Two-stage two-locus models in genome-wide association.
Studies in model organisms suggest that epistasis may play an important role in the etiology of complex diseases and traits in humans. With the era of large-scale genome-wide association studies fast approaching, it is important to quantify whether it will be possible to detect interacting loci using realistic sample sizes in humans and to what extent undetected epistasis will adversely affect power to detect association when single-locus approaches are employed. We therefore investigated the power to detect association for an extensive range of two-locus quantitative trait models that incorporated varying degrees of epistasis. We compared the power to detect association using a single-locus model that ignored interaction effects, a full two-locus model that allowed for interactions, and, most important, two two-stage strategies whereby a subset of loci initially identified using single-locus tests were analyzed using the full two-locus model. Despite the penalty introduced by multiple testing, fitting the full two-locus model performed better than single-locus tests for many of the situations considered, particularly when compared with attempts to detect both individual loci. Using a two-stage strategy reduced the computational burden associated with performing an exhaustive two-locus search across the genome but was not as powerful as the exhaustive search when loci interacted. Two-stage approaches also increased the risk of missing interacting loci that contributed little effect at the margins. Based on our extensive simulations, our results suggest that an exhaustive search involving all pairwise combinations of markers across the genome might provide a useful complement to single-locus scans in identifying interacting loci that contribute to moderate proportions of the phenotypic variance.


The impact of recurrent abdominal pain: predictors of outcome in a large population cohort.
Recurrent abdominal pain is one of the commonest complaints of childhood, affecting approximately 10% of children at any one time. This study aims to describe the outcome of recurrent abdominal pain amongst 6-year-old children, and to identify risk factors (in both the children and their parents), which predict these outcomes. 7128 6-year-old children in the Avon Longitudinal Study of Parents and Children (ALSPAC) were followed up for 1 year. The principle outcomes were abdominal pain, number of days missed from school in the preceding year and psychiatric diagnoses. Children with recurrent abdominal pain at age 6 years had higher rates of further abdominal pain [odds ratio 4.88 (95% CI: 4.01, 5.95)], school absence (10 or more days off school in a year) [OR 1.89 (1.53, 2.33)] and anxiety disorders [OR 2.36 (1.68, 3.32)] at age 7 years. Maternal anxiety was the most consistent predictor of subsequent adverse outcomes for these children. Children with recurrent abdominal pain are at significant and continuing risk of adverse functioning. It is important for clinicians to take a whole family perspective, and particularly to consider parental anxiety, when a child with recurrent abdominal pain presents to them.


P2Y6 signaling in alveolar macrophages prevents leukotriene-dependent type 2 allergic lung inflammation.
Antagonists of the type 1 cysteinyl leukotriene receptor (CysLT1R) are widely used to treat asthma and allergic rhinitis, with variable response rates. Alveolar macrophages express UDP-specific P2Y6 receptors that can be blocked by off-target effects of CysLT1R antagonists. Sensitizing intranasal doses of an extract from the house dust mite Dermatophagoides farinae (Df) sharply increased the levels of UDP detected in bronchoalveolar lavage fluid of mice. Conditional deletion of P2Y6 receptors before sensitization exacerbated eosinophilic lung inflammation and type 2 cytokine production in response to subsequent Df challenge. P2Y6 receptor signaling was necessary for dectin-2-dependent production of protective IL-12p40 and Th1 chemokines by alveolar macrophages, leading to activation of NK cells to generate IFN-γ. Administration of CysLT1R antagonists during sensitization blocked UDP-elicited potentiation of IL-12p40 production by macrophages in vitro, suppressed the Df-induced production of IL-12p40 and IFN-γ in vivo, and suppressed type 2 inflammation only in P2Y6-deficient mice. Thus, P2Y6 receptor signaling drives an innate macrophage/IL-12/NK cell/IFN-γ axis that prevents inappropriate allergic type 2 immune responses on respiratory allergen exposure and counteracts the Th2 priming effect of CysLT1R signaling at sensitization. Targeting P2Y6 signaling might prove to be a potential additional treatment strategy for allergy.


A randomized controlled trial of mindfulness meditation versus relaxation training: effects on distress, positive states of mind, rumination, and distraction.
Although mindfulness meditation interventions have recently shown benefits for reducing stress in various populations, little is known about their relative efficacy compared with relaxation interventions. This randomized controlled trial examines the effects of a 1-month mindfulness meditation versus somatic relaxation training as compared to a control group in 83 students (M age = 25; 16 men and 67 women) reporting distress. Psychological distress, positive states of mind, distractive and ruminative thoughts and behaviors, and spiritual experience were measured, while controlling for social desirability. Hierarchical linear modeling reveals that both meditation and relaxation groups experienced significant decreases in distress as well as increases in positive mood states over time, compared with the control group (p < .05 in all cases). There were no significant differences between meditation and relaxation on distress and positive mood states over time. Effect sizes for distress were large for both meditation and relaxation (Cohen's d = 1.36 and .91, respectively), whereas the meditation group showed a larger effect size for positive states of mind than relaxation (Cohen's d =.71 and .25, respectively). The meditation group also demonstrated significant pre-post decreases in both distractive and ruminative thoughts/behaviors compared with the control group (p < .04 in all cases; Cohen's d = .57 for rumination and .25 for distraction for the meditation group), with mediation models suggesting that mindfulness meditation's effects on reducing distress were partially mediated by reducing rumination. No significant effects were found for spiritual experience. The data suggest that compared with a no-treatment control, brief training in mindfulness meditation or somatic relaxation reduces distress and improves positive mood states. However, mindfulness meditation may be specific in its ability to reduce distractive and ruminative thoughts and behaviors, and this ability may provide a unique mechanism by which mindfulness meditation reduces distress.


Towards understanding language organisation in the brain using fMRI.
Functional magnetic resonance imaging (fMRI), which allows non-invasive mapping of human cognitive functions, has become an important tool for understanding language function. An understanding of component processes and sources of noise in the images is contributing to increased confidence in the reproductability of studies. This allows clinical applications, e.g., for pre-surgical lateralisation of language functions in patients with temporal lobe epilepsy. fMRI is a sensitive method for mapping regions involved in language functions. We recently have applied it to study the effect of word surface form on reading with a comparison of responses to Chinese characters or alphabetical Pinyin. Interpretation of fMRI activations must be made with caution; fMRI suggests task-associated activation, but does not independently confirm that such activity is necessary. However, complementary studies can be performed using transcranial magnetic stimulation (TMS), which can be used to interfere with brain activity in a specific region transiently for characterisation of the behavioural effects. We describe how TMS combined with fMRI has confirmed a role for the left inferior frontal cortex in semantic processing.


A role beyond learning for NMDA receptors in reward-based decision-making-a pharmacological study using d-cycloserine.
N-methyl-D-aspartate (NMDA) receptors are known to fulfill crucial functions in many forms of learning and plasticity. More recently, biophysical models, however, have suggested an additional role of NMDA receptors in evidence integration for decision-making, going beyond their role in learning. We designed a task to study the role of NMDA receptors in human reward-guided learning and decision-making. Human participants were assigned to receive either 250 mg of the partial NMDA agonist d-cycloserine (n=20) or matching placebo capsules (n=27). Reward-guided learning and decision-making were assessed using a task in which participants had to integrate learnt and explicitly shown value information to maximize their monetary wins and minimize their losses. To tease apart the effects of NMDA on learning and decision-making we used simple learning models. D-cycloserine shifted decision-making towards a more optimal integration of the learnt and the explicitly shown information, in the absence of a direct learning effect. In conclusion, our results reveal a distinct role for NMDA receptors in reward-guided decision-making. We discuss these findings in the context of NMDA's roles in neuronal super-additivity and as crucial for evidence integration for decisions.


Charge separation in type II tunneling multilayered structures of CdTe and CdSe nanocrystals directly proven by surface photovoltage spectroscopy.
Charge separation and diffusion in type II multilayered structures of CdTe and CdSe nanocrystals with a polymer spacer are unambiguously proven by surface photovoltage spectroscopy. Holes accumulate in CdTe nanocrystal layers, and the electrons in CdSe nanocrystal layers. An increase of thickness of the polymer spacer strongly decreases the charge separation efficiency. Surface photovoltage transients demonstrate diffusion of the separated charges over several layers of the same kind of nanocrystals.


Effect of acupuncture therapy for postponing Wallerian degeneration of cerebral infarction as shown by diffusion tensor imaging.
One aim of this study was to investigate the effects of acupuncture on cerebral function of patients with acute cerebral infarction. Another goal was to evaluate the relationship between acupuncture treatment and motor recovery patients with stroke and to provide a foundation for using acupuncture therapy for such patients. Twenty (20) patients with recent cerebral infarction were divided randomly to an acupuncture group and a control group. The infarction area in each patient was in the basal ganglia or included the basal ganglia with an area size of > 1 cm(2). Serial diffusion tensor imaging (DTI), fluid-attenuated inversion recovery (FLAIR), and T2-weighted imaging (T(2)WI) scans were performed on all patients and the results were evaluated using the National Institute of Health Stroke Scale and the Barthel Index each week. DTI images were postprocessed and analyzed. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values of abnormal signals on DTI in the infarction areas and cerebral peduncles were calculated for both groups and compared with one another. (1) The ADC value of infarction lesions decreased at stroke onset; then, a significant elevation was observed after the acute stage, and a significant reduction in FA values was observed from stroke onset to the chronic stage. (2) The ADC of the bilateral cerebral peduncle was reduced on the infarction side. (3) There was a significant difference in ADC and FA values between the acupuncture and control groups. The FA value was higher in the acupuncture group than the control group. ADC and FA values might correlate to patient recovery and reveal the progress of secondary degeneration. Acupuncture treatment is effective for protecting neurons and facilitating recovery.


