mTSS), respectively. The mean age of the participants was 59.5 years with the mean disease duration of 7.1 years. Out of the 50 patients, 29 (58%) were maintained in DAS28 (ESR) < 2.6 at 24 weeks after discontinuing ADA. A logistic regression analysis showed that DAS28 (ESR) at baseline significantly predicted a DAS28 (ESR) < 2.6 maintained after discontinuation of ADA, and a receiver-operating characteristic (ROC) analysis showed that the cut-off value of DAS28 (ESR) at discontinuation was 2.16. The mean HAQ-DI at six months after discontinuing ADA was 0.1 in patients who kept in DAS28 (ESR) < 2.6, and 94.9% (37/39) showed no evidence of radiographic progression (> 0.5 per year of a change in mTSS) at 1 year. It was possible to maintain DAS28 (ESR) < 2.6 after discontinuation of ADA without functional and radiographic progression and very low DAS28 (ESR) at the discontinuation was associated with successful ADA-free DAS28 (ESR) < 2.6 in patients with RA. University Hospital Medical Information Network Identifier: UMIN000006669.


Nonlinear blind equalization schemes using complex-valued multilayer feedforward neural networks.
Among the useful blind equalization algorithms, stochastic-gradient iterative equalization schemes are based on minimizing a nonconvex and nonlinear cost function. However, as they use a linear FIR filter with a convex decision region, their residual estimation error is high. In this paper, four nonlinear blind equalization schemes that employ a complex-valued multilayer perceptron instead of the linear filter are proposed and their learning algorithms are derived. After the important properties that a suitable complex-valued activation function must possess are discussed, a new complex-valued activation function is developed for the proposed schemes to deal with QAM signals of any constellation sizes. It has been further proven that by the nonlinear transformation of the proposed function, the correlation coefficient between the real and imaginary parts of input data decreases when they are jointly Gaussian random variables. Last, the effectiveness of the proposed schemes is verified in terms of initial convergence speed and MSE in the steady state. In particular, even without carrier phase tracking procedure, the proposed schemes correct an arbitrary phase rotation caused by channel distortion.


Loss of polycystin-1 causes centrosome amplification and genomic instability.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenetic disease predominantly caused by alteration or dysregulation of the PKD1 gene, which encodes polycystin-1 (PC1). The disease is characterized by the progressive expansion of bilateral fluid-filled renal cysts that ultimately lead to renal failure. Individual cysts, even within patients with germline mutations, are genetically heterogeneous, displaying diverse chromosomal abnormalities. To date, the molecular mechanisms responsible for this genetic heterogeneity remain unknown. Using a lentiviral-mediated siRNA expression model of Pkd1 hypomorphism, we show that loss of PC1 function is sufficient to produce centrosome amplification and multipolar spindle formation. These events lead to genomic instability characterized by gross polyploidism and mitotic catastrophe. Following these dramatic early changes, the cell population rapidly converges toward a stable ploidy in which centrosome amplification is significantly decreased, though cytological abnormalities such as micronucleation, chromatin bridges and aneuploidy remain common. In agreement with our in vitro findings, we provide the first in vivo evidence that significant centrosome amplification occurs in kidneys from conditional Pkd1 knockout mice at early and late time during the disease progression as well as in human ADPKD patients. These findings establish a novel function of PC1 in ADPKD pathogenesis and a genetic mechanism that may underlie the intrafamilial variability of ADPKD progression.


Does the supine sleeping position have any adverse effects on the child? I. Health in the first six months. The ALSPAC Study Team.
To assess whether the recommendations that infants sleep supine could have adverse health consequences. A prospective study of infants, delivered before, during, and after the Back to Sleep Campaign in the United Kingdom (UK), followed to 6 months of age. The children were part of the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC). Subjects. Singletons born to mothers resident in the three former Bristol-based health districts of Avon in the period June 1991 to December 1992, and for whom questionnaires were completed on sleeping position at 4 to 6 weeks of age (n = 9777); for these infants 8524 questionnaires were also completed at 6 to 8 months of age. Subjective measures of health, the presence of specific signs and symptoms, duration of sleep at night, and calling the family doctor to the home. Of 43 outcomes considered, after adjustment for 12 factors using logistic regression only 2 were associated with raised risk among infants put to sleep on their back (diaper rash and cradle cap). Infants put to sleep prone had increased risk of a number of health outcomes, including cough and possibly pyrexia. There is no evidence that putting infants to sleep in the supine position results in increased morbidity, although changes in prevalence of rare disorders would not have been identified.