TBBPA exposure during a sensitive developmental window produces neurobehavioral changes in larval zebrafish.
Tetrabromobisphenol A (TBBPA), one of the most widely used brominated flame retardants (BFRs), is a ubiquitous contaminant in the environment and in the human body. This study demonstrated that zebrafish embryos exposed to TBBPA during a sensitive window of 8-48 h post-fertilization (hpf) displayed morphological malformations and mortality. Zebrafish exposed exclusively between 48 and 96 hpf were phenotypically normal. TBBPA was efficiently absorbed and accumulated in zebrafish embryos, but was eliminated quickly when the exposure solution was removed. Larval behavior assays conducted at 120 hpf indicated that exposure to 5 μM TBBPA from 8 to 48 hpf produced larvae with significantly lower average activity and speed of movement in the normal condition than in those exposed from 48 to 96 hpf. Specifically, 8-48 hpf-exposed larvae spent significantly less time in both activity bursts and gross movements compared to control or 48-96 hpf exposed larvae. Consistent with the motor deficits, TBBPA induced apoptotic cell death, delayed cranial motor neuron development, inhibited primary motor neuron development and loosed muscle fiber during the early developmental stages. To further explore TBBPA-induced developmental and neurobehavioral toxicity, RNA-Seq analysis was used to identify early transcriptional changes following TBBPA exposure. In total, 1969 transcripts were significantly differentially expressed (P < 0.05, FDR < 0.05, 1.5-FC) upon TBBPA exposure. Functional and pathway analysis of the TBBPA transcriptional profile identified biological processes involved in nerve development, muscle filament sliding and contraction, and extracellular matrix disassembly and organization changed significantly. In addition, TBBPA also led to an elevation in the expression of genes encoding uridine diphosphate glucuronyl transferases (ugt), which could affect thyroxine (T4) metabolism and subsequently lead to neurobehavioral changes. In summary, TBBPA exposure during a narrow, sensitive developmental window perturbs various molecular pathways and results in neurobehavioral deficits in zebrafish.


Quantitative transrectal shear wave elastography undergoing salvage extraperitoneal laparoscopic radical prostatectomy following failed radiotherapy.
To evaluate pre-surgical quantitative transrectal shear wave elastography (SWE) in the detection and characterisation of radioresistant prostate cancer. Twelve men with recurrent prostate cancer following external beam radiotherapy were included in a prospective protocol-driven study. All underwent MR imaging and quantitative shear wave elastographic assessment of recurrent disease prior to salvage laparoscopic radical prostatectomy procedures. Images were used to construct 3D mold printing and histopathological processing of surgical specimen. Statistical analyses including ROC were generated using software programmes. There were 48 cancer foci identified on final histopathology using patient-specific mold-based approach in 12 patients. Mean number of lesion was 3.4 (range 2-4). Quantitative transrectal SWE showed a sensitivity and specificity 0.77 (95% CI 0.627-0.880) and 0.82 (95% CI 0.642-0.942), respectively. The diagnostic accuracy increased with increasing size of the lesions with overall AUC of 0.89. In our series, quantitative transrectal SWE showed a good diagnostic accuracy in the detection and characterisation of recurrent prostate cancer following failed radiotherapy treatment. These findings may help in targeting biopsies or future focal treatment options.


Composition and structure of synaptic ectosomes exporting antigen receptor linked to functional CD40 ligand from helper T cells.
Planar supported lipid bilayers (PSLB) presenting T cell receptor (TCR) ligands and ICAM-1 induce budding of extracellular microvesicles enriched in functional TCR, defined here as synaptic ectosomes (SE), from helper T cells. SE bind peptide-MHC directly exporting TCR into the synaptic cleft, but incorporation of other effectors is unknown. Here, we utilized bead supported lipid bilayers (BSLB) to capture SE from single immunological synapses (IS), determined SE composition by immunofluorescence flow cytometry and enriched SE for proteomic analysis by particle sorting. We demonstrate selective enrichment of CD40L and ICOS in SE in response to addition of CD40 and ICOSL, respectively, to SLB presenting TCR ligands and ICAM-1. SE are enriched in tetraspanins, BST-2, TCR signaling and ESCRT proteins. Super-resolution microscopy demonstrated that CD40L is present in microclusters within CD81 defined SE that are spatially segregated from TCR/ICOS/BST-2. CD40L+ SE retain the capacity to induce dendritic cell maturation and cytokine production.


A new method for quantifying the needling component of acupuncture treatments.
The highly variable nature of acupuncture needling creates challenges to systematic research. The goal of this study was to test the feasibility of quantifying acupuncture needle manipulation using motion and force measurements. It was hypothesised that distinct needling styles and techniques would produce different needle motion and force patterns that could be quantified and differentiated from each other. A new needling sensor tool (Acusensor) was used to record needling in real time as performed by six New England School of Acupuncture staff from the 'Chinese acupuncture' (style 1) and 'Japanese acupuncture' (style 2) programmes (three from each). Each faculty expert needled 12 points (6 bilateral locations) in 12 healthy human subjects using tonification (technique 1) and dispersal (technique 2). Parameters calculated from the raw needling data were displacement amplitude, displacement frequency, rotation amplitude, rotation frequency, force amplitude and torque amplitude. Data analysis revealed significant differences in the amplitude of displacement and rotation between needling performed by staff from two different acupuncture styles. Significant overall differences in the frequency of displacement between techniques 1 and 2 that were not dependent of the style of acupuncture being performed were also found. The relationships between displacement and rotation frequencies, as well as between displacement and force amplitudes showed considerable variability across individual acupuncturists and subjects. Needling motion and force parameters can be quantified in a treatment-like setting. Needling data can subsequently be analysed, providing an objective method for characterising needling in basic and clinical acupuncture research.


Patient safety incidents from acupuncture treatments: a review of reports to the National Patient Safety Agency.
Acupuncture is frequently employed to treat chronic pain syndromes or other chronic conditions. Nevertheless, there is a growing literature on adverse events (AEs) from treatments including pneumothorax, cardiac tamponade and spinal cord injury. Acupuncture is provided in almost all NHS pain clinics and by an increasing number of GP's and physiotherapists. Considering acupuncture's popularity, its safety has become an important public health issue. To evaluate the harm caused to patients through acupuncture treatments within NHS organisations. The National Reporting and Learning System (NRLS) database was searched for incidents reported from 1st January 2009 to 31st December 2011. The free text fields of all reports received from all healthcare settings and specialties were searched for the keyword 'acupuncture'. All relevant incidents were reviewed to provide a qualitative theme of the harm to patients. 468 patient safety incidents were identified; 325 met our inclusion criteria for analysis. Adverse events reported include retained needles (31%), dizziness (30%), loss of consciousness/unresponsive (19%), falls (4%), Bruising or soreness at needle site (2%), Pneumothorax (1%) and other adverse reactions (12%). The majority (95%) of the incidents were categorised as low or no harm. A number of AEs are recorded after acupuncture treatments in the NHS but the majority is not severe. However, miscategorisation and under-reporting may distort the overall picture. Acupuncture practitioners should be aware of, and be prepared to manage, any significant harm from treatments.


Factors Leading to Poor Water Sanitation Hygiene Among Primary School Going Children in Chitungwiza.
Although the world has progressed in the area of water and sanitation, more than 2.3 billion people still live without access to sanitation facilities and some are unable to practice basic hygiene. Access to water and basic sanitation has deteriorated in Chitungwiza and children are at risk of developing illness and missing school due to the deterioration. We sought to investigate the predisposing, enabling and reinforcing factors that are causally related to water- and sanitation- related hygiene practices among school going children. A random sample of 400 primary school children (196 males, 204 females) in four schools in Chitungwiza town, Zimbabwe was interviewed. Behavioural factors were assessed through cross examination of the PROCEED PRECEDE Model. The respondents had been stratified through the random sampling where strata were classes. A structured observation checklist was also administered to assess hygiene enabling facilities for each school. Children's knowledge and perceptions were inconsistent with hygienic behaviour. The family institution seemed to play a more important role in life skills training and positive reinforcement compared to the school (50% vs 27.3%). There was no association between a child's sex, age and parents' occupation with any of the factors assessed (P=0.646). Schools did not provide a hygiene enabling environment as there were no learning materials, policy and resources on hygiene and health. The challenges lay in the provision of hygiene enabling facilities, particularly, the lack of access to sanitation for the maturing girl child and a school curriculum that provides positive reinforcement and practical life skills training approach.