Overlapping plant signal transduction pathways induced by a parasitic nematode and a rhizobial endosymbiont.
Root-knot nematodes and rhizobia establish interactions with roots characterized by the de novo induction of host structures, termed giant cells and nodules, respectively. Two transcription regulators, PHAN and KNOX, required for the establishment of meristems were previously shown to be expressed in tomato giant cells. We isolated the orthologues of PHAN and KNOX (Mt-phan and Mt-knox-1) from the model legume Medicago truncatula, and established the spatial distribution of their expression in situ. We confirmed that Mt-phan and Mt-knox-1 are expressed in lateral root initials and in nematode-induced giant cells and showed that they are expressed in nodules induced by Sinorhizobium meliloti. Expression of both genes becomes spatially restricted as the nodules develop. We further examined nematode feeding sites for the expression of two genes involved in nodule formation, ccs52 (encodes a mitotic inhibitor) and ENOD40 (encodes an early, nodulation mitogen), and found transcripts of both genes to be present in and around giant cells induced in Medicago. Collectively, these results reveal common elements of host responses to mutualistic and parasitic plant endosymbionts and imply that overlapping regulatory pathways lead to giant cells and nodules. We discuss these pathways in the context of phytohormones and parallels between beneficial symbiosis and disease.


Vulnerability of continence structures to injury by simulated childbirth.
The goal of this study was to examine acute morphological changes, edema, muscle damage, inflammation, and hypoxia in urethral and vaginal tissues with increasing duration of vaginal distension (VD) in a rat model. Twenty-nine virgin Sprague-Dawley rats underwent VD under anesthesia with the use of a modified Foley catheter inserted into the vagina and filled with saline for 0, 1, 4, or 6 h. Control animals were anesthetized for 4 h without catheter placement. Urogenital organs were harvested after intracardiac perfusion of fixative. Tissues were embedded, sectioned, and stained with Masson's trichrome or hematoxylin and eosin stains. Regions of hypoxia were measured by hypoxyprobe-1 immunohistochemistry. Within 1 h of VD, the urethra became vertically elongated and displaced anteriorly. Edema was most prominent in the external urethral sphincter (EUS) and urethral/vaginal septum within 4 h of VD, while muscle disruption and fragmentation of the EUS occurred after 6 h. Inflammatory damage was characterized by the presence of polymorphonuclear leukocytes in vessels and tissues after 4 h of VD, with the greatest degree of infiltration occurring in the EUS. Hypoxia localized mostly to the vaginal lamina propria, urethral smooth muscle, and EUS within 4 h of VD. Increasing duration of VD caused progressively greater tissue edema, muscle damage, and morphological changes in the urethra and vagina. The EUS underwent the greatest insult, demonstrating its vulnerability to childbirth injury.


Dapagliflozin and the Incidence of Type 2 Diabetes in Patients With Heart Failure and Reduced Ejection Fraction: An Exploratory Analysis From DAPA-HF.
The sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of cardiovascular mortality and worsening heart failure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial. This report explores the effect of dapagliflozin on incident type 2 diabetes (T2D) in the cohort without diabetes enrolled in the trial. The subgroup of 2,605 patients with heart failure and reduced ejection fraction (HFrEF), no prior history of diabetes, and an HbA1c of <6.5% at baseline was randomized to dapagliflozin 10 mg daily or placebo. In this exploratory analysis, surveillance for new-onset diabetes was accomplished through periodic HbA1c testing as part of the study protocol and comparison between the treatment groups assessed through a Cox proportional hazards model. At baseline, the mean HbA1c was 5.8%. At 8 months, there were minimal changes, with a placebo-adjusted change in the dapagliflozin group of -0.04%. Over a median follow-up of 18 months, diabetes developed in 93 of 1,307 patients (7.1%) in the placebo group and 64 of 1,298 (4.9%) in the dapagliflozin group. Dapagliflozin led to a 32% reduction in diabetes incidence (hazard ratio 0.68, 95% CI 0.50-0.94; P = 0.019). More than 95% of the participants who developed T2D had prediabetes at baseline (HbA1c 5.7-6.4%). Participants who developed diabetes in DAPA-HF had a higher subsequent mortality than those who did not. In this exploratory analysis among patients with HFrEF, treatment with dapagliflozin reduced the incidence of new diabetes. This potential benefit needs confirmation in trials of longer duration and in people without heart failure.


Cascade of Provider-Initiated Human Immunodeficiency Virus Testing and Counselling at Specific Life Events (Pregnancy, Sexually Transmitted Infections, Marriage) in Côte d'Ivoire.
Despite the implementation of Provider Initiated Testing and Counselling (PITC) in 2009, PITC coverage remains low in Cote d'Ivoire. The purpose of this study is to determine whether an human immunodeficiency virus (HIV) test was offered and performed at specific life events where PITC is recommended by national guidelines. In 2017, a cross-sectional telephone survey was conducted among a representative sample of 3,867 adults from the general population in Côte d'Ivoire. The occurrences of the following events over the past 5 years were documented: pregnancy (event A) or partner's pregnancy (event B) of the last child, sexually transmitted infection (event C) and marriage (event D). For each of these events, participants were asked (i) if they consulted a health care professional, (ii) if they were offered an HIV test during that consultation and (iii) if they accepted it. Consulting a health care provider was reported by 94.9%, 58.3%, 70.3% and 19.1% of those who reported events A, B, C and D respectively. In case of medical consultations following events A, B, C and D, respectively 70.1%, 33.1%, 28.1%, and 78.8% of individuals were offered an HIV test. The testing acceptance was high regardless of the event. Overall, testing coverage was 63.7%, 16.9%, 13.4% and 14.5% for events A, B, C and D respectively. Increasing HIV testing coverage in Côte d'Ivoire requires (i) facilitating attendance to health services in case of sexually transmitted infections, marriage and pregnancy-for men-and (ii) strengthening routine testing offer on these occasions.


TNF-α Deficiency Prevents Renal Inflammation and Oxidative Stress in Obese Mice.
Obese patients and experimental animals exhibit high levels of inflammatory cytokines, such as tumor necrosis factor (TNF)-α. However, the role of TNF-α in the pathophysiologic process in obesity induced kidney damage is still unknown. We used TNF-α deficient mice and wild-type (WT) C57/BJ6 mice controls to study the effect of TNF-α on inflammation and oxidative stress in kidney by the model of high-fat diet (HFD) and primary isolated mouse renal proximal tubule cells treated with a mixture of free fatty acids (FFA). Compared with the chow diet group, HFD-fed WT mice had higher urinary albumin and increased levels of renal fibrosis, glomerulosclerosis, inflammation, oxidative stress and apoptosis in the kidney. These changes were co-related with increased expression of TNF-α in the kidney and were attenuated by TNF-α deficiency. In vitro, accumulation of intracellular lipids induced TNF-α expression and oxidative stress in FFA treated primary proximal tubule cells. However, TNF-α inhibition with siRNA or TNF-α deficiency decreased the lipid induced oxidative stress in these cells. These findings suggest that TNF-α plays an important role in the HFD induced kidney damage, and targeting TNF-α and/or its receptors could be a promising therapeutic regimen for progressive nephropathy.


Comparison of laser acupuncture and metoclopramide in PONV prevention in children.
Postoperative nausea and vomiting (PONV) are frequent side effects of general anesthesia in children. The aim of this study was to compare the effectiveness of laser acupuncture with metoclopramide in prevention of PONV in children after sevoflurane anesthesia. A total of 120 children ASA I and II, scheduled for hernia repair, circumcision or orchidopexy were randomly assigned into three groups: group I, received laser acupuncture on P6 point and saline infusion; group II, metoclopramide 0.1 mg.kg(-1) i.v. and sham laser; group III had sham laser and saline infusion. Anesthesia was maintained with sevoflurane and N(2)O/O(2). Patients were monitored for any symptoms of retching and vomiting at 2, 6 and 24 h postoperatively. The incidence of vomiting was higher in the control group in the first 2 h postoperatively (P < 0.001), compared with the other groups. There was no statistically significant difference between acupuncture and metoclopramide groups in occurrence and timing of vomiting (P < 0.001). Laser acupuncture is equally effective as metoclopramide in preventing PONV in children.


C1-CBP-vancomycin: Impact of a Vancomycin C-Terminus Trimethylammonium Cation on Pharmacological Properties and Insights into Its Newly Introduced Mechanism of Action.
C1-CBP-vancomycin (3) was examined alongside CBP-vancomycin for susceptibility to acquired resistance upon serial exposure against two vancomycin-resistant enterococci strains where its activity proved more durable and remarkably better than many current therapies. Combined with earlier studies, this observation confirmed an added mechanism of action was introduced by incorporation of the trimethylammonium cation and that C1-CBP-vancomycin exhibits activity against vancomycin-resistant organisms through two synergistic mechanisms of action, both independent of d-Ala-d-Ala/d-Lac binding. New insights into this added mechanism of action, induced cell membrane permeabilization, can be inferred from studies that show added exogenous lipoteichoic acid reduces antimicrobial activity, rescues bacteria cell growth inhibition, and blocks induced cell permeabilization properties of C1-CBP-vancomycin, suggesting a direct binding interaction with embedded teichoic acid is responsible for the added mechanism of action and enhanced antimicrobial activity. Further studies indicate that the trimethylammonium cation does not introduce new liabilities in common pharmacological properties of the analogue and established that 3 is well tolerated in mice, displays substantial PK improvements over both vancomycin and CBP-vancomycin, and exhibits in vivo efficacy against a challenging multidrug-resistant and vancomycin-resistant S. aureus strain that is representative of the resistant pathogens all fear will emerge in the general population.


Transient expression assay of Agamma-588 (A/G) mutations in the K562 cell line.
In the previous study, we have shown that the presence of A allele at position -588 in Agamma-globin gene was highly frequent and closely associated with fetal hemoglobin elevation among beta-thalassemia intermedia patients. Therefore, we decided to investigate whether this allele (A allele at -588) could result in an increase in Agamma-globin gene expression to ameliorate the severity of the disease in thalassemia patients. Three constructs containing mu locus control region, Agamma-globin and beta-globin genes were designed and employed in the transient expression assay. The difference among constructs was in the promoter region of Agamma-globin gene (A and G alleles at -588). A construct with T to C base substitution at -175 of Agamma-globin, created by site-directed mutagenesis, was selected as positive control. The K562 cell line was transfected with the above constructs. Subsequently, the expression of Agamma-globin gene was determined by quantitative real-time reverse transcription-PCR. There was not a significant increase in the expression of Agamma-globin gene in the construct containing A allele comparing the one with G allele at -588. -588 (A>G) mutation does not play a major role in regulation of Agamma-globin gene, suggesting that other factors may be involved.