Immunogenicity of two investigational serogroup B meningococcal vaccines in the first year of life: a randomized comparative trial.
An investigational vaccine against serogroup B meningococcal (MenB) disease containing 3 main recombinant proteins (factor H-binding protein, Neisserial adhesion A, and Neisserial heparin-binding antigen) has been developed. We evaluated the immunogenicity and reactogenicity of a 3-dose course of this vaccine administered alone (recombinant MenB [rMenB]) or combined with the outer membrane vesicle (OMV) component of the vaccine used in New Zealand (rMenB+OMV). A randomized, single-blind, comparative study of 60 healthy infants enrolled at 6 to 8 months of age and immunized with rMenB or rMenB+OMV at day 0, day 60, and at age 12 months. Blood samples obtained at baseline and 1 month following the second and third doses of vaccine were analyzed for serum bactericidal antibody (SBA) using human complement (hSBA) against 7 MenB strains. The putative correlate of protection was an hSBA titer of ≥4. The per-protocol analysis included 24 of 30 participants randomized to each group. After 3 doses of rMenB+OMV, 90% or more of participants had an hSBA titer ≥4 for 5 MenB strains, with 70% of participants having an hSBA titer ≥4 for a sixth strain. rMenB alone was immunogenic for only 3 strains. Both vaccines were well tolerated. Three doses of rMenB+OMV in the second half of infancy induce bactericidal antibodies against strains expressing vaccine antigens, demonstrating the potential for broader vaccine prevention of MenB disease. This vaccine is now in phase III clinical trials.


Phylogenetic identification and in situ detection of individual microbial cells without cultivation.
The frequent discrepancy between direct microscopic counts and numbers of culturable bacteria from environmental samples is just one of several indications that we currently know only a minor part of the diversity of microorganisms in nature. A combination of direct retrieval of rRNA sequences and whole-cell oligonucleotide probing can be used to detect specific rRNA sequences of uncultured bacteria in natural samples and to microscopically identify individual cells. Studies have been performed with microbial assemblages of various complexities ranging from simple two-component bacterial endosymbiotic associations to multispecies enrichments containing magnetotactic bacteria to highly complex marine and soil communities. Phylogenetic analysis of the retrieved rRNA sequence of an uncultured microorganism reveals its closest culturable relatives and may, together with information on the physicochemical conditions of its natural habitat, facilitate more directed cultivation attempts. For the analysis of complex communities such as multispecies biofilms and activated-sludge flocs, a different approach has proven advantageous. Sets of probes specific to different taxonomic levels are applied consecutively beginning with the more general and ending with the more specific (a hierarchical top-to-bottom approach), thereby generating increasingly precise information on the structure of the community. Not only do rRNA-targeted whole-cell hybridizations yield data on cell morphology, specific cell counts, and in situ distributions of defined phylogenetic groups, but also the strength of the hybridization signal reflects the cellular rRNA content of individual cells. From the signal strength conferred by a specific probe, in situ growth rates and activities of individual cells might be estimated for known species. In many ecosystems, low cellular rRNA content and/or limited cell permeability, combined with background fluorescence, hinders in situ identification of autochthonous populations. Approaches to circumvent these problems are discussed in detail.


Pharmacogenomics of statin therapy: any new insights in efficacy or safety?
To examine the current evidence concerning the effects of genetic variation on statin-related low-density lipoprotein cholesterol reductions, clinical efficacy, and adverse events and the relevance for patient care. Recent years have seen the emergence of large-scale genetic experiments, including genome-wide association studies and candidate gene studies, exploring the impact of common genetic variation on patient response to statins. These studies have built on previous smaller scale evidence, providing improved statistical power and enhanced ability to explore the genome. Current evidence suggests that common genetic variants do not alter low-density lipoprotein cholesterol response by more than a few percent, or materially alter the effect of statin on vascular risk reduction, and therefore that patients benefit from statins independent of common genetic variation. However, knowledge of SLCO1B1 genotypes is believed to have clinical utility for predicting myopathy risk and ensuring that statins are prescribed as safely as possible. Furthermore, new hypothesis-generating studies, such as those associating GATM with myopathy risk, offer potential insights for the future. Common genetic variation does not appear to be an important determinant of statin response, with the exception of SLCO1B1 and risk of myopathy. Future studies will help to determine the impact of low-frequency and rare genetic variation on statin response.


Accelerated modern human-induced species losses: Entering the sixth mass extinction.
The oft-repeated claim that Earth's biota is entering a sixth "mass extinction" depends on clearly demonstrating that current extinction rates are far above the "background" rates prevailing between the five previous mass extinctions. Earlier estimates of extinction rates have been criticized for using assumptions that might overestimate the severity of the extinction crisis. We assess, using extremely conservative assumptions, whether human activities are causing a mass extinction. First, we use a recent estimate of a background rate of 2 mammal extinctions per 10,000 species per 100 years (that is, 2 E/MSY), which is twice as high as widely used previous estimates. We then compare this rate with the current rate of mammal and vertebrate extinctions. The latter is conservatively low because listing a species as extinct requires meeting stringent criteria. Even under our assumptions, which would tend to minimize evidence of an incipient mass extinction, the average rate of vertebrate species loss over the last century is up to 100 times higher than the background rate. Under the 2 E/MSY background rate, the number of species that have gone extinct in the last century would have taken, depending on the vertebrate taxon, between 800 and 10,000 years to disappear. These estimates reveal an exceptionally rapid loss of biodiversity over the last few centuries, indicating that a sixth mass extinction is already under way. Averting a dramatic decay of biodiversity and the subsequent loss of ecosystem services is still possible through intensified conservation efforts, but that window of opportunity is rapidly closing.


Growth and bone development.
Osteoporosis is a major cause of morbidity and mortality through its association with age-related fractures. Although most effort in fracture prevention has been directed at retarding the rate of age-related bone loss, and reducing the frequency and severity of trauma among elderly people, evidence is growing that peak bone mass is an important contributor to bone strength during later life. The normal patterns of skeletal growth have been well characterized in cross-sectional and longitudinal studies. It has been confirmed that boys have higher bone mineral content, but not volumetric bone density, than girls. Furthermore, there is a dissociation between the peak velocities for height gain and bone mineral accrual, in both genders. Puberty is the period during which volumetric density appears to increase in both axial and appendicular sites. Many factors influence the accumulation of bone mineral during childhood and adolescence, including heredity, gender, diet, physical activity, endocrine status, and sporadic risk factors such as cigarette smoking. In addition to these modifiable factors during childhood, evidence has also accrued that fracture risk might be programmed during intrauterine life. Epidemiological studies have demonstrated a relationship between birthweight, weight in infancy, and adult bone mass. This appears to be mediated through modulation of the set-point for basal activity of pituitary-dependent endocrine systems such as the hypothalamicpituitary-adrenal and growth hormone/insulin-like growth factor-1 axes. Maternal smoking, diet (particularly vitamin D deficiency), and physical activity also appear to modulate bone mineral acquisition during intrauterine life; furthermore, both low birth size and poor childhood growth are directly linked to the later risk of hip fracture. The optimization of maternal nutrition and intrauterine growth should also be included within preventive strategies against osteoporotic fracture, albeit for future generations.


Image statistics and the perception of surface qualities.
The world is full of surfaces, and by looking at them we can judge their material qualities. Properties such as colour or glossiness can help us decide whether a pancake is cooked, or a patch of pavement is icy. Most studies of surface appearance have emphasized textureless matte surfaces, but real-world surfaces, which may have gloss and complex mesostructure, are now receiving increased attention. Their appearance results from a complex interplay of illumination, reflectance and surface geometry, which are difficult to tease apart given an image. If there were simple image statistics that were diagnostic of surface properties it would be sensible to use them. Here we show that the skewness of the luminance histogram and the skewness of sub-band filter outputs are correlated with surface gloss and inversely correlated with surface albedo (diffuse reflectance). We find evidence that human observers use skewness, or a similar measure of histogram asymmetry, in making judgements about surfaces. When the image of a surface has positively skewed statistics, it tends to appear darker and glossier than a similar surface with lower skewness, and this is true whether the skewness is inherent to the original image or is introduced by digital manipulation. We also find a visual after-effect based on skewness: adaptation to patterns with skewed statistics can alter the apparent lightness and glossiness of surfaces that are subsequently viewed. We suggest that there are neural mechanisms sensitive to skewed statistics, and that their outputs can be used in estimating surface properties.


Widespread increase of tree mortality rates in the western United States.
Persistent changes in tree mortality rates can alter forest structure, composition, and ecosystem services such as carbon sequestration. Our analyses of longitudinal data from unmanaged old forests in the western United States showed that background (noncatastrophic) mortality rates have increased rapidly in recent decades, with doubling periods ranging from 17 to 29 years among regions. Increases were also pervasive across elevations, tree sizes, dominant genera, and past fire histories. Forest density and basal area declined slightly, which suggests that increasing mortality was not caused by endogenous increases in competition. Because mortality increased in small trees, the overall increase in mortality rates cannot be attributed solely to aging of large trees. Regional warming and consequent increases in water deficits are likely contributors to the increases in tree mortality rates.