The population history of northeastern Siberia since the Pleistocene.
Northeastern Siberia has been inhabited by humans for more than 40,000 years but its deep population history remains poorly understood. Here we investigate the late Pleistocene population history of northeastern Siberia through analyses of 34 newly recovered ancient genomes that date to between 31,000 and 600 years ago. We document complex population dynamics during this period, including at least three major migration events: an initial peopling by a previously unknown Palaeolithic population of 'Ancient North Siberians' who are distantly related to early West Eurasian hunter-gatherers; the arrival of East Asian-related peoples, which gave rise to 'Ancient Palaeo-Siberians' who are closely related to contemporary communities from far-northeastern Siberia (such as the Koryaks), as well as Native Americans; and a Holocene migration of other East Asian-related peoples, who we name 'Neo-Siberians', and from whom many contemporary Siberians are descended. Each of these population expansions largely replaced the earlier inhabitants, and ultimately generated the mosaic genetic make-up of contemporary peoples who inhabit a vast area across northern Eurasia and the Americas.


Intuitive probabilistic inference in capuchin monkeys.
The ability to reason about probabilities has ecological relevance for many species. Recent research has shown that both preverbal infants and non-human great apes can make predictions about single-item samples randomly drawn from populations by reasoning about proportions. To further explore the evolutionary origins of this ability, we conducted the first investigation of probabilistic inference in a monkey species (capuchins; Sapajus spp.). Across four experiments, capuchins (N = 19) were presented with two populations of food items that differed in their relative distribution of preferred and non-preferred items, such that one population was more likely to yield a preferred item. In each trial, capuchins had to select between hidden single-item samples randomly drawn from each population. In Experiment 1 each population was homogeneous so reasoning about proportions was not required; Experiments 2-3 replicated previous probabilistic reasoning research with infants and apes; and Experiment 4 was a novel condition untested in other species, providing an important extension to previous work. Results revealed that at least some capuchins were able to make probabilistic inferences via reasoning about proportions as opposed to simpler quantity heuristics. Performance was relatively poor in Experiment 4, so the possibility remains that capuchins may use quantity-based heuristics in some situations, though further work is required to confirm this. Interestingly, performance was not at ceiling in Experiment 1, which did not involve reasoning about proportions, but did involve sampling. This suggests that the sampling task posed demands in addition to reasoning about proportions, possibly related to inhibitory control, working memory, and/or knowledge of object permanence.


Adsorption of uranium(VI) to manganese oxides: X-ray absorption spectroscopy and surface complexation modeling.
The mobility of hexavalent uranium in soil and groundwater is strongly governed by adsorption to mineral surfaces. As strong naturally occurring adsorbents, manganese oxides may significantly influence the fate and transport of uranium. Models for U(VI) adsorption over a broad range of chemical conditions can improve predictive capabilities for uranium transport in the subsurface. This study integrated batch experiments of U(VI) adsorption to synthetic and biogenic MnO(2), surface complexation modeling, ζ-potential analysis, and molecular-scale characterization of adsorbed U(VI) with extended X-ray absorption fine structure (EXAFS) spectroscopy. The surface complexation model included inner-sphere monodentate and bidentate surface complexes and a ternary uranyl-carbonato surface complex, which was consistent with the EXAFS analysis. The model could successfully simulate adsorption results over a broad range of pH and dissolved inorganic carbon concentrations. U(VI) adsorption to synthetic δ-MnO(2) appears to be stronger than to biogenic MnO(2), and the differences in adsorption affinity and capacity are not associated with any substantial difference in U(VI) coordination.


Rational design of mesoporous metals and related nanomaterials by a soft-template approach.
We review recent developments in the preparation of mesoporous metals and related metal-based nanomaterials. Among the many types of mesoporous materials, mesoporous metals hold promise for a wide range of potential applications, such as in electronic devices, magnetic recording media, and metal catalysts, owing to their metallic frameworks. Mesoporous metals with highly ordered networks and narrow pore-size distributions have traditionally been produced by using mesoporous silica as a hard template. This method involves the formation of an original template followed by deposition of metals within the mesopores and subsequent removal of the template. Another synthetic method is the direct-template approach from lyotropic liquid crystals (LLCs) made of nonionic surfactants at high concentrations. Direct-template synthesis creates a novel avenue for the production of mesoporous metals as well as related metal-based nanomaterials. Many mesoporous metals have been prepared by the chemical or electrochemical reduction of metal salts dissolved in aqueous LLC domains. As a soft template, LLCs are more versatile and therefore more advantageous than hard templates. It is possible to produce various nanostructures (e.g., lamellar, 2D hexagonal (p6mm), and 3D cubic (Ia\3d)), nanoparticles, and nanotubes simply by controlling the composition of the reaction bath.