9,400 years of cosmic radiation and solar activity from ice cores and tree rings.
Understanding the temporal variation of cosmic radiation and solar activity during the Holocene is essential for studies of the solar-terrestrial relationship. Cosmic-ray produced radionuclides, such as (10)Be and (14)C which are stored in polar ice cores and tree rings, offer the unique opportunity to reconstruct the history of cosmic radiation and solar activity over many millennia. Although records from different archives basically agree, they also show some deviations during certain periods. So far most reconstructions were based on only one single radionuclide record, which makes detection and correction of these deviations impossible. Here we combine different (10)Be ice core records from Greenland and Antarctica with the global (14)C tree ring record using principal component analysis. This approach is only possible due to a new high-resolution (10)Be record from Dronning Maud Land obtained within the European Project for Ice Coring in Antarctica in Antarctica. The new cosmic radiation record enables us to derive total solar irradiance, which is then used as a proxy of solar activity to identify the solar imprint in an Asian climate record. Though generally the agreement between solar forcing and Asian climate is good, there are also periods without any coherence, pointing to other forcings like volcanoes and greenhouse gases and their corresponding feedbacks. The newly derived records have the potential to improve our understanding of the solar dynamics and to quantify the solar influence on climate.


Integrating genealogical and dynamical modelling to infer escape and reversion rates in HIV epitopes.
The rates of escape and reversion in response to selection pressure arising from the host immune system, notably the cytotoxic T-lymphocyte (CTL) response, are key factors determining the evolution of HIV. Existing methods for estimating these parameters from cross-sectional population data using ordinary differential equations (ODEs) ignore information about the genealogy of sampled HIV sequences, which has the potential to cause systematic bias and overestimate certainty. Here, we describe an integrated approach, validated through extensive simulations, which combines genealogical inference and epidemiological modelling, to estimate rates of CTL escape and reversion in HIV epitopes. We show that there is substantial uncertainty about rates of viral escape and reversion from cross-sectional data, which arises from the inherent stochasticity in the evolutionary process. By application to empirical data, we find that point estimates of rates from a previously published ODE model and the integrated approach presented here are often similar, but can also differ several-fold depending on the structure of the genealogy. The model-based approach we apply provides a framework for the statistical analysis and hypothesis testing of escape and reversion in population data and highlights the need for longitudinal and denser cross-sectional sampling to enable accurate estimate of these key parameters.


Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.
The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk-outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk-outcome pairs, and new data on risk exposure levels and risk-outcome associations. We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk-outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017. In 2017, 34·1 million (95% uncertainty interval [UI] 33·3-35·0) deaths and 1·21 billion (1·14-1·28) DALYs were attributable to GBD risk factors. Globally, 61·0% (59·6-62·4) of deaths and 48·3% (46·3-50·2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10·4 million (9·39-11·5) deaths and 218 million (198-237) DALYs, followed by smoking (7·10 million [6·83-7·37] deaths and 182 million [173-193] DALYs), high fasting plasma glucose (6·53 million [5·23-8·23] deaths and 171 million [144-201] DALYs), high body-mass index (BMI; 4·72 million [2·99-6·70] deaths and 148 million [98·6-202] DALYs), and short gestation for birthweight (1·43 million [1·36-1·51] deaths and 139 million [131-147] DALYs). In total, risk-attributable DALYs declined by 4·9% (3·3-6·5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23·5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18·6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low. By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning. Bill & Melinda Gates Foundation.


Modeling of the knee joint load in rehabilitative knee extension exercises under water.
A biomechanical and hydrodynamic theoretical model has been developed in order to calculate the knee joint load during underwater knee extension exercises. The hydrodynamic force has been evaluated within the framework of a strip-theory approach, when a blunt rectangular resistive device is applied proximally to the shank to increase its frontal area. Analytical expressions of the patellar tendon force (F(PT)), the axial (phi(n)) and the shear (phi(t)) component of the tibiofemoral joint load have been derived as a function of joint angle (theta), angular velocity (theta ), angular acceleration (theta ), resistive device density, length (L(x)), width (L(z)) and thickness, and average hydrodynamic drag and added mass coefficients. An inverse dynamic problem has been solved, assuming for theta and theta a dependence on theta consistent with the experimental kinematic data available in the literature. The results highlight that the characteristics of the resistive device and the level of muscular activation can be adjusted reciprocally in order to control the peak value of F(PT), phi(n) and phi(t), and the position of these peaks within the joint range of motion (ROM). No anterior cruciate ligament (ACL) stress is observed (phi(t)>0) over the whole ROM, independent of the level of muscular activation, for a light resistive device with L(x) < or = 0.3 m and L(z) < or = 0.4 m. This work highlights that aquatic exercises can be usefully and safely implemented in the rehabilitation program following ACL surgery, and whenever it is important to avoid excessive shear joint forces that constrain the tibial plateau anterior translation with respect to the femur.


The meiotic differentiation program uncouples S-phase from cell size control in Saccharomyces cerevisiae.
Cell size homeostasis in proliferating cell populations is maintained in part by linking the initiation of a cell division cycle to growth such that a specific "size threshold" must be achieved prior to cell cycle initiation. In Saccharomyces cerevisiae the size threshold is responsive to environmental conditions and cell cycle entry is initiated at smaller sizes in poor growth medium and larger sizes in rich medium. In response to starvation for nitrogen and glucose diploid S. cerevisiae abandon proliferation and initiate gametogenesis (sporulation). The ability of both small and large cells to sporulate was investigated and the data reported here indicate that very small S. cerevisiae cells derived from the SK1 genetic background are able to sporulate. Although larger cells progress through the process more rapidly than small cells, sporulation of very small cells appears to be normal as they undergo meiotic recombination and form viable spores. Genetic analysis indicates that this trait is determined by multiple genes and may explain why some S. cerevisiae strains appear to display a minimal size threshold for sporulation. These data support a model where cell size controls can be bypassed or profoundly altered specifically to allow cellular differentiation in response to environmental signals.


Mutations in SETBP1 are recurrent in myelodysplastic syndromes and often coexist with cytogenetic markers associated with disease progression.
Whole exome sequencing was performed in a patient with myelodysplastic syndrome before and after progression to acute myeloid leukaemia. Mutations in several genes, including SETBP1, were identified following leukaemic transformation. Screening of 328 patients with myeloid disorders revealed SETBP1 mutations in 14 patients (4·3%), 7 of whom had -7/del(7q) and 3 had i(17)(q10), cytogenetic markers associated with shortened overall survival and increased risk of leukaemic evolution. SETBP1 mutations were frequently acquired at the time of leukaemic evolution, coinciding with increase of leukaemic blasts. These data suggest that SETBP1 mutations may play a role in MDS and chronic myelomonocytic leukaemia disease progression.


Multidisciplinary crisis simulations: the way forward for training surgical teams.
High-reliability organizations have stressed the importance of non-technical skills for safety and of regularly providing such training to their teams. Recently safety skills training has been applied in the practice of medicine. In this study, we developed and piloted a module using multidisciplinary crisis scenarios in a simulated operating theatre to train entire surgical teams. Twenty teams participated (n = 80); each consisted of a trainee surgeon, anesthetist, operating department practitioner (ODP), and scrub nurse. Crisis scenarios such as difficult intubation, hemorrhage, or cardiac arrest were simulated. Technical and non-technical skills (leadership, communication, team skills, decision making, and vigilance), were assessed by clinical experts and by two psychologists using relevant technical and human factors rating scales. Participants received technical and non-technical feedback, and the whole team received feedback on teamwork. Trainees assessed the training favorably. For technical skills there were no differences between surgical trainees' assessment scores and the assessment scores of the trainers. However, nurses overrated their technical skill. Regarding non-technical skills, leadership and decision making were scored lower than the other three non-technical skills (communication, team skills, and vigilance). Surgeons scored lower than nurses on communication and teamwork skills. Surgeons and anesthetists scored lower than nurses on leadership. Multidisciplinary simulation-based team training is feasible and well received by surgical teams. Non-technical skills can be assessed alongside technical skills, and differences in performance indicate where there is a need for further training. Future work should focus on developing team performance measures for training and on the development and evaluation of systematic training for technical and non-technical skills to enhance team performance and safety in surgery.


Molecular MRI approaches to the detection of CNS inflammation.
Inflammation is a key component of many neurological diseases, yet our understanding of the contribution of these processes to tissue damage remains poor. For many such diseases, magnetic resonance imaging (MRI) has become the method of choice for clinical diagnosis. However, many of the MRI parameters that enable disease detection, such as passive contrast enhancement across a compromised blood-brain barrier, are weighted towards late-stage disease. Moreover, whilst these methods may report on disease severity, they are not able to provide information on either disease activity or the underlying molecular processes. There is a need, therefore, to develop methods that enable earlier disease detection, potentially long before clinical symptoms become apparent, together with identification of specific molecular processes that may guide specific therapy. This chapter describes the methodology for the synthesis and validation of two novel, functional MRI-detectable probes, based on microparticles of iron oxide (MPIO), which target endothelial adhesion molecules. These contrast agents enable the detection of acute brain inflammation in vivo, at a time when pathology is undetectable by conventional MRI. Such molecular MRI methods are opening new vistas for the acute diagnosis of CNS disease, together with the possibility for individually tailored therapy and earlier, more sensitive assessment of the efficacy of novel therapies.