Circumventing the WHO Code? An observational study.
This study compares the formula milk advertisements that appeared in parenting magazines published in two countries that have enacted measures to restrict the advertising of infant formula products in response to the international code with two that have not. Content analysis was used to compare the type and frequency of formula milk advertisements that appeared in parenting magazines collected from the USA, Canada, the UK and Australia during 2007, and to examine whether there was a relationship between these frequencies and advertising regulations. Advertisements that promoted formula products or brands occurred in all of the magazines sampled but the type of product advertised differed. Follow-on formula advertisements occurred more frequently in titles from the UK, where infant formula advertising is prohibited (RR 3.82, 95% CI 2.65 to 5.50, p<0.0001) than they did in titles from the USA/Canada where infant and/or follow-on formula advertising is permitted. Toddler milk advertisements appeared more frequently in titles from Australia, where infant and follow-on formula advertising is prohibited, than they did in titles from countries where direct-to-consumer infant and/or follow-on formula advertising is permitted. Rate ratios were as follows: UK only 0.03 (95% CI 0.01 to 0.11, p<0.0001); USA/Canada only 0.02 (95% CI 0.01 to 0.06, p<0.0001). Bans on the advertising of infant formula products do not prevent companies from advertising (follow-on or toddler formula). These products are presented in ways that encourage consumers to associate the claims made in them with a group of products (a product line) that includes infant formula.


Effects of proprioceptive exercises on pain and function in chronic neck- and low back pain rehabilitation: a systematic literature review.
Proprioceptive training (PrT) is popularly applied as preventive or rehabilitative exercise method in various sports and rehabilitation settings. Its effect on pain and function is only poorly evaluated. The aim of this systematic review was to summarise and analyse the existing data on the effects of PrT on pain alleviation and functional restoration in patients with chronic (≥ 3 months) neck- or back pain. Relevant electronic databases were searched from their respective inception to February 2014. Randomised controlled trials comparing PrT with conventional therapies or inactive controls in patients with neck- or low back pain were included. Two review authors independently screened articles and assessed risk of bias (RoB). Data extraction was performed by the first author and crosschecked by a second author. Quality of findings was assessed and rated according to GRADE guidelines. Pain and functional status outcomes were extracted and synthesised qualitatively and quantitatively. In total, 18 studies involving 1380 subjects described interventions related to PrT (years 1994-2013). 6 studies focussed on neck-, 12 on low back pain. Three main directions of PrT were identified: Discriminatory perceptive exercises with somatosensory stimuli to the back (pPrT, n=2), multimodal exercises on labile surfaces (mPrT, n=13), or joint repositioning exercise with head-eye coordination (rPrT, n=3). Comparators entailed usual care, home based training, educational therapy, strengthening, stretching and endurance training, or inactive controls. Quality of studies was low and RoB was deemed moderate to high with a high prevalence of unclear sequence generation and group allocation (>60%). Low quality evidence suggests PrT may be more effective than not intervening at all. Low quality evidence suggests that PrT is no more effective than conventional physiotherapy. Low quality evidence suggests PrT is inferior to educational and behavioural approaches. There are few relevant good quality studies on proprioceptive exercises. A descriptive summary of the evidence suggests that there is no consistent benefit in adding PrT to neck- and low back pain rehabilitation and functional restoration.


[Outpatient surgical treatment of female stress urinary incontinence].
To evaluate the results of the outpatient surgical treatment of genuine female stress urinary incontinence (SUI) over a five year period since the integration of the Department of Urology in the Ambulatory Surgery Unit at our hospital "Consorcio Hospital General Universitario de Valencia" (CHGUV). Between January 2000 and December 2004 26 patients (ages 49-78; mean age 69.8 yr) with the diagnosis of SUI underwent tension-free suburethral mesh sling (TVT) outpatient operations under local anesthesia-sedation at the ambulatory surgery unit of the CHGUV. All patients had clinical and urodynamic evaluation, excluding those presenting genital prolapse or non compliance with the social requirements for ambulatory surgery. Previous anti-incontinence surgery was not an exclusion criterion. We evaluate inclusion and discharge criteria, results and satisfaction degree measured by a questionnaire. 22 patients (85%) had genuine SUI and 4 (15%) had mixed UI with predominance of the stress component. 54% (14) of the patients were ASA I, 31% (8) ASA II, and 15% (4) well compensated ASA III. Operation tolerance under local anesthesia (20-30 ml 1% lidocaine) was good in all patients, having used additional sedation-analgesia (propofol-remifentanil IV perfusion) in 10 of them (38%). Mean operative time was 30 minutes (25-45) and stay at the unit discharge was 100 min. (80-140). All patients were discharged the same day. None of them required readmission or presented urinary retention after catheter removal. SUI disappeared in all of them. Three patients presented postoperative urge incontinence responsive to oral anticolinergic drugs. Our results are similar to those obtained with epidural anesthesia and hospital admission, being the degree of satisfaction with treatment higher than 95%. The development of new, revolutionary systems for the treatment of SUI has simplified the surgical treatment of this entity, so that we can say a high percentage of patients may be included in an ambulatory surgery program, significantly improving cost-efficacy without diminishment of health-care quality or patient satisfaction.