A data-driven weighting scheme for multivariate phenotypic endpoints recapitulates zebrafish developmental cascades.
Zebrafish have become a key alternative model for studying health effects of environmental stressors, partly due to their genetic similarity to humans, fast generation time, and the efficiency of generating high-dimensional systematic data. Studies aiming to characterize adverse health effects in zebrafish typically include several phenotypic measurements (endpoints). While there is a solid biomedical basis for capturing a comprehensive set of endpoints, making summary judgments regarding health effects requires thoughtful integration across endpoints. Here, we introduce a Bayesian method to quantify the informativeness of 17 distinct zebrafish endpoints as a data-driven weighting scheme for a multi-endpoint summary measure, called weighted Aggregate Entropy (wAggE). We implement wAggE using high-throughput screening (HTS) data from zebrafish exposed to five concentrations of all 1060 ToxCast chemicals. Our results show that our empirical weighting scheme provides better performance in terms of the Receiver Operating Characteristic (ROC) curve for identifying significant morphological effects and improves robustness over traditional curve-fitting approaches. From a biological perspective, our results suggest that developmental cascade effects triggered by chemical exposure can be recapitulated by analyzing the relationships among endpoints. Thus, wAggE offers a powerful approach for analysis of multivariate phenotypes that can reveal underlying etiological processes.


Mechanism of compensation of aberrations in the human eye.
We studied the mechanism of compensation of aberrations within the young human eye by using experimental data and advanced ray-tracing modeling. Corneal and ocular aberrations along with the alignment properties (angle kappa, lens tilt, and decentration) were measured in eyes with different refractive errors. Predictions from individualized ray-tracing optical models were compared with the actual measurements. Ocular spherical aberration was, in general, smaller than corneal spherical aberration without relation to refractive error. However, horizontal coma compensation was found to be significantly larger for hyperopic eyes where angle kappa tended to also be larger. We propose a simple analytical model of the relationship between the corneal coma compensation effect with the field angle and corneal and crystalline shape factors. The actual shape factors corresponded approximately to the optimum shapes that automatically provide this coma compensation. We showed that the eye behaves as an aplanatic optical system, an optimized design solution rendering stable retinal image quality for different ocular geometries.


Fine mapping genetic determinants of the highly variably expressed MHC gene ZFP57.
ZFP57 is an important transcriptional regulator involved in DNA methylation and genomic imprinting during development. Here we demonstrate that gene expression also occurs at a low level in adult peripheral blood cells and other tissues including the kidney and thymus, but is critically dependent on underlying local genetic variation within the MHC. We resolve a highly significant expression quantitative trait locus for ZFP57 involving single-nucleotide polymorphisms (SNPs) in the first intron of the gene co-localizing with a DNase I hypersensitive site and evidence of CTCF recruitment. These data identify ZFP57 as a candidate gene underlying reported MHC disease associations, notably for putative regulatory variants associated with cancer and HIV-1. The work highlights the role that ZFP57 may play in DNA methylation and epigenetic regulation beyond early development into adult life dependent on genetic background, with important potential implications for disease.


Effect of corruption on perceived difficulties in healthcare access in sub-Saharan Africa.
Achieving Universal Health Coverage (UHC) by improving financial protection and effective service coverage is target 3.8 of the Sustainable Development Goals. Little is known, however, about the extent to which paying bribes within healthcare acts as a financial barrier to access and, thus, UHC. Using survey data in adults from 32 sub-Saharan African countries in 2014-2015, we constructed a multilevel model to evaluate the relationship between paying bribes and reported difficulties of obtaining medical care. We controlled for individual-, region-, and country-level variables. Having paid bribes for medical care significantly increased the odds of reporting difficulties in obtaining care by 4.11 (CI: 3.70-4.57) compared to those who never paid bribes, and more than doubled for those who paid bribes often (OR = 9.52; 95% CI: 7.77-11.67). Respondents with higher levels of education and more lived poverty also had increased odds. Those who lived in rural areas or within walking distance to a health clinic had reduced odds of reporting difficulties. Sex, age, living in a capital region, healthcare expenditures per capita, and country Corruption Perception Index were not significant predictors. We found that bribery in healthcare is a significant barrier to healthcare access, negatively affecting the potential of African countries to make progress toward UHC. Future increases in health expenditures-which are needed in many countries to achieve UHC-should be accompanied by greater efforts to fight corruption in order to avoid wasting money. Measuring and tracking health sector-specific corruption is critical for progress toward UHC.


Cardiac valve annulus manual segmentation using computer assisted visual feedback in three-dimensional image data.
Annulus manual segmentation is an important tool for the study of valve anatomy and physiology, for the four main valves of the heart (mitral, tricuspid, aortic and pulmonary). In this paper we review two traditional manual segmentation approaches: slice-by-slice and interpolating a sparse set of landmarks with a spline curve. We propose a new Spline Tool for the open source software platform Seg3D, that is fast and improves spatial coherence by providing visual feedback of the segmentation in real time. The Spline Tool was tested successfully on 14 rat hearts, on all four valves.


Actin nemaline myopathy mouse reproduces disease, suggests other actin disease phenotypes and provides cautionary note on muscle transgene expression.
Mutations in the skeletal muscle α-actin gene (ACTA1) cause congenital myopathies including nemaline myopathy, actin aggregate myopathy and rod-core disease. The majority of patients with ACTA1 mutations have severe hypotonia and do not survive beyond the age of one. A transgenic mouse model was generated expressing an autosomal dominant mutant (D286G) of ACTA1 (identified in a severe nemaline myopathy patient) fused with EGFP. Nemaline bodies were observed in multiple skeletal muscles, with serial sections showing these correlated to aggregates of the mutant skeletal muscle α-actin-EGFP. Isolated extensor digitorum longus and soleus muscles were significantly weaker than wild-type (WT) muscle at 4 weeks of age, coinciding with the peak in structural lesions. These 4 week-old mice were ~30% less active on voluntary running wheels than WT mice. The α-actin-EGFP protein clearly demonstrated that the transgene was expressed equally in all myosin heavy chain (MHC) fibre types during the early postnatal period, but subsequently became largely confined to MHCIIB fibres. Ringbinden fibres, internal nuclei and myofibrillar myopathy pathologies, not typical features in nemaline myopathy or patients with ACTA1 mutations, were frequently observed. Ringbinden were found in fast fibre predominant muscles of adult mice and were exclusively MHCIIB-positive fibres. Thus, this mouse model presents a reliable model for the investigation of the pathobiology of nemaline body formation and muscle weakness and for evaluation of potential therapeutic interventions. The occurrence of core-like regions, internal nuclei and ringbinden will allow analysis of the mechanisms underlying these lesions. The occurrence of ringbinden and features of myofibrillar myopathy in this mouse model of ACTA1 disease suggests that patients with these pathologies and no genetic explanation should be screened for ACTA1 mutations.


Studying survivors of near-lethal suicide attempts as a proxy for completed suicide in prisons.
Suicides in prisons are common. There is a pressing need to understand more about the causes and prevention of prisoner suicides. A particularly informative approach is through studying survivors of near-lethal suicide attempts. However, the extent to which this approach is a good proxy for completed suicide requires verification. In this article we aimed to assess (1) the extent to which male and female prisoners who made near-lethal suicide attempts in prison are similar to prisoners who die by suicide; (2) the suicidal intent of those making near-lethal suicide attempts; and (3) the applicability of the Suicide Intent Scale in prisons. Survivors of near-lethal suicide attempts and prisoners who died by suicide were compared on sociodemographic and criminological characteristics. The suicidal intent of prisoners engaging in near-lethal self-harm was assessed using Beck's Suicide Intent Scale. There were no significant differences when the sociodemographic and criminological profiles of prisoners who made near-lethal suicide attempts and those who died by suicide were compared, except that male prisoners who made near-lethal suicide attempts were somewhat younger. Most prisoners carrying out near-lethal acts had high suicidal intent. However, some questions in the Suicide Intent Scale were inappropriate for assessing intent in prisoners. Prisoners who survive near-lethal self-harm would appear to be a valid proxy for those who die by suicide in prison. The Suicide Intent Scale requires some modifications for use in prisons.


Functionally inert HIV-specific cytotoxic T lymphocytes do not play a major role in chronically infected adults and children.
The highly sensitive quantitation of virus-specific CD8(+) T cells using major histocompatibility complex-peptide tetramer assays has revealed higher levels of cytotoxic T lymphocytes (CTLs) in acute and chronic virus infections than were recognized previously. However, studies in lymphocytic choriomeningitis virus infection have shown that tetramer assays may include measurement of a substantial number of tetramer-binding cells that are functionally inert. Such phenotypically silent CTLs, which lack cytolytic function and do not produce interferon (IFN)-gamma, have been hypothesized to explain the persistence of virus in the face of a quantitatively large immune response, particularly when CD4 help is impaired. In this study, we examined the role of functionally inert CTLs in chronic HIV infection. Subjects studied included children and adults (n = 42) whose viral loads ranged from <50 to >100,000 RNA copies/ml plasma. Tetramer assays were compared with three functional assays: enzyme-linked immunospot (Elispot), intracellular cytokine staining, and precursor frequency (limiting dilution assay [LDA]) cytotoxicity assays. Strong positive associations were observed between cell numbers derived by the Elispot and the tetramer assay (r = 0.90). An even stronger association between tetramer-derived numbers and intracellular cytokine staining for IFN-gamma was present (r = 0.97). The majority (median 76%) of tetramer-binding cells were consistently detectable via intracellular IFN-gamma cytokine staining. Furthermore, modifications to the LDA, using a low input cell number into each well, enabled LDAs to reach equivalence with the other methods of CTL enumeration. These data together show that functionally inert CTLs do not play a significant role in chronic pediatric or adult HIV infection.


Acupuncture for chronic pain: individual patient data meta-analysis.
Although acupuncture is widely used for chronic pain, there remains considerable controversy as to its value. We aimed to determine the effect size of acupuncture for 4 chronic pain conditions: back and neck pain, osteoarthritis, chronic headache, and shoulder pain. We conducted a systematic review to identify randomized controlled trials (RCTs) of acupuncture for chronic pain in which allocation concealment was determined unambiguously to be adequate. Individual patient data meta-analyses were conducted using data from 29 of 31 eligible RCTs, with a total of 17 922 patients analyzed. In the primary analysis, including all eligible RCTs, acupuncture was superior to both sham and no-acupuncture control for each pain condition (P < .001 for all comparisons). After exclusion of an outlying set of RCTs that strongly favored acupuncture, the effect sizes were similar across pain conditions. Patients receiving acupuncture had less pain, with scores that were 0.23 (95% CI, 0.13-0.33), 0.16 (95% CI, 0.07-0.25), and 0.15 (95% CI, 0.07-0.24) SDs lower than sham controls for back and neck pain, osteoarthritis, and chronic headache, respectively; the effect sizes in comparison to no-acupuncture controls were 0.55 (95% CI, 0.51-0.58), 0.57 (95% CI, 0.50-0.64), and 0.42 (95% CI, 0.37-0.46) SDs. These results were robust to a variety of sensitivity analyses, including those related to publication bias. Acupuncture is effective for the treatment of chronic pain and is therefore a reasonable referral option. Significant differences between true and sham acupuncture indicate that acupuncture is more than a placebo. However, these differences are relatively modest, suggesting that factors in addition to the specific effects of needling are important contributors to the therapeutic effects of acupuncture.


A protocol for the delivery of cannabidiol (CBD) and combined CBD and ∆9-tetrahydrocannabinol (THC) by vaporisation.
Significant interest has emerged in the therapeutic and interactive effects of different cannabinoids. Cannabidiol (CBD) has been shown to have anxiolytic and antipsychotic effects with high doses administered orally. We report a series of studies conducted to determine the vaporisation efficiency of high doses of CBD, alone and in combination with ∆9-tetrahydrocannabinol (THC), to achieve faster onset effects in experimental and clinical trials and emulate smoked cannabis. Purified THC and CBD (40 mg/ml and 100 mg/ml respectively) were loaded onto a liquid absorbing pad in a Volcano vaporiser, vaporised and the vapours quantitatively analysed. Preliminary studies determined 200 mg CBD to be the highest dose effectively vaporised at 230 ° C, yielding an availability of approximately 40% in the vapour phase. Six confirmatory studies examined the quantity of each compound delivered when 200 mg or 4 mg CBD was loaded together with 8 mg of THC. THC showed 55% availability when vaporised alone or with low dose CBD, while large variation in the availability of high dose CBD impacted upon the availability of THC when co-administered, with each compound affecting the vaporisation efficiency of the other in a dynamic and dose-dependent manner. We describe optimised protocols that enable delivery of 160 mg CBD through vaporisation. While THC administration by vaporisation is increasingly adopted in experimental studies, often with oral predosing with CBD to examine interactive effects, no studies to date have reported the administration of CBD by vaporisation. We report the detailed methodology aimed at optimising the efficiency of delivery of therapeutic doses of CBD, alone and in combination with THC, by vaporisation. These protocols provide a technical advance that may inform methodology for clinical trials in humans, especially for examining interactions between THC and CBD and for therapeutic applications of CBD. Current Controlled Trials ISRCTN24109245.


Diverse microbiota identified in whole intact nest chambers of the red mason bee Osmia bicornis (Linnaeus 1758).
Microbial activity is known to have profound impact on bee ecology and physiology, both by beneficial and pathogenic effects. Most information about such associations is available for colony-building organisms, and especially the honey bee. There, active manipulations through worker bees result in a restricted diversity of microbes present within the colony environment. Microbial diversity in solitary bee nests remains unstudied, although their larvae face a very different situation compared with social bees by growing up in isolated compartments. Here, we assessed the microbiota present in nests and pre-adults of Osmia bicornis, the red mason bee, by culture-independent pyrosequencing. We found high bacterial diversity not comparable with honey bee colonies. We identified a variety of bacteria potentially with positive or negative interactions for bee larvae. However, most of the other diverse bacteria present in the nests seem to originate from environmental sources through incorporated nest building material and stored pollen. This diversity of microorganisms may cause severe larval mortality and require specific physiological or symbiotic adaptations against microbial threats. They may however also profit from such a diverse environment through gain of mutualistic partners. We conclude that further studies of microbiota interaction in solitary bees will improve the understanding of fitness components and populations dynamics.


Fatal outcome in a Hispanic woman with moyamoya syndrome and Graves' disease.
We describe the case of a young Hispanic female who presented with thyrotoxicosis with seizures and ischemic stroke. She was diagnosed with a rare vasculopathy - moyamoya syndrome. After starting antithyroid therapy, her neurologic symptoms did not improve. Acute neurosurgical intervention had relieved her symptoms in the immediate post-operative period after re-anastomosis surgery. However, 2 post-operative days later, she was found to be in status epilepticus and in hyperthyroid state. She quickly deteriorated clinically and had expired a few days afterward. This is the second case in literature of a fatality in a patient with moyamoya syndrome and Graves' disease. However, unlike the other case report, our patient had undergone successful revascularization surgery. We believe her underlying non-euthyroid state had potentiated her clinical deterioration. Case studies have shown positive correlation between uncontrolled hyperthyroidism and stroke-like symptoms in moyamoya syndrome. Mostly all patients with these two disease processes become symptomatic in marked hyperthyroid states. Thus, it may be either fluctuations in baseline thyroid function or thyrotoxicosis that potentiate otherwise asymptomatic moyamoya vasculopathy. Awareness of the association between Graves' disease and moyamoya syndrome in younger patients presenting with stroke-like symptoms.Obtaining euthyroid states before undergoing revascularization surgery may protect the patient from perioperative mortality and morbidity.Although moyamoya disease is usually thought to be genetically associated, there are reports that thyroid antibodies may play a role in its pathogenesis and have an autoimmune link.Fluctuations in baseline thyroid function for patients with known Graves' disease may be a potentiating factor in exacerbating moyamoya vasculopathy.


Empirical Studies in Information Visualization: Seven Scenarios.
We take a new, scenario-based look at evaluation in information visualization. Our seven scenarios, evaluating visual data analysis and reasoning, evaluating user performance, evaluating user experience, evaluating environments and work practices, evaluating communication through visualization, evaluating visualization algorithms, and evaluating collaborative data analysis were derived through an extensive literature review of over 800 visualization publications. These scenarios distinguish different study goals and types of research questions and are illustrated through example studies. Through this broad survey and the distillation of these scenarios, we make two contributions. One, we encapsulate the current practices in the information visualization research community and, two, we provide a different approach to reaching decisions about what might be the most effective evaluation of a given information visualization. Scenarios can be used to choose appropriate research questions and goals and the provided examples can be consulted for guidance on how to design one's own study.


Endoscopic third ventriculostomy in children: prospective, multicenter results from the Hydrocephalus Clinical Research Network.
OBJECTIVE Endoscopic third ventriculostomy (ETV) is now established as a viable treatment option for a subgroup of children with hydrocephalus. Here, the authors report prospective, multicenter results from the Hydrocephalus Clinical Research Network (HCRN) to provide the most accurate determination of morbidity, complication incidence, and efficacy of ETV in children and to determine if intraoperative predictors of ETV success add substantially to preoperative predictors. METHODS All children undergoing a first ETV (without choroid plexus cauterization) at 1 of 7 HCRN centers up to June 2013 were included in the study and followed up for a minimum of 18 months. Data, including detailed intraoperative data, were prospectively collected as part of the HCRN's Core Data Project and included details of patient characteristics, ETV failure (need for repeat hydrocephalus surgery), and, in a subset of patients, postoperative complications up to the time of discharge. RESULTS Three hundred thirty-six eligible children underwent initial ETV, 18.8% of whom had undergone shunt placement prior to the ETV. The median age at ETV was 6.9 years (IQR 1.7-12.6), with 15.2% of the study cohort younger than 12 months of age. The most common etiologies were aqueductal stenosis (24.8%) and midbrain or tectal lesions (21.2%). Visible forniceal injury (16.6%) was more common than previously reported, whereas severe bleeding (1.8%), thalamic contusion (1.8%), venous injury (1.5%), hypothalamic contusion (1.5%), and major arterial injury (0.3%) were rare. The most common postoperative complications were CSF leak (4.4%), hyponatremia (3.9%), and pseudomeningocele (3.9%). New neurological deficit occurred in 1.5% cases, with 0.5% being permanent. One hundred forty-one patients had documented failure of their ETV requiring repeat hydrocephalus surgery during follow-up, 117 of them during the first 6 months postprocedure. Kaplan-Meier rates of 30-day, 90-day, 6-month, 1-year, and 2-year failure-free survival were 73.7%, 66.7%, 64.8%, 61.7%, and 57.8%, respectively. According to multivariate modeling, the preoperative ETV Success Score (ETVSS) was associated with ETV success (p < 0.001), as was the intraoperative ability to visualize a "naked" basilar artery (p = 0.023). CONCLUSIONS The authors' documented experience represents the most detailed account of ETV results in North America and provides the most accurate picture to date of ETV success and complications, based on contemporaneously collected prospective data. Serious complications with ETV are low. In addition to the ETVSS, visualization of a naked basilar artery is predictive of ETV success.