Vitamin E supplementation and cardiovascular events in high-risk patients.
Observational and experimental studies suggest that the amount of vitamin E ingested in food and in supplements is associated with a lower risk of coronary heart disease and atherosclerosis. We enrolled a total of 2545 women and 6996 men 55 years of age or older who were at high risk for cardiovascular events because they had cardiovascular disease or diabetes in addition to one other risk factor. These patients were randomly assigned according to a two-by-two factorial design to receive either 400 IU of vitamin E daily from natural sources or matching placebo and either an angiotensin-converting-enzyme inhibitor (ramipril) or matching placebo for a mean of 4.5 years (the results of the comparison of ramipril and placebo are reported in a companion article). The primary outcome was a composite of myocardial infarction, stroke, and death from cardiovascular causes. The secondary outcomes included unstable angina, congestive heart failure, revascularization or amputation, death from any cause, complications of diabetes, and cancer. A total of 772 of the 4761 patients assigned to vitamin E (16.2 percent) and 739 of the 4780 assigned to placebo (15.5 percent) had a primary outcome event (relative risk, 1.05; 95 percent confidence interval, 0.95 to 1.16; P=0.33). There were no significant differences in the numbers of deaths from cardiovascular causes (342 of those assigned to vitamin E vs. 328 of those assigned to placebo; relative risk, 1.05; 95 percent confidence interval, 0.90 to 1.22), myocardial infarction (532 vs. 524; relative risk, 1.02; 95 percent confidence interval, 0.90 to 1.15), or stroke (209 vs. 180; relative risk, 1.17; 95 percent confidence interval, 0.95 to 1.42). There were also no significant differences in the incidence of secondary cardiovascular outcomes or in death from any cause. There were no significant adverse effects of vitamin E. In patients at high risk for cardiovascular events, treatment with vitamin E for a mean of 4.5 years had no apparent effect on cardiovascular outcomes.


Cinnamon extract improves the body composition and attenuates lipogenic processes in the liver and adipose tissue of rats.
In models of metabolic disorders, cinnamon improves glucose and lipid metabolism. This study explores the effect of chronic supplementation with aqueous cinnamon extract (CE) on the lipid metabolism of rats. Male adult Wistar rats were separated into a control group (CTR) receiving water and a CE Group receiving aqueous cinnamon extract (400 mg of cinnamon per kg body mass per day) by gavage for 25 consecutive days. Cinnamon supplementation did not change the food intake or the serum lipid profile but promoted the following changes: lower body mass gain (P = 0.008), lower relative mass of white adipose tissue (WAT) compartments (P = 0.045) and higher protein content (percentage of the carcass) (P = 0.049). The CE group showed lower leptin mRNA expression in the WAT (P = 0.0017) and an important tendency for reduced serum leptin levels (P = 0.059). Cinnamon supplementation induced lower mRNA expression of SREBP1c (sterol regulatory element-binding protein 1c) in the WAT (P = 0.001) and liver (P = 0.013) and lower mRNA expression of SREBP2 (P = 0.002), HMGCoA reductase (3-hydroxy-3-methylglutaryl-CoA reductase) (P = 0.0003), ACAT1 (acetyl-CoA acetyltransferase 1) (P = 0.032) and DGAT2 (diacylglycerol O-acyltransferase 2) (P = 0.03) in the liver. These changes could be associated with the reduced esterified cholesterol and triacylglycerol content detected in this tissue. Our results suggest that chronic ingestion of aqueous cinnamon extract attenuates lipogenic processes, regulating the expression of key enzymes and transcriptional factors and their target genes, which are directly involved in lipogenesis. These molecular changes possibly promote adaptations that would prevent an increase in circulating cholesterol and triacylglycerol levels and prevent lipid accumulation in tissues, such as liver and WAT. Therefore, we speculate that cinnamon may also be useful for preventing or retarding the development of lipid disorders.


Molecular hydrogen protects against oxidative stress-induced SH-SY5Y neuroblastoma cell death through the process of mitohormesis.
Inhalation of molecular hydrogen (H2) gas ameliorates oxidative stress-induced acute injuries in the brain. Consumption of water nearly saturated with H2 also prevents chronic neurodegenerative diseases including Parkinson's disease in animal and clinical studies. However, the molecular mechanisms underlying the remarkable effect of a small amount of H2 remain unclear. Here, we investigated the effect of H2 on mitochondria in cultured human neuroblastoma SH-SY5Y cells. H2 increased the mitochondrial membrane potential and the cellular ATP level, which were accompanied by a decrease in the reduced glutathione level and an increase in the superoxide level. Pretreatment with H2 suppressed H2O2-induced cell death, whereas post-treatment did not. Increases in the expression of anti-oxidative enzymes underlying the Nrf2 pathway in H2-treated cells indicated that mild stress caused by H2 induced increased resistance to exacerbated oxidative stress. We propose that H2 functions both as a radical scavenger and a mitohormetic effector against oxidative stress in cells.