Lipids and lipoproteins and risk of different vascular events in the MRC/BHF Heart Protection Study.
Low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol are established risk factors for vascular disease, but lipoprotein particle concentrations may be stronger determinants of risk. Associations between vascular events and baseline concentrations of cholesterol fractions, apolipoproteins B and A(1), and lipoprotein particles assessed by nuclear magnetic resonance were considered in the Heart Protection Study randomized trial of simvastatin versus placebo (>5000 vascular events during 5.3 years of follow-up among 20 000 participants). Major occlusive coronary events were equally strongly associated with the cholesterol- and particle-based total LDL measures; adjusted hazard ratios per 1-SD-higher level were 1.25 (95% confidence interval [CI], 1.16-1.34) for LDL cholesterol, 1.22 (95% CI, 1.14-1.32) for non-HDL cholesterol, 1.23 (95% CI, 1.15-1.33) for apolipoprotein B, and 1.25 (95% CI, 1.16-1.35) for LDL particle number. Given the total LDL particle number, the distribution between small and large particles did not add predictive value. Associations of these different LDL-related measures were similar with arterial revascularization procedures but much weaker or nonexistent with ischemic stroke and other cardiac events (mainly heart failure). After adjustment for LDL particle number, the hazard ratios for major occlusive coronary event per 1-SD-higher level were 0.91 (95% CI, 0.86-0.96) for HDL cholesterol and 0.89 (95% CI, 0.85-0.93) for HDL particle number. Other cardiac events were inversely associated with total (hazard ratio, 0.84; 95% CI, 0.79-0.90) and small (0.82; 95% CI, 0.76-0.89) HDL particle number but only very weakly associated with HDL cholesterol (0.94; 95% CI, 0.88-1.00). In a population at 2% average coronary event risk per year, cholesterol, apolipoprotein, and particle measures of LDL were strongly correlated and had similar predictive values for incident major occlusive vascular events. It is unclear whether the associations between HDL particle numbers and other cardiac events represent a causal or reverse-causal effect.


Using a mobile health application to support self-management in chronic obstructive pulmonary disease: a six-month cohort study.
Self-management strategies have the potential to support patients with chronic obstructive pulmonary disease (COPD). Telehealth interventions may have a role in delivering this support along with the opportunity to monitor symptoms and physiological variables. This paper reports findings from a six-month, clinical, cohort study of COPD patients' use of a mobile telehealth based (mHealth) application and how individually determined alerts in oxygen saturation levels, pulse rate and symptoms scores related to patient self-initiated treatment for exacerbations. The development of the mHealth intervention involved a patient focus group and multidisciplinary team of researchers, engineers and clinicians. Individual data thresholds to set alerts were determined, and the relationship to exacerbations, defined by the initiation of stand-by medications, was measured. The sample comprised 18 patients (age range of 50-85 years) with varied levels of computer skills. Patients identified no difficulties in using the mHealth application and used all functions available. 40% of exacerbations had an alert signal during the three days prior to a patient starting medication. Patients were able to use the mHealth application to support self- management, including monitoring of clinical data. Within three months, 95% of symptom reporting sessions were completed in less than 100 s. Home based, unassisted, daily use of the mHealth platform is feasible and acceptable to people with COPD for reporting daily symptoms and medicine use, and to measure physiological variables such as pulse rate and oxygen saturation. These findings provide evidence for integrating telehealth interventions with clinical care pathways to support self-management in COPD.


Impact of family planning health education on the knowledge and attitude among Yasoujian women.
The aim of this study was to determine the effect of health education on the knowledge and attitude regarding family planning and contraception's method among the women who obligatory attended the Premarital Counseling Center in Yasouj city, Iran. An experimental study was carried out and a total of 200 women were selected for the study using convenience sampling method among women who attended in the health centre in order to utilize the necessary premarital actions. Respondents were divided by two experimental and control groups randomly. A pre-evaluation was done on the knowledge and attitude on family planning using a structured questionnaire. After which, the health education for experimental group was done within four educational sessions during 4 consecutive weeks and control group underwent traditional education method. Post evaluation was utilized for any changes regarding their knowledge and attitude among the respondents immediately after the intervention. Independent and paired t-test was used to evaluate the mean knowledge and attitude scores differences among both groups. RESULTS showed that there was a significant improvement in respondents' knowledge and attitude after educational program in experimental group (p<0.001), while no significant difference was observed in knowledge and attitude of control group. The finding also indicated that age was significantly associated with the level of respondents' knowledge. These results deal the effectiveness of the educational method. In conclusion, the educational method is effective in increasing the knowledge and improving the attitude of women regarding family planning in Yasouj compared to current used educational method. Future educational programs need to incorporate the features that have been associated with successful interventions in the past, as well as including their own evaluation procedures.


Directed functional connectivity using dynamic graphical models.
There are a growing number of neuroimaging methods that model spatio-temporal patterns of brain activity to allow more meaningful characterizations of brain networks. This paper proposes dynamic graphical models (DGMs) for dynamic, directed functional connectivity. DGMs are a multivariate graphical model with time-varying coefficients that describe instantaneous directed relationships between nodes. A further benefit of DGMs is that networks may contain loops and that large networks can be estimated. We use network simulations and human resting-state fMRI (N = 500) to investigate the validity and reliability of the estimated networks. We simulate systematic lags of the hemodynamic response at different brain regions to investigate how these lags potentially bias directionality estimates. In the presence of such lag confounds (0.4-0.8 s offset between connected nodes), our method has a sensitivity of 72%-77% to detect the true direction. Stronger lag confounds have reduced sensitivity, but do not increase false positives (i.e., directionality estimates of the opposite direction). In human resting-state fMRI, the default mode network has consistent influence on the cerebellar, the limbic and the auditory/temporal networks. We also show a consistent reciprocal relationship between the visual medial and visual lateral network. Finally, we apply the method in a small mouse fMRI sample and discover a highly plausible relationship between areas in the hippocampus feeding into the cingulate cortex. We provide a computationally efficient implementation of DGM as a free software package for R.


SAT2 Foot-and-Mouth Disease Virus Structurally Modified for Increased Thermostability.
Foot-and-mouth disease virus (FMDV), particularly strains of the O and SAT serotypes, is notoriously unstable. Consequently, vaccines derived from heat-labile SAT viruses have been linked to the induction of immunity with a poor duration and hence require more frequent vaccinations to ensure protection. In silico calculations predicted residue substitutions that would increase interactions at the interpentamer interface, supporting increased stability. We assessed the stability of the 18 recombinant mutant viruses in regard to their growth kinetics, antigenicity, plaque morphology, genetic stability, and temperature, ionic, and pH stability by using Thermofluor and inactivation assays in order to evaluate potential SAT2 vaccine candidates with improved stability. The most stable mutant for temperature and pH stability was the S2093Y single mutant, while other promising mutants were the E3198A, L2094V, and S2093H single mutants and the F2062Y-H2087M-H3143V triple mutant. Although the S2093Y mutant had the greatest stability, it exhibited smaller plaques, a reduced growth rate, a change in monoclonal antibody footprint, and poor genetic stability properties compared to those of the wild-type virus. However, these factors affecting production can be overcome. The addition of 1 M NaCl was found to further increase the stability of the SAT2 panel of viruses. The S2093Y and S2093H mutants were selected for future use in stabilizing SAT2 vaccines.IMPORTANCE Foot-and-mouth disease virus (FMDV) causes a highly contagious acute vesicular disease in cloven-hoofed livestock and wildlife. The control of the disease by vaccination is essential, especially at livestock-wildlife interfaces. The instability of some serotypes, such as SAT2, affects the quality of vaccines and therefore the duration of immunity. We have shown that we can improve the stability of SAT2 viruses by mutating residues at the capsid interface through predictive modeling. This is an important finding for the potential use of such mutants in improving the stability of SAT2 vaccines in countries where FMD is endemic, which rely heavily on the maintenance of the cold chain, with potential improvement to the duration of immune responses.


The weirdest people in the world?
Behavioral scientists routinely publish broad claims about human psychology and behavior in the world's top journals based on samples drawn entirely from Western, Educated, Industrialized, Rich, and Democratic (WEIRD) societies. Researchers - often implicitly - assume that either there is little variation across human populations, or that these "standard subjects" are as representative of the species as any other population. Are these assumptions justified? Here, our review of the comparative database from across the behavioral sciences suggests both that there is substantial variability in experimental results across populations and that WEIRD subjects are particularly unusual compared with the rest of the species - frequent outliers. The domains reviewed include visual perception, fairness, cooperation, spatial reasoning, categorization and inferential induction, moral reasoning, reasoning styles, self-concepts and related motivations, and the heritability of IQ. The findings suggest that members of WEIRD societies, including young children, are among the least representative populations one could find for generalizing about humans. Many of these findings involve domains that are associated with fundamental aspects of psychology, motivation, and behavior - hence, there are no obvious a priori grounds for claiming that a particular behavioral phenomenon is universal based on sampling from a single subpopulation. Overall, these empirical patterns suggests that we need to be less cavalier in addressing questions of human nature on the basis of data drawn from this particularly thin, and rather unusual, slice of humanity. We close by proposing ways to structurally re-organize the behavioral sciences to best tackle these challenges.


Evaluation of Brazil's public health surveillance system within the context of the International Health Regulations (2005).
To evaluate Brazil's public health surveillance system (HSS), identifying its core capacities, shortcomings, and limitations in dealing with public health emergencies, within the context of the International Health Regulations (IHR 2005). In 2008-2009 an evaluative cross-sectional study was conducted using semistructured questionnaires administered to key informants (municipal, state, and national government officials) to assess Brazilian HSS structure (legal framework and resources) and surveillance and response procedures vis-à-vis compliance with the IHR (2005) requirements for management of public health emergencies of national and international concern. Evaluation criteria included the capacity to detect, assess, notify, investigate, intervene, and communicate. Responses were analyzed separately by level of government (municipal health departments, state health departments, and national Ministry of Health). Overall, at all three levels of government, Brazil's HSS has a well-established legal framework (including the essential technical regulations) and the infrastructure, supplies, materials, and mechanisms required for liaison and coordination. However, there are still some weaknesses at the state level, especially in land border areas and small towns. Professionals in the field need to be more familiar with the IHR 2005 Annex 2 decision tool (designed to increase sensitivity and consistency in the notification process). At the state and municipal level, the capacity to detect, assess, and notify is better than the capacity to investigate, intervene, and communicate. Surveillance activities are conducted 24 hours a day, 7 days a week in 40.7% of states and 35.5% of municipalities. There are shortcomings in organizational activities and methods, and in the process of hiring and training personnel. In general, the core capacities of Brazil's HSS are well established and fulfill most of the requisites listed in the IHR 2005 with respect to both structure and surveillance and response procedures, particularly at the national and state levels.


Advancing gender equality through the Athena SWAN Charter for Women in Science: an exploratory study of women's and men's perceptions.
While in the United Kingdom, Ireland, and Australia, higher education and research institutions are widely engaged with the Athena SWAN Charter for Women in Science to advance gender equality, empirical research on this process and its impact is rare. This study combined two data sets (free- text comments from a survey and qualitative interviews) to explore the range of experiences and perceptions of participation in Athena SWAN in medical science departments of a research-intensive university in Oxford, United Kingdom. The study is based on the secondary analysis of data from two projects: 59 respondents to an anonymous online survey (42 women, 17 men) provided relevant free-text comments and, separately, 37 women participated in face-to-face narrative interviews. Free-text survey comments and narrative interviews were analysed thematically using constant comparison. Both women and men said that participation in Athena SWAN had brought about important structural and cultural changes, including increased support for women's careers, greater appreciation of caring responsibilities, and efforts to challenge discrimination and bias. Many said that these positive changes would not have happened without linkage of Athena SWAN to government research funding, while others thought there were unintended consequences. Concerns about the programme design and implementation included a perception that Athena SWAN has limited ability to address longstanding and entrenched power and pay imbalances, persisting lack of work-life balance in academic medicine, questions about the sustainability of positive changes, belief that achieving the award could become an end in itself, resentment about perceived positive discrimination, and perceptions that further structural and cultural changes were needed in the university and wider society. The findings from this study suggest that Athena SWAN has a positive impact in advancing gender equality, but there may be limits to how much it can improve gender equality without wider institutional and societal changes. To address the fundamental causes of gender inequality would require cultural change and welfare state policies incentivising men to increase their participation in unpaid work in the family, which is beyond the scope of higher education and research policy.


Prevention and Reversion of Pancreatic Tumorigenesis through a Differentiation-Based Mechanism.
Activating mutations in Kras are nearly ubiquitous in human pancreatic cancer and initiate precancerous pancreatic intraepithelial neoplasia (PanINs) when induced in mouse acinar cells. PanINs normally take months to form but are accelerated by deletion of acinar cell differentiation factors such as Ptf1a, suggesting that loss of cell identity is rate limiting for pancreatic tumor initiation. Using a genetic mouse model that allows for independent control of oncogenic Kras and Ptf1a expression, we demonstrate that sustained Ptf1a is sufficient to prevent Kras-driven tumorigenesis, even in the presence of tumor-promoting inflammation. Furthermore, reintroducing Ptf1a into established PanINs reverts them to quiescent acinar cells in vivo. Similarly, Ptf1a re-expression in human pancreatic cancer cells inhibits their growth and colony-forming ability. Our results suggest that reactivation of an endogenous differentiation program can prevent and reverse oncogene-driven transformation in cells harboring tumor-driving mutations, introducing a potential paradigm for solid tumor prevention and treatment.


Applying an attentional set to perceived and remembered features.
Previous research has examined our ability to attend selectively to particular features of perceptual objects, as well as our ability to switch from attending to one type of feature to another. This is usually done in the context of anticipatory attentional-set control, comparing the neural mechanisms involved as participants prepare to attend to the same stimulus feature as on the previous trial ("task-stay" trials) with those required as participants prepare to attend to a different stimulus feature to that previously attended ("task-switch" trials). We wanted to establish how participants maintain or switch attentional set retrospectively, as they attend to features of objects held in visual short-term memory (VSTM). We found that switching, relative to maintaining attentional set retrospectively, was associated with a performance cost, which can be reduced over time. This control process was mirrored by a large parietal and frontal amplitude difference in the event-related brain potentials (ERPs) and significant differences in global field power (GFP) between switch and stay trials. However, when taking into account the switch/stay GFP differences, thereby controlling for this difference in amplitude, we could not distinguish these trial types topographically. By contrast, we found clear topographic differences between preparing an anticipatory feature-based attentional set versus applying it retrospectively within VSTM. These complementary topographical and amplitude analyses suggested that anticipatory and retrospective set control recruited a qualitatively different configuration of underlying neural generators. In contrast, switch/stay differences were largely quantitative, with them differing primarily in terms of amplitude rather than topography.


Expanding the Nomological Net of the Pathological Narcissism Inventory: German Validation and Extension in a Clinical Inpatient Sample.
The Pathological Narcissism Inventory (PNI) is a multidimensional measure for assessing grandiose and vulnerable features in narcissistic pathology. The aim of the present research was to construct and validate a German translation of the PNI and to provide further information on the PNI's nomological net. Findings from a first study confirm the psychometric soundness of the PNI and replicate its seven-factor first-order structure. A second-order structure was also supported but with several equivalent models. A second study investigating associations with a broad range of measures ( DSM Axis I and II constructs, emotions, personality traits, interpersonal and dysfunctional behaviors, and well-being) supported the concurrent validity of the PNI. Discriminant validity with the Narcissistic Personality Inventory was also shown. Finally, in a third study an extension in a clinical inpatient sample provided further evidence that the PNI is a useful tool to assess the more pathological end of narcissism.


A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo.
Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for ligating amino acids to cognate tRNA molecules. Mutations in four genes encoding an ARS have been implicated in inherited peripheral neuropathy with an axonal pathology, suggesting that all ARS genes are relevant candidates for disease in patients with related phenotypes. Here, we present results from a mutation screen of the histidyl-tRNA synthetase (HARS) gene in a large cohort of patients with peripheral neuropathy. These efforts revealed a rare missense variant (c.410G>A/p.Arg137Gln) that resides at a highly conserved amino acid, represents a loss-of-function allele when evaluated in yeast complementation assays, and is toxic to neurons when expressed in a worm model. In addition to the patient with peripheral neuropathy, p.Arg137Gln HARS was detected in three individuals by genome-wide exome sequencing. These findings suggest that HARS is the fifth ARS locus associated with axonal peripheral neuropathy. Implications for identifying ARS alleles in human populations and assessing them for a role in neurodegenerative phenotypes are discussed.


Polysomnographic and subjective profiles of sleep continuity before and after mindfulness-based cognitive therapy in partially remitted depression.
To examine whether mindfulness meditation (MM) was associated with changes in objectively measured polysomnographic (PSG) sleep profiles and to relate changes in PSG sleep to subjectively reported changes in sleep and depression within the context of a randomized controlled trial. Previous studies have indicated that mindfulness and other forms of meditation training are associated with improvements in sleep quality. However, none of these studies used objective PSG sleep recordings within longitudinal randomized controlled trials of naïve subjects. Twenty-six individuals with partially remitted depression were randomized into an 8-week Mindfulness-Based Cognitive Therapy (MBCT) course or a waitlist control condition. Pre-post measurements included PSG sleep studies and subjectively reported sleep and depression symptoms. According to PSG sleep, MM practice was associated with several indices of increased cortical arousal, including more awakenings and stage 1 sleep and less slow-wave sleep relative to controls, in proportion to amount of MM practice. According to sleep diaries, subjectively reported sleep improved post MBCT but not above and beyond controls. Beck Depression Inventory scores decreased more in the MBCT group than controls. Improvements in depression were associated with increased subjective sleep continuity and increased PSG arousal. MM is associated with increases in objectively measured arousal during sleep with simultaneous improvements in subjectively reported sleep quality and mood disturbance. This pattern is similar to the profiles of positive responders to common antidepressant medications.