Telephone interventions for co-morbid insomnia and osteoarthritis pain: The OsteoArthritis and Therapy for Sleep (OATS) randomized trial design.
The OsteoArthritis and Therapy for Sleep (OATS) study is a population-based randomized controlled trial of cognitive behavioral therapy for insomnia (CBTI) with four innovative methodological aims. These are to: (1) Enroll representative participants across Washington state, including those from medically underserved communities; (2) Enroll persons with persistent insomnia and chronic osteoarthritis (OA) pain; (3) Test a scalable CBT-I intervention; and (4) Evaluate patient-reported outcomes (insomnia, pain severity, fatigue, depression) and cost-effectiveness over one year. This paper describes progress towards achieving these aims. The target population was persons age 60+ who had received OA care within the Kaiser Permanente Washington (KPW) health care system. We employed a two-phase screening via mail survey and telephone follow-up, with a 3-week interval between screens to exclude persons with spontaneous improvement in sleep or pain symptoms. Participants were randomized to a 6-session telephone-delivered CBT-I intervention or a 6-session telephone education only control condition (EOC). Blinded outcome assessments (completed online or on mailed paper forms) included primary and secondary sleep and pain outcome measures and quality of life measures. We obtained healthcare utilization from administrative claims data. Intent to treat analyses, including all participants randomized when they scheduled the first telephone session, will be conducted to compare CBT-I and EOC outcomes. The trial will be the largest experimental evaluation of telephone CBT-I to date, and the first to evaluate its cost-effectiveness. Trial registration: ClinicalTrials.gov identifier: NCT02946957.


Malaria paediatric hospitalization between 1999 and 2008 across Kenya.
Intervention coverage and funding for the control of malaria in Africa has increased in recent years, however, there are few descriptions of changing disease burden and the few reports available are from isolated, single site observations or are of reports at country-level. Here we present a nationwide assessment of changes over 10 years in paediatric malaria hospitalization across Kenya. Paediatric admission data on malaria and non-malaria diagnoses were assembled for the period 1999 to 2008 from in-patient registers at 17 district hospitals in Kenya and represented the diverse malaria ecology of the country. These data were then analysed using autoregressive moving average time series models with malaria and all-cause admissions as the main outcomes adjusted for rainfall, changes in service use and populations-at-risk within each hospital's catchment to establish whether there has been a statistically significant decline in paediatric malaria hospitalization during the observation period. Among the 17 hospital sites, adjusted paediatric malaria admissions had significantly declined at 10 hospitals over 10 years since 1999; had significantly increased at four hospitals, and remained unchanged in three hospitals. The overall estimated average reduction in malaria admission rates was 0.0063 cases per 1,000 children aged 0 to 14 years per month representing an average percentage reduction of 49% across the 10 hospitals registering a significant decline by the end of 2008. Paediatric admissions for all-causes had declined significantly with a reduction in admission rates of greater than 0.0050 cases per 1,000 children aged 0 to 14 years per month at 6 of 17 hospitals. Where malaria admissions had increased three of the four sites were located in Western Kenya close to Lake Victoria. Conversely there was an indication that areas with the largest declines in malaria admission rates were areas located along the Kenyan coast and some sites in the highlands of Kenya. A country-wide assessment of trends in malaria hospitalizations indicates that all is not equal, important variations exist in the temporal pattern of malaria admissions between sites and these differences require more detailed investigation to understand what is required to promote a clinical transition across Africa.


A Unified Abaqus Implementation of the Phase Field Fracture Method Using Only a User Material Subroutine.
We present a simple and robust implementation of the phase field fracture method in Abaqus. Unlike previous works, only a user material (UMAT) subroutine is used. This is achieved by exploiting the analogy between the phase field balance equation and heat transfer, which avoids the need for a user element mesh and enables taking advantage of Abaqus' in-built features. A unified theoretical framework and its implementation are presented, suitable for any arbitrary choice of crack density function and fracture driving force. Specifically, the framework is exemplified with the so-called AT1, AT2 and phase field-cohesive zone models (PF-CZM). Both staggered and monolithic solution schemes are handled. We demonstrate the potential and robustness of this new implementation by addressing several paradigmatic 2D and 3D boundary value problems. The numerical examples show how the current implementation can be used to reproduce numerical and experimental results from the literature, and efficiently capture advanced features such as complex crack trajectories, crack nucleation from arbitrary sites and contact problems. The code developed is made freely available.


Improving the diabetes-patient encounter by reflective tutoring for staff.
There is relative consensus about the advantages of patient-centred consultations. However, they have not been easy to realise in clinical praxis. The aim of this study was to investigate whether an intervention focused on health care professionals' understanding of the diabetes-patient encounter could facilitate a patient-centred way to encounter these patients. Two GPs and two nurses participated in the year-long intervention. The intervention focused on the staff's understanding of the encounter. Staff video recorded four to five encounters each and reflected together with a supervisor on their understanding of the encounters and how they were conducted. The encounters were analysed with the Verona-MICS/Dr coding system and patients' comments were analysed separately. The content of the consultations and how they were conducted was also assessed. There was a significant change of two patient-centred items by the staff over time. Two staff seemed to change their educational model. Modern theories of competence development seem to be useful in clinical settings.


Discovery of germacrene A synthases in Barnadesia spinosa: The first committed step in sesquiterpene lactone biosynthesis in the basal member of the Asteraceae.
The Andes-endemic Barnadesioideae lineage is the oldest surviving and phylogenetically basal subfamily of the Asteraceae (Compositae), a prolific group of flowering plants with world-wide distribution (∼24,000 species) marked by a rich diversity of sesquiterpene lactones (STLs). Intriguingly, there is no evidence that members of the Barnadesioideae produce STLs, specialized metabolites thought to have contributed to the adaptive success of the Asteraceae family outside South America. The biosynthesis of STLs requires the intimate expression and functional integration of germacrene A synthase (GAS) and germacrene A oxidase (GAO) to sequentially cyclize and oxidize farnesyl diphosphate into the advanced intermediate germacrene A acid leading to diverse STLs. Our previous discovery of GAO activity conserved across all major subfamilies of Asteraceae, including the phylogenetically basal lineage of Barnadesioideae, prompted further investigation of the presence of the gateway GAS in Barnadesioideae. Herein we isolated two terpene synthases (BsGAS1/BsGAS2) from the basal Barnadesia spinosa (Barnadesioideae) that displayed robust GAS activity when reconstituted in yeast and characterized in vitro. Despite the apparent lack of STLs in the Barnadesioideae, this work unambiguously confirms the presence of GAS in the basal genera of the Asteraceae. Phylogenetic analysis reveals that the two BsGASs fall into two distinct clades of the Asteraceae's GASs, and BsGAS1 clade is only retained in the evolutionary closer Cichorioideae subfamily, implicating BsGAS2 is likely the ancestral base of most GASs found in the lineages outside the Barnadesioideae. Taken together, these results show the enzymatic capacities of GAS and GAO emerged prior to the subsequent radiation of STL-producing Asteraceae subfamilies.


Development of the anti-cancer food scoring system 2.0: Validation and nutritional analyses of quantitative anti-cancer food scoring model.
We have previously designed the anti-cancer food scoring model (ACFS) 1.0, an evidence-based quantitative tool analyzing the anti-cancer or carcinogenic potential of diets. Analysis was performed using simple quantitative indexes divided into 6 categories (S, A, B, C, D, and E). In this study, we applied this scoring model to wider recipes and evaluated its nutritional relevance. National or known regional databases were searched for recipes from 6 categories: Korean out-dining, Korean home-dining, Western, Chinese, Mediterranean, and vegetarian. These recipes were scored using the ACFS formula and the nutrition profiles were analyzed. Eighty-eight international recipes were analyzed. All S-graded recipes were from vegetarian or Mediterranean categories. The median code values of each category were B (Korean home-dining), C (Korean out-dining), B (Chinese), A (Mediterranean), S (vegetarian), and D (Western). The following profiles were correlated (P < 0.05) with ACFS grades in the univariate trend analysis: total calories, total fat, animal fat, animal protein, total protein, vitamin D, riboflavin, niacin, vitamin B12, pantothenic acid, sodium, animal iron, zinc, selenium, and cholesterol (negative trends), and carbohydrate rate, fiber, water-soluble fiber, vitamin K, vitamin C, and plant calcium (positive trends). Multivariate analysis revealed that animal fat, animal iron, and niacin (negative trends) and animal protein, fiber, and vitamin C (positive trends) were statistically significant. Pantothenic acid and sodium showed non-significant negative trends (P < 0.1), and vitamin B12 showed a non-significant positive trend. This study provided a nutritional basis and extended the utility of ACFS, which is a bridgehead for future cancer-preventive clinical trials using ACFS.


The impact of two semiannual treatments with albendazole alone on lymphatic filariasis and soil-transmitted helminth infections: a community-based study in the Republic of Congo.
Implementation of mass drug administration (MDA) with ivermectin plus albendazole (ALB) for lymphatic filariasis (LF) has been delayed in central Africa because of the risk of serious adverse events in subjects with high Loa loa microfilaremia. We conducted a community trial to assess the impact of semiannual MDA with ALB (400 mg) alone on LF and soil-transmitted helminth (STH) infections in the Republic of Congo. Evaluation at 12 months showed that ALB MDA had not significantly reduced Wuchereria bancrofti antigenemia or microfilaria (mf) rates in the community (from 17.3% to 16.6% and from 5.3% to 4.2%, respectively). However, the geometric mean mf count in mf-positive subjects was reduced from 202.2 to 80.9 mf/mL (60% reduction, P = 0.01). The effect of ALB was impressive in 38 subjects who were mf-positive at baseline and retested at 12 months: 37% had total mf clearance, and individual mf densities were reduced by 73.0%. MDA also dramatically reduced the hookworm infection rate in the community from 6.5% to 0.6% (91% reduction), with less impressive effects on Ascaris and Trichuris. These preliminary results suggest that semiannual community MDA with ALB is a promising strategy for controlling LF and STH in areas with coendemic loiasis